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1
Hasan, S. M. Raquibul. "Modulation of the TRPA1 and TRPV1 ion channels." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708079.
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Sinha, Sayantani. "Role of TRPA1 and TRPV1 in Propofol Induced Vasodilation." Thesis, Kent State University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3618926.
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Aims: Propofol, clinically named as Diprivan is an intravenous anesthetic known to cause hypotension in patients presenting for surgery. We have investigated the vasodilatory signaling cascade by which propofol causes hypotension using both in vivo and in vitro experimental approaches.
Methods and Results: Using high-fidelity microtip transducer catheter, mean arterial blood pressure (MAP) was measured in control, transient receptor potential ankyrin subtype 1 knock-out (TRPA1-/-), transient receptor potential vanilloid 1 knock-out (TRPV1-/-) and TRPA1-TRPV1 double-knockout mice (TRPAV-/-) in the presence and absence of L-NAME (an endothelial nitric oxide synthase inhibitor) and penitrem A [a big-conductance calcium gated (BKCa) channel inhibitor]. To further support our in-vivo data, murine coronary microvessels were isolated and cannulated for vasoreactivity studies. Furthermore, NO production from endothelial cells isolated from mouse aorta was also measured and immunocytochemical (ICC) studies were performed to show the intracellular localization of TRPA1 and TRPV1. Our in-vivo data shows that the characteristic propofol-induced depressor response is dependent on TRPA1-NO-BKCa pathway. Interestingly, vasoreactivity studies in isolated murine left anterior ascending (LAD) arteries demonstrate that TRPA1 and TRPV1 communicate with each other and propofol-induced vasodilation is dependent on both TRPA1 and TRPV1. Moreover our data also suggest that NO production and BK channel activation are the downstream mediators in this pathway. Finally, we demonstrate that NO production is attenuated in primary endothelial cells isolated from TRPAV-/- mice. ICC data also shows the co-localization of these channels in mouse aortic endothelial cells.
Conclusions: This is the first study which has shown that propofol-induced vasodilation involves TRPA1 in-vivo and also there is an implication of cross-talk between TRPA1 and TRPV1 in the coronary bed. Furthermore by understanding the mechanisms by which this anesthetic causes hypotension and coronary dilation will help to mitigate the potential harmful side-effects of anesthesia in patients with little cardiovascular reserve. This will in turn ensure a better and faster post-operative recovery in patients, especially benefiting those suffering from diabetes and other cardiovascular disorders.
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SINHA, SAYANTANI. "Role of TRPA1 and TRPV1 in Propofol Induced Vasodilation." Kent State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=kent1384901930.
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Sinharoy, Pritam. "Cross Talk Between TRPA1 and TRPV1 Ion-Channels: Role of Nitric Oxide." Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1467381679.
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Sprague, Jared Michael. "TRPV1 Sensitization in Primary Sensory Neurons." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11441.
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Pain is a major personal and community burden throughout the world with currently limited treatment options for persistent pain due to unacceptable side effects, dependence or frank inefficacy. It is necessary to understand the anatomical and molecular pathways leading to pain to better cope with the current challenge of treating it.
6
Fernandes, Maria Antionetta. "An investigation of the roles of TRPV1, TRPA1 and hydrogen sulfide in thermoregulation." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/an-investigation-of-the-roles-of-trpv1-trpa1-and-hydrogen-sulfide-in-thermoregulation(811086d3-46c1-4f3f-9288-131bebf36431).html.
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The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is an integrator of noxious stimuli, including noxious heat ( > 43°C), low pH ( < 6) and capsaicin (the pungent component of chilli peppers). Transient Receptor Potential Ankyrin 1 (TRPA1) is a closely related channel, activated by reactive oxygen species, hydrogen sulfide (H2S) and mustard oil. Their expression on primary sensory neurons is well characterised. Recent studies show that they are also expressed in non‐neuronal tissue. Whilst TRPV1 and TRPA1 antagonism is a promising analgesic and anti‐inflammatory strategy, early generation TRPV1 antagonists produced a poorly understood cross‐species side effect of hyperthermia. H2S is a vasodilator and TRPA1 activator. Inhalation of H2S can suspend animation, a state that includes a decreased body temperature. The role of TRPA1 and H2S in TRPV1‐mediated hyperthermia was investigated using TRPV1 and TRPA1 antagonists, knockout mice, H2S donors and modulators of endogenous H2S producing enzymes. The effects of TRPV1 antagonists SB366791 and JNJ17203212 and TRPA1 antagonists HC030031 and TCS5861528 on thermal and mechanical nociceptive thresholds of naïve mice were determined using the Hargreaves and automated Von Frey techniques, respectively. Antagonist‐induced changes in core body temperature of conscious, ambulatory mice were determined using radiotelemetry. Only JNJ17203212 produced a significant increase in core body temperature. The effects of the same antagonists on capsaicin‐ and mustard oil‐ induced blood flow changes in the pinna and knee were investigated, using full‐field laser Doppler perfusion. The capsaicin‐induced increase in pinna blood flow demonstrated a neuronal response; in the knee decreased flux demonstrated nonneuronal TRPV1 activation. Mustard oil similarly increased flux in the pinna and knee: TRPA1 does not exhibit any vasoconstrictor activity in this model. JNJ17203212 significantly attenuated capsaicin‐induced blood flow changes in the pinna and knee. No inhibition was observed with SB366791. HC030031 significantly reduced mustard oil‐induced blood flow increases in the pinna and knee whilst TCS5861528 had no effect. Finally, the involvement of TRPA1 blockade and H2S in JNJ17203212‐mediated hyperthermia was determined, using HC030031 and GYY4137, respectively. Whilst TRPA1 was not directly involved in our model, GYY4137 attenuated the hyperthermia elicited by JNJ17203212, suggesting H2S may have a role in TRPV1 antagonist‐mediated hyperthermia.
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Grace, Megan Stacey. "Investigating the role of TRPA1 and TRPV1 ion channels in the cough reflex." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/14571.
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Cough is under the control of sensory afferents which innervate the airways via the vagus nerve. Cough is an important protective reflex that clears the airway, but can become exacerbated and deleterious when associated with airways diseases, in which there is enhanced release of inflammatory mediators and a decrease in lung pH. These mediators sensitise airway afferents and could be driving enhanced cough associated with inflammation. Transient Receptor Potential (TRP) ion channels are associated with several disease pathologies. TRPV1 has an established role in cough, and is implicated in the aetiology of chronic cough; and TRPA1 is a promising new target. Involvement of these ion channels in the tussive reflex is awaiting comprehensive investigation. I have therefore explored the role of TRPA1 and TRPV1 in tussive responses to the endogenous irritants prostaglandin E2 (PGE2), bradykinin (BK) and low pH. To do this I have used selective antagonists and genetically modified mice in models of human, guinea pig and mouse vagal sensory nerve depolarisation; conscious guinea pig cough; and guinea pig primary ganglia cell imaging. TRPA1 and TRPV1 were shown to mediate PGE2 and BK-induced nerve depolarisation, cough, and activation of ganglia cells. In contrast, low pH-induced nerve depolarisation and ganglia cell activation was mediated via TRPV1 or Acid Sensing Ion Channels (ASICs); whereas, cough was partially attenuated with TRPA1 or TRPV1 antagonists. In summary, I have identified that TRPA1 and TRPV1 mediate PGE2 and BK-induced cough; and provided evidence that low pH-induced sensory nerve activation is mediated via TRPV1 and ASICs, but a role for TRPA1 is still unclear. These are exciting findings which add to our understanding of the mechanisms that drive the cough reflex in the healthy state; builds a base for investigating cough hypersensitivity in disease; and could help to guide the development of novel efficacious anti-tussive therapies.
8
Ibarra, Yessenia Michelle. "Characterization of human TRPA1 and TRPV1 channels in response to naturally occurring defensive compounds." Thesis, Harvard University, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3566933.
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The transient receptor potential channels, ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), are non-selective cation-permeable channels that have retained their function as chemical sensors since their first appearance in metazoan species several hundred million years ago. In vertebrates, TRP channels have evolved multiple functions which make it difficult to understand exactly how they transmit signals to the brain that are interpreted very differently. For example, TRPA1 and TRPV1 are sensitive to various chemicals and activation of these channels produce sensations with opposing effects. Pain is felt when TRPV1 is activated by spider toxins, but activation by plant cannabidiol results in a pain-relieving sensation. Similarly, TRPA1 activation by delta-tetrahydrocannabinol is reported to relieve symptoms of pain, but TRPA1 activation by the active ingredient in wasabi results in a repulsive or noxious sensation. Much of what we know about TRPA1 and TRPV1 comes from the use of plant products or exposure to substances that cause or alleviate pain and inflammation. In this study, whole-cell voltage clamp recordings of heterologously expressed human TRPA1 and human TRPV1 were tested for sensitivity to a hallucinogenic plant compound, salvinorin A and an arthropod-defensive compound, para-benzoquinone. Neither compound has yet been reported to activate TRP channels but both are known to be involved in pain and inflammation signaling in humans. I show that the arthropod compound, para-benzoquinone, activates and desensitizes TRPA1 in a cysteine-dependent manner, but activation of TRPV1 is not dependent on cysteine reactivity. Although salvinorin A is known to be a potent agonist of the kappa-opioid and cannabinoid receptors, here I show that it also acts as a highly potent agonist of both TRPA1 and TRPV1. Its interaction with TRP channels may contribute to its antinociceptive effects in behavioral studies with animals that are reported to be independent of opioid signaling.
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DEMARTINI, CHIARA. "The role of TRPA1 and TRPV1 channels in trigeminal pain: data from animal models." Doctoral thesis, Università degli studi di Pavia, 2018. http://hdl.handle.net/11571/1214824.
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Experimental and clinical observations pointed out a critical involvement of transient receptor potential (TRP) channels, particularly TRPA1 and TRPV1, in trigeminal pain and associated symptoms, including hyperalgesia and allodynia. In this study the role of TRP channels was investigate in two animal models of diseases related to the trigeminal system: migraine and trigeminal neuropathic pain (TNP).
TRPA1 and TRPV1 antagonists (ADM_12 and AMG9810 respectively) were used in the nitroglycerin (NTG)-induced hyperalgesia at the trigeminal level induced by means of the orofacial formalin test, a well validated animal model of migraine. The behavioral effects of AMG9810 gave inconclusive results, probably because its effect was confounded by the vehicle used. Nonetheless, it appears that TRPV1 channels are somehow involved in NTG-induced trigeminal hyperalgesia, since the TRPV1 mRNA levels were found to be strongly increased after NTG injection in medulla, cervical spinal cord and trigeminal ganglia (TG). NTG also up-regulated the mRNA levels of TRPA1, c-fos, calcitonin gene-related peptide (CGRP) and Substance P (SP) in the same areas. Those transcripts, but TRPV1, were reduced after ADM_12 treatment, which abolished the NTG-induced trigeminal hyperalgesia. The increased availability of nitric oxide after NTG promotes the formation of pro-inflammatory agents which can activate and/or sensitize nociceptors by means of TRPA1 and TRPV1 channels, causing the release of CGRP and SP. Although no differences in CGRP and SP protein expression were found at nucleus trigeminalis caudalis (NTC) level, the increased transcripts may reflect compensatory mechanisms aimed at reintegrating CGRP and SP stores depleted after NTG administration. It is possible that ADM_12 caused a reduction of Ca2+ influx through TRPA1 channels, which in turn interfered with the cascade of second-messenger molecules and with the Ca2+-interacting proteins, ultimately preventing NTG-induced inflammatory pathways.
For TNP, the role of TRPA1 channels (by means of ADM_12) was investigated by evaluating mechanical allodynia in a model of chronic constriction injury of the infraorbital nerve (IoN-CCI). The IoN-CCI rats showed a hyperresponsiveness (4 weeks after surgery) at the ipsilateral side that reflects a condition of mechanical allodynia, and a significant increase in TRPA1, TRPV1, CGRP and SP mRNA expression levels. Although a tendency towards a decrease was seen in the ipsilateral compared to the contralateral side in the IoN-CCI rats, no significant differences in CGRP and SP protein expression at the NTC level were seen. However, their transcripts were highly increased in the central areas containing the NTC, as well as the TG ipsilateral to the IoN ligation. Both the allodynic response and the increased mRNA levels of operated rats were abolished after ADM_12 treatment. Probably, the blockade of TRPA1 channels located on the trigeminal afferents prevented neuropeptides release thus resulting in a reduced neurogenic inflammation and the nociceptors sensitization. Contrary to the migraine model, ADM_12 reduced transcript levels of both TRPs in IoN-CCI rats. Thus, ADM_12 appears to be a specific antagonist for TRPA1 in migraine pain, but in TNP it seems to act also on TRPV1. Probably, the damage induced by the nerve injury lead to a re-organization in expression and nature of the channels that made ADM_12 able to block TRPV1 channels. Since TRPA1 and TRPV1 are functionally linked, ADM_12 could have a direct effect on TRPA1 and an indirect effect on TRPV1 channels.
In conclusion, TRPA1 blockade might be useful in the treatment of these trigeminal pain disorders. Moreover, our data suggest an important role also for TRPV1 channels, which could be differently involved depending on the type of pain. Further exploration on the mechanisms underlying the antinociceptive effects of these TRPs should improve our understanding of trigeminal pain processing.Experimental and clinical observations pointed out a critical involvement of transient receptor potential (TRP) channels, particularly TRPA1 and TRPV1, in trigeminal pain and associated symptoms, including hyperalgesia and allodynia. In this study the role of TRP channels was investigate in two animal models of diseases related to the trigeminal system: migraine and trigeminal neuropathic pain (TNP). TRPA1 and TRPV1 antagonists (ADM_12 and AMG9810 respectively) were used in the nitroglycerin (NTG)-induced hyperalgesia at the trigeminal level induced by means of the orofacial formalin test, a well validated animal model of migraine. The behavioral effects of AMG9810 gave inconclusive results, probably because its effect was confounded by the vehicle used. Nonetheless, it appears that TRPV1 channels are somehow involved in NTG-induced trigeminal hyperalgesia, since the TRPV1 mRNA levels were found to be strongly increased after NTG injection in medulla, cervical spinal cord and trigeminal ganglia (TG). NTG also up-regulated the mRNA levels of TRPA1, c-fos, calcitonin gene-related peptide (CGRP) and Substance P (SP) in the same areas. Those transcripts, but TRPV1, were reduced after ADM_12 treatment, which abolished the NTG-induced trigeminal hyperalgesia. The increased availability of nitric oxide after NTG promotes the formation of pro-inflammatory agents which can activate and/or sensitize nociceptors by means of TRPA1 and TRPV1 channels, causing the release of CGRP and SP. Although no differences in CGRP and SP protein expression were found at nucleus trigeminalis caudalis (NTC) level, the increased transcripts may reflect compensatory mechanisms aimed at reintegrating CGRP and SP stores depleted after NTG administration. It is possible that ADM_12 caused a reduction of Ca2+ influx through TRPA1 channels, which in turn interfered with the cascade of second-messenger molecules and with the Ca2+-interacting proteins, ultimately preventing NTG-induced inflammatory pathways. For TNP, the role of TRPA1 channels (by means of ADM_12) was investigated by evaluating mechanical allodynia in a model of chronic constriction injury of the infraorbital nerve (IoN-CCI). The IoN-CCI rats showed a hyperresponsiveness (4 weeks after surgery) at the ipsilateral side that reflects a condition of mechanical allodynia, and a significant increase in TRPA1, TRPV1, CGRP and SP mRNA expression levels. Although a tendency towards a decrease was seen in the ipsilateral compared to the contralateral side in the IoN-CCI rats, no significant differences in CGRP and SP protein expression at the NTC level were seen. However, their transcripts were highly increased in the central areas containing the NTC, as well as the TG ipsilateral to the IoN ligation. Both the allodynic response and the increased mRNA levels of operated rats were abolished after ADM_12 treatment. Probably, the blockade of TRPA1 channels located on the trigeminal afferents prevented neuropeptides release thus resulting in a reduced neurogenic inflammation and the nociceptors sensitization. Contrary to the migraine model, ADM_12 reduced transcript levels of both TRPs in IoN-CCI rats. Thus, ADM_12 appears to be a specific antagonist for TRPA1 in migraine pain, but in TNP it seems to act also on TRPV1. Probably, the damage induced by the nerve injury lead to a re-organization in expression and nature of the channels that made ADM_12 able to block TRPV1 channels. Since TRPA1 and TRPV1 are functionally linked, ADM_12 could have a direct effect on TRPA1 and an indirect effect on TRPV1 channels. In conclusion, TRPA1 blockade might be useful in the treatment of these trigeminal pain disorders. Moreover, our data suggest an important role also for TRPV1 channels, which could be differently involved depending on the type of pain. Further exploration on the mechanisms underlying the antinociceptive effects of these TRPs should improve our understanding of trigeminal pain processing.
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Rosenzweig, Mark Ph D. Massachusetts Institute of Technology. "Drosophila TRPA1 controls thermotactic behavior." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/34581.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Includes bibliographical references.
Temperature perception is an intricate process, essential for survival of many organisms. Temperatures far outside of the preferred range are usually harmful and are perceived as noxious (or painful), thus encouraging the animal to change its location or behavior. However, animals also have mechanisms to perceive more moderate, innocuous temperatures. Some animals exhibit clear directed movements in response to changes in temperature, a behavior known as thermotaxis. Thermotactic behavior has been most intensely studied in the nematode C. elegans, and a number of neurons and molecules that mediate thermotaxis in C. elegans have been identified. However, molecular mechanisms of temperature perception in general, and thermotaxis in particular, are still poorly understood. Drosophila melanogaster also exhibits strong temperature preferences and robust thermotactic behaviors, although the molecular mechanisms that mediate thermotaxis in Drosophila were unknown. We used a reverse genetic RNA interference (RNAi)-based strategy to identify Drosophila TRPA1 as a key regulator of thermotaxis. Larvae in which dTRPA1 expression has been knocked down with RNAi fail to avoid regions of moderately elevated temperature (~310C--350C).
(cont.) In heterologous cells, dTRPA1 protein is activated by warming (Viswanath, et al., 2003, Nature, 423:6942), suggesting that the role dTRPA1 plays in thermotaxis might be to sense the environmental temperature. We generated mutants in dTRPA1 using homologous recombination-mediated insertional mutagenesis. As expected, dtrpAl mutants were defective for thermotaxis at elevated temperatures, and surprisingly were also defective for thermotaxis at cold temperatures. Interestingly, dtrpAl mutants were not defective for avoidance of all cold temperatures, but the thermotactic defects of dtrpAl mutants were more pronounced at colder temperatures than at more moderate temperatures, suggesting that other mechanisms might compensate for the loss of dTRPA1 at more moderate temperatures. Temperature sensors were traditionally thought to be activated by and to mediate behavioral responses to restricted ranges of temperatures, either hot or cold temperatures, but not both. However, dTRPA1 appears to be required for thermotaxis behavior at both elevated and cold temperatures, raising an exciting possibility that dTRPA1 protein might mediate thermotaxis by serving as a sensor of both hot and cold temperatures.
(cont.) We also identified dTRPAl-expressing cells and implicated a subset of these cells in mediating thermotactic response to elevated temperatures. Surprisingly, our results suggest that the cells required for thermotaxis at elevated temperatures (dtrpAl-promoter-Gal4-expressing cells) are located in the larval central brain and not in the peripheral nervous system (PNS) where most thermal sensors are thought to function for mediating thermosensory behaviors. We further demonstrated that neither PAINLESS, a TRP channel required for proper larval responses to a high-temperature (38C--52C) nociceptive stimulus, nor the peripherally located neurons that mediatepainless behavior, were required for thermotaxis at elevated temperatures. On the other hand, dTRPA1 and the dtrpAl-promoter-Gal4-expressing central brain neurons that mediate thermotactic response to elevated temperatures appeared dispensable for larval responses to a high-temperature nociceptive stimulus. These findings suggest that different TRP channels and different neurons are used to mediate different thermosensory behaviors in Drosophila.
by Mark Rosenzweig.
Ph.D.
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Niedermirtl, Florian [Verfasser], and Carla [Akademischer Betreuer] Nau. "Das intravenöse Anästhetikum Propofol aktiviert nozizeptive Neurone über TRPA1-, TRPV1- und GABAA-Rezeptoren / Florian Niedermirtl. Betreuer: Carla Nau." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2011. http://d-nb.info/1018309101/34.
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Meents, Jannis Enno. "Modulation of the irritant-sensing ion channel TRPA1." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708226.
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Takaya, Junichiro. "A Potent and Site-Selective Agonist of TRPA1." Kyoto University, 2016. http://hdl.handle.net/2433/215437.
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This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright ©American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jacs.5b10162.Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19611号
医博第4118号
新制||医||1015(附属図書館)
32647
京都大学大学院医学研究科医学専攻
(主査)教授 齊藤 博英, 教授 渡邊 直樹, 教授 松原 和夫
学位規則第4条第1項該当
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Jorge, Carolina Ocanha 1990. "Envolvimento dos receptores TRPV1 e TRPA1 na hiperalgesia muscular induzida pela contração isométrica sustentada no músculo gastrocnêmio de ratos." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/244490.
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Orientadores: Maria Cláudia Gonçalves de Oliveira Fusaro, Andrea Maculano EstevesDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas
Made available in DSpace on 2018-08-27T04:11:06Z (GMT). No. of bitstreams: 1 Jorge_CarolinaOcanha_M.pdf: 1325403 bytes, checksum: 6635807ae28ce8dbb49ec5d1bcc74a75 (MD5) Previous issue date: 2015
Resumo: A dor musculoesquelética é um importante problema de saúde mundial. Dentre todos os tipos de dor, àquela induzida pela contração isométrica sustentada está relacionada com os movimentos corporais nas atividades da vida diárias e apresenta um alto impacto socioeconômico. Apesar da sua relevância clínica, os mecanismos moleculares envolvidos no desenvolvimento da dor muscular induzida pela contração isométrica sustentada são pouco conhecidos. Portanto, o objetivo deste estudo foi avaliar o envolvimento dos receptores TRPV1 e TRPA1 na hiperalgesia muscular mecânica induzida pela contração isométrica sustentada no músculo gastrocnêmio de ratos machos, da linhagem wistar. O antagonista seletivo do receptor TRPV1, AMG9810, reduziu significativamente a hiperalgesia muscular mecânica induzida pela contração isométrica sustentada quando administrado no músculo gastrocnêmio ipsilateral, mas não no contralateral. A administração intratecal de AMG9810 apresentou a mesma resposta. Similar ao TRPV1, a administração intramuscular e intratecal do antagonista seletivo do receptor TRPA1, HC030031, reduziu significativamente a hiperalgesia muscular induzida pela contração isométrica sustentada. No entanto, não foi observado modificação da expressão proteica dos receptores TRPV1 e TRPA1 no tecido muscular após a contração isométrica sustentada. Os dados sugerem que os receptores TRPV1 e TRPA1 expressos no músculo gastrocnêmio e corno dorsal da medula espinhal estão envolvidos na hiperalgesia muscular mecânica induzida pela contração isométrica sustentada em ratos. Sugerimos, portanto, que os receptores TRPV1 e TRPA1 co-expressos nas fibras aferentes primárias trabalhem juntos para ativar os nociceptores das fibras aferentes durante a contração isométrica sustentada. Além disso, nós sugerimos que os receptores TRPV1 e TRPA1 sejam potenciais alvos para o controle da dor muscular inflamatória
Abstract: Musculoskeletal pain is an important health issue in the world. Among the kinds of muscle pain, the one induced by sustained isometric contraction is associated with body movements of the daily life and has a high socio-economic impact. Despite its clinical relevance, the molecular mechanisms involved in the development of muscle pain induced by sustained isometric contraction are poorly understood. Therefore, the aim of this study was to evaluate the involvement of TRPV1 and TRPA1 receptors in the mechanical muscle hyperalgesia induced by sustained isometric contraction of the gastrocnemius muscle of rats. The selective TRPV1 receptor antagonist AMG 9810 reduced the mechanical muscle hyperalgesia induced by sustained isometric contraction when administered in the ipsilateral but not in the contralateral gastrocnemius muscle. Also, the intratecal administration of AMG9810 reduced the same response. Similar to TRPV1, intramuscular and intrathecal administration of selective TRPA1 receptor antagonist HC030031 reduced the mechanical muscle hyperalgesia induced by sustained isometric contraction. Finally, the sustained isometric contraction did not modify the protein expression of TRPV1 and TRPA1 receptors in muscle tissue. We concluded that TRPV1 and TRPA1 receptors expressed in gastrocnemius muscle and spinal cord dorsal horn are involved with the mechanical muscle hyperalgesia induced by sustained isometric contraction in rats. We suggest that TRPV1 and TRPA1 receptors co-expressed in primary afferent fibers work together to activate nociceptive afferent fibers during sustained isometric contraction. Also, we suggest that TRPV1 and TRPA1 receptors are potential target to control inflammatory muscle pain
Mestrado
Biodinâmica do Movimento Humano e Esporte
Mestra em Ciências da Nutrição e do Esporte e Metabolismo
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Sawada, Yosuke. "Ionotropic receptor (TRPA1) which mediates cooling-and H2O2-induceｄ pain." 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/123836.
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Dunham, James Philip. "On the role of TRPA1 in acute and inflammatory nociception." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492637.
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Injury is detected by a population of sensory nerves called nociceptors. Nociceptor sensitisation enhances pain and serves as a protective mechanism which promotes recovery. However, pain can become chronic. When this occurs pain becomes pathological in its own right and has extremely deleterious effects on the patient. A fuller understanding of the mechanisms by which nociceptors become sensitised and detect physiological stimuli is required to better treat chronic pain.
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Zurborg, Sandra [Verfasser]. "Defining a function for the ion channel TRPA1 / Sandra Zurborg." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023498405/34.
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Schäfer, Eva. "Non-neuronale Expression und Funktion des sensorischen Kationenkanals TRPA1 in Tumorzellen." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-169057.
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TRPA1 ist ein Kationenkanal aus der Familie der "transient receptor potential" (TRP)-Kanäle. Die Expression und Funktion dieses Ionenkanals wurde bisher hauptsächlich in neuronalen Zellen, insbesondere in Schmerzneuronen, untersucht. Dort übt TRPA1 eine Warnfunktion aus und fungiert als Sensormolekül für Reizstoffe. Dementsprechend wird TRPA1 durch eine Reihe von irritativen oder toxischen Substanzen direkt aktiviert, z. B. durch Allylisothiocyanat (AITC), Formalin, Zigarettenrauch, Tränengas oder Ozon. Im Einklang mit dieser Funktion wurde eine neuronale Expression von TRPA1 in vielen Grenzflächen des Körpers, z. B. in der Haut, im Gastrointestinaltrakt oder in der Lunge gefunden. Im Respirationstrakt konnte TRPA1 in sensorischen Nervenendigungen in den luftleitenden Atemwegen nachgewiesen werden, wo seine Aktivierung durch inhalative Schadstoffe mit entzündlichen und asthmatoiden Reaktionen in Verbindung gebracht wird. Im Gegensatz zur gut charakterisierten Rolle von TRPA1 in Neuronen ist bisher noch relativ wenig über die Expression von TRPA1 in non-neuronalen Zellen bekannt. Auch eine Funktion von TRPA1 in Tumoren ist bisher weitgehend unerforscht. In dieser Arbeit wurde eine Reihe von Zelllinien des Kleinzelligen Bronchialkarzinoms (engl.: "small cell lung cancer", SCLC) im Hinblick auf die Expression von TRP-Kanälen und im Speziellen von TRPA1 untersucht. Dabei zeigte sich, dass TRPA1 in SCLC-Zelllinien exprimiert wird und seine Aktivierung zur Stimulierung von Tumor-relevanten Signalkaskaden führt. Die Aktivierung von TRPA1 durch AITC oder durch ein wässriges Extrakt aus Zigarettenrauch führte in diesen Zellen zu einer Erhöhung der intrazellulären Calciumionenkonzentration ([Ca2+]i). Diese Ca2+-Erhöhung erwies sich als transmembranärer Ca2+-Einstrom und konnte von TRPA1-Inhibitoren blockiert werden. Darüber hinaus führte die TRPA1-abhängige Erhöhung der [Ca2+]i zu einer Aktivierung der extrazellulär signalregulierten Kinase ERK1/2 über einen Src-abhängigen Mechanismus. Des Weiteren wirkte eine TRPA1-Aktivierung in SCLC-Zellen anti-apoptotisch und förderte das Überleben der Zellen in serumfreiem Medium. Umgekehrt hatte die siRNA-vermittelte Herunterregulierung von TRPA1 eine schwere Wachstumsreduzierung von SCLC-Zellen in semisolidem Medium zur Folge. Die potentielle tumorbiologische Relevanz dieser Befunde wird durch die Tatsache unterstrichen, dass in humanen Tumorproben von Patienten mit SCLC eine gegenüber non-SCLC-Proben und normalem Lungengewebe deutlich erhöhte TRPA1-Expression zu verzeichnen war. Interessanterweise fand sich eine funktionelle Expression von TRPA1 außerdem auch in zwei Pankreaskarzinom-Zelllinien sowie einer Lungenzelllinie mit Alveolarzell-Typ-II-Charakteristika. Die Tatsache, dass eine Aktivierung von TRPA1 das Überleben von SCLC-Zellen förderte, weist auf potentielle Tumor-promovierende Wirkungen von TRPA1-Aktivatoren hin. Bekanntermaßen stimulieren zahlreiche Inhaltsstoffe des Tabakrauchs den TRPA1-Kanal und Nikotinabusus ist einer der Hauptfaktoren bei der Entstehung des SCLC. Insofern weist die vorliegende Untersuchung auf einen möglichen neuen Signalweg hin, der neben den etablierten genotoxischen Effekten von Tabakrauch für die Entstehung von Lungentumoren wichtig ist. Weiterhin sind die hier vorgestellten Befunde ein Anknüpfungspunkt für weitere Studien zur Rolle von TRPA1 im Pankreaskarzinom und in epithelialen Zellen in der Lunge.
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PEREIRA, Ione Cristna de Paiva. "Participação do receptor TRPA1 como um componente imunomodulador na artrite reumatóide." Universidade Federal do Maranhão, 2017. https://tedebc.ufma.br/jspui/handle/tede/tede/2044.
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INCT
The transient receptor potential ankyrin 1 (TRPA1) is a non-selective Ca+2 channel expressed on neuronal and non-neuronal cells, and mediates pain and inflammation; being implicated in rheumatoid arthritis (RA). Here, we evaluated the expression of TRPA1 on peripheral blood leukocytes obtained from RA patients, as well as its correlation with pain and disability, in addtition to the immune alterations in RA patients treated or not with antirheumatic drugs: the disease-modifying angent leflunomide (LFN) and the anti-TNFα adalimumab (ADA); in comparison with healthy subjects. Peripheral blood samples were taken from 15 healthy subjects (controls), 10 RA patients not undertaking anti-rheumatic therapy (NST), 15 patients treated with LFN and 15 patients treated with ADA. C reactive protein (CRP), rheumatoid factor (FR), hydrogen peroxide (H2O2), 4-hydroxynonenal (4- HNE) and tumour necrose factor α (TNFα) levels were quantified. Also, leukocyte subpopulations, the number of red blood cells, the levels of haemoglobin and the expression of TRPA1 on peripheral blood leukocytes, were evaluated. TRPA1 expression was increased on NST leukocytes and this was correlated with pain and disability and was associated with the number of polymorphonuclear cells and the activation of CD14+ cells. It was also demonstrated that treatment with either LFN or ADA attenuates anaemia in AR, with those treatments being effective in treating both the intra- and extra-articular disease. Overall, our data showns that TRPA1 influences pain and disability in RA and that its expression is reduced in patients treated with LFN or ADA. These evidences, together with the promissing data on the anti-rheumatic therapy in reducing anaemia in RA patients suggest that these drugs are effective in treating both the intra- and extra-articular alterations of RA.
O receptor de potencial transitório anquirina 1 (TRPA1) é um canal não seletivo para Ca+2 , expresso em neurônios sensoriais e células não neuronais, o qual medeia a transdução da dor e a inflamação; tendo sido implicado na artrite reumatoide (AR). Este trabalho avaliou a expressão de TRPA1 em leucócitos de sangue periférico de pacientes com AR, bem como sua correlação com a dor e a prda de função articular, além de alterações imunes encontradas em indivíduos com AR recebendo ou não terapia anti-reumática com o modificador da doença leflunomida (LFN) e ou o anti-TNFα adalimumab (ADA); em comparação à indivíduos sadios. Amostras de sangue foram coletadas de 15 indivíduos sadíos (controle), 10 pacientes artríticos não submetidos à terapia anti-reumática específica (NST), 15 pacientes tratados com LFN e 15 pacientes tratados com ADA. Os níveis circulantes de proteína C reativa (PCR), fator reumatóide (FR), peróxido de hidrogênio (H2O2), 4-hidroxinonenal (4-HNE) e fator de necrose tumoral (TNFα) foram quantificados. Ainda, avaliou-se as populações de leucócitos, o número de hemácias, os níveis de hemoglobina e a expressão de TRPA1 em leucócitos do sangue periférico. Observou-se que a expressão de TRPA1 em leucócitos de sangue periférico está aumentada em pacientes NST, e que isto está associado ao aumento do número de células polimorfonucleares e à ativação de células CD14+ . Ainda, a expressão de TRPA1 correlaciona-se com a dor e disfunção articular, alterações estas, que encontram-se reduzidas em pacientes tratados com LFN e ADA. Demonstrou-se ainda que o tratamento com LFN ou ADA previne a anemia relacionada à AR, sendo efetivos tanto no tratamento das alterações intra quanto extra articulares decorrentes da doença.. Em conjunto, os dados demonstram que o TRPA1 influencia a resposta dolorosa e a disfunção articular da AR, e que sua expressão é reduzida pelo tratamento com LFN ou ADA. Estas evidências, aliadas com dados promissores na redução da anemia dos pacientes artríticos sugerem que o tratamento com estas drogas anti-reumáticas é efetivo no tratamento de manifestações intra- e extra-articulares da AR
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Montrucchio, Deise Prehs. "Avaliação da atividade antinociceptiva do extrato e do alcaloide s-(+)-dicentrina extraído de frutos de Ocotea puberula (lauraceae)." Universidade Federal de Santa Maria, 2012. http://repositorio.ufsm.br/handle/1/3840.
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Ocotea puberula (Lauraceae) is a brazilian native tree, known in the South regions as canela guaicá or canela amarela. Its phytochemical composition includes several alkaloids of aporphinic type, some of them with biological activities already reported. Fruits collected in
Curitiba, state of Paraná, were submitted to extraction and fractioning processes, allowing the isolation of an alkaloid identified as dicentrine, present as the majoritarian substance. In the present work we investigated the antinociceptive potential of the organic fractions
obtained from O. puberula fruits extract and dicentrine (DCTN) isolated from the chloroform fraction (CF). Both CF and DCTN, given by oral route, were able to reduce the nociception induced by formalin and acetic acid with similar ID50, suggesting that the CF effect is due to
the presence of DCTN. Hexanic (HF) or ethyl acetate (EAF) fractions had no antinociceptive effect. DCTN also presented antinociceptive effects in chronic models such as inflammatory (induced by intraplantar injection of Freund s complete adjuvant) and neuropathic (induced by partial sciatic nerve ligation), being able to reduce mechanical and cold hypersensitivity,with no changes in the response to heat. When evaluated against the thermo-receptors
activation, DCTN administered either systemically (by oral route) or locally (by intraplantar route) reduced the nociception induced by cinnamaldehyde, a TRPA1 activator, but did not alter the response induced by capsaicin, a TRPV1 activator. The antinociceptive effect of DCTN was not affected by the pretreatment with antagonists of opioid, adrenergic or cannabinoid receptors, and neither by the pretreatment with an inhibitor of serotonin synthesis, suggesting that these descending mechanisms of pain control are not involved in the DCTN mechanism of action. On the other hand, DCTN was able to prevent the hypersensitivity induced by cAMP/PKA pathway activators, forskolin and PGE2, and it also reduced PKA activation, demonstrated by western blotting analysis, suggesting that DCTN may act by interaction with this signaling pathway. On the other hand, DCTN presented few or none action on the hypersensitivity induced by bradikinin or PMA, respectively, suggesting
that the PLC/PKC pathway is not involved in DCTN antinociceptive action. Additionally, DCTN did not cause any sedative effect, neither alterations on motor activity or body temperature, and although daily treatment caused a slight increase in liver relative weight, alterations on AST, ALT or γ-GT levels were not observed. Together, these results demonstrate that DCTN has an important antinociceptive effect in acute and chronic models
of pain, mainly of inflammatory origin, and its mechanism of action seems to involve an interaction with TRPA1 channels and the cAMP/PKA signaling pathway. In this way, DCTN
may be considered a potential candidate to further pre-clinical and even clinical investigations for development of analgesic drugs.A Ocotea puberula (Lauraceae) é uma árvore nativa brasileira, conhecida nos estados da região sul por canela guaicá ou canela amarela, cuja composição fitoquímica inclui diversos alcaloides do tipo aporfínicos, alguns dos quais com atividades biológicas já demonstradas. Frutos coletados na região de Curitiba, Paraná, foram submetidos a processos de extração e fracionamento, permitindo isolar um alcaloide identificado como dicentrina, presente como componente majoritário. Neste trabalho, foi investigado o potencial antinociceptivo das frações orgânicas obtidas a partir do extrato dos frutos de O. puberula e da dicentrina (DCTN) isolada da fração clorofórmica (FC). Tanto a FC quanto a DCTN, administradas por via oral, foram capazes de reduzir a nocicepção induzida pela formalina e pelo ácido acético, com DI50 semelhantes, sugerindo que o efeito de FC seja devido à presença da DCTN. As frações hexânica (FH) e acetato de etila (FAE), por sua vez, não apresentaram efeito antinociceptivo. A DCTN também apresentou efeito antinociceptivo em modelos crônicos, tanto inflamatório (injeção intraplantar de Adjuvante Completo de Freund) quanto neuropático (ligadura parcial do nervo ciático), sendo capaz de reduzir a hipersensibilidade mecânica e ao frio, porém sem alterar a resposta ao calor. Quando avaliada frente à ativação de termo-receptores, a DCTN administrada tanto por via sistêmica (via oral) quanto local (via intraplantar) reduziu a nocicepção induzida pelo cinamaldeído, um ativador de canais TRPA1, mas não alterou a resposta induzida pela capsaicina, um ativador de canais TRPV1. O efeito antinociceptivo da DCTN não foi revertido pelo pré-tratamento com antagonistas de receptores opióides, adrenérgicos ou canabinóides e nem pelo prétratamento com um inibidor da síntese de serotonina, sugerindo que estes sistemas descendentes de controle da dor não estão envolvidos no mecanismo de ação da DCTN. Por outro lado, a DCTN foi capaz de prevenir a hipersensibilidade induzida pelos ativadores da via AMPc/PKA, forscolina e PGE2, e também foi capaz de reduzir a ativação da PKA, demonstrada por análise de western blotting, sugerindo que a DCTN possa agir por interação com essa via de sinalização. Por outro lado, a DCTN apresentou pouca ou nenhuma ação frente à hipersensibilidade mecânica induzida pela bradicinina ou pelo PMA, respectivamente, o que sugere que a via PLC/PKC não está envolvida no seu efeito antinociceptivo. A DCTN não causou efeitos sedativos, alteração motora ou alteração na temperatura corporal dos animais e, embora o tratamento diário durante 14 dias tenha aumentado o peso relativo do fígado, não foram observadas alterações nos níveis sanguíneos de AST, ALT ou γ-GT. Coletivamente, os dados deste trabalho demonstram que a DCTN apresenta um importante efeito antinociceptivo em modelos de dor agudos e crônicos, principalmente de cunho inflamatório, e seu mecanismo de ação parece envolver interação com canais TRPA1 e com a via de sinalização AMPc/PKA. Desta forma, a DCTN constitui-se como uma potencial candidata para a continuidade de estudos pré-clínicos aprofundados, e futuramente clínicos, visando o desenvolvimento de fármacos analgésicos.
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趙, 萌. "オキサリプラチンによる急性末梢神経障害におけるTRPA1チャネルの関与." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188729.
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Hsieh, Tsung-han. "PANCREATIC EXPRESSION OF TRPA1, ITS ROLE IN INSULIN SECRETION AND ITS POSSIBLE EFFECT ON POSTPRANDIAL BLOOD GLUCOSE LEVELS." OpenSIUC, 2013. https://opensiuc.lib.siu.edu/theses/1331.
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Approximately 25.8 million people, 8.3% of the population in the United States have diabetes mellitus (DM), which makes this disease one of the biggest public health problems facing this country. Type 2 diabetes (T2DM) is a heterogeneous disease characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Currently, the insulin secretagogues known as sulfonylureas represent the major mainline drug class for long-term treatment. However, serious side effects, such as hypoglycemia and loss of potency with long-term use necessitate the development of novel insulin secretagogues. Transient receptor potential (TRP) channels have been reported to be involved in pancreatic insulin secretion. TRPA1 is a Ca2+-permeable nonselective cation channel. TRPA1 can be activated by molecules produced during oxidative glycolysis. TRPA1 may be an attractive candidate for drug development because of its involvement in the mechanism of insulin secretion. Previous studies have shown TRPA1 is expressed in rat pancreatic islets and that its activation promotes insulin release. This study was designed to determine if TRPA1 is expressed in mouse and human pancreatic β cells and whether it can promote insulin secretion. I demonstrated that TRPA1 is expressed in mouse and human pancreatic islets. I measured TRPA1-induced membrane currents using patch-clamp and used Ca2+ imaging to demonstrate that TRPA1 agonists induce Ca2+ influx in rat β cell-derived RINm5F cells. I confirmed that TRPA1 KO mice have no TRPA1 mRNA or protein in pancreatic β cells. I used isolated islet cells to demonstrate TRPA1-induced Ca2+ influx using Ca2+ imaging. By using pancreatic islets obtained from wild-type and TRPA1 KO mice, I determined that TRPA1 is important for insulin secretion. Finally, I determined that intraperitoneal administration of a TRPA1 agonist and antagonist affected blood glucose levels and plasma insulin levels in a manner consistent with the TRPA1 acting to increase insulin secretion. Furthermore, glucose tolerance was impaired in TRPA1 KO mice upon intraperitoneal glucose tolerance test (IPGTT) challenge compared to wild-type mice. In summary, I have shown TRPA1 is expressed not only in rat pancreatic islets but also in mouse and human pancreatic islets. I confirmed the localization of TRPA1 in pancreatic β cells. All of the experimental results are consistent with the concept that TRPA1 acts as to increase the insulin-secreting capacity of pancreatic β cells. According to my data, TRPA1 may play a role in promoting insulin secretion in patients with T2DM. Therefore, pharmacological activation of TRPA1 may be a novel therapeutic method for the treatment of diabetes.
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Velez-Ortega, Alejandra C. "TRPA1 CHANNELS IN COCHLEAR SUPPORTING CELLS REGULATE HEARING SENSITIVITY AFTER NOISE EXPOSURE." UKnowledge, 2014. http://uknowledge.uky.edu/physiology_etds/20.
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TRPA1 channels are sensors for noxious stimuli in a subset of nociceptive neurons. TRPA1 channels are also expressed in cells of the mammalian inner ear, but their function in this tissue remains unknown given that Trpa1–/– mice exhibit normal hearing, balance and sensory mechanotransduction. Here we show that non-sensory (supporting) cells of the hearing organ in the cochlea detect tissue damage via the activation of TRPA1 channels and subsequently modulate cochlear amplification through active cellshape changes.
We found that cochlear supporting cells of wild type but not Trpa1–/– mice generate inward currents and robust long-lasting Ca2+ responses after stimulation with TRPA1 agonists. These Ca2+ responses often propagated between different types of supporting cells and were accompanied by prominent tissue displacements. The most prominent shape changes were observed in pillar cells which here we show possess Ca2+-dependent contractile machinery. Increased oxidative stress following acoustic overstimulation leads to the generation of lipid peroxidation byproducts such as 4-hydroxynonenal (4-HNE) that could directly activate TRPA1. Therefore, we exposed mice to mild noise and found a longer-lasting inhibition of cochlear amplification in wild type than in Trpa1–/– mice.
Our results suggest that TRPA1-dependent changes in pillar cell shape can alter the tissue geometry and affect cochlear amplification. We believe this novel mechanism of cochlear regulation may protect or fine-tune the organ of Corti after noise exposure or other cochlear injuries.
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Vancauwenberghe, Eric. "Rôle du canal TRPA1 dans le microenvironnement tumoral des cancers prostatiques humains." Thesis, Lille 1, 2016. http://www.theses.fr/2016LIL10210.
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Le cancer de la prostate (CaP) est le second cancer le plus fréquent chez l’homme. Le microenvironnement tumoral (MET) joue un rôle important dans la cancérogenèse prostatique et la formation de métastases indépendamment des androgènes. Il existe une communication étroite entre les cellules épithéliales tumorales et le stroma via la sécrétion de facteurs solubles permettant la survie et la métastase des cellules cancéreuses. La modulation de la sécrétion de ces facteurs pourrait donc constituer un moyen d’intervention thérapeutique dans le traitement des cancers prostatiques. Les canaux ioniques et le calcium intracellulaire sont connus pour moduler la sécrétion. Dans ce contexte, nous avons montré que le canal TRPA1 est exprimé au niveau des fibroblastes associés au cancer (CAF) de la prostate humaine. L’activation de ce canal par les facteurs épithéliaux conduit à une augmentation du taux de calcium intracellulaire favorisant l’expression et la sécrétion de facteurs de croissance. Nos données montrent que ces derniers induisent la transition épithélio-mésenchymateuse, la migration et la résistance aux agents chimiothérapeutiques des cellules cancéreuses. Enfin, nous avons mis en évidence des polymorphismes et des mutations du canal TRPA1 des CAF permettant son activation par des facteurs environnementaux et la sécrétion de facteurs de croissance induisant la résistance à l’apoptose des cellules cancéreuses prostatiques. L’ensemble de ces données suggèrent que le canal TRPA1 constitue une cible potentielle pour les thérapies futures des CaP en permettant d’interrompre les interactions épithélio-stromales du MET et d’empêcher l’évolution de ces cancersProstate cancer (PCa) is the second most common cancer in men. The tumor microenvironment (TME) plays an important role in prostate carcinogenesis and metastasis independently of androgens. There is a close communication between tumor epithelial cells and stroma through the secretion of soluble factors promoting survival and metastasis of cancer cells. Modulating the secretion of these factors could therefore be a potential therapeutic option in the treatment of prostate cancers. Ion channels and the intracellular calcium are known to modulate secretion. In this context, we have shown that the TRPA1 channel is expressed in fibroblasts associated to cancers (CAF) in human prostate. Here, we describe that the activation of TRPA1 channel by epithelial factors leads to an increase in intracellular calcium levels promoting expression and secretion of growth factors. Our data show that these latter induce the epithelial-mesenchymal transition, migration and resistance to chemotherapeutic agents in cancer cells. Finally, we identified polymorphisms and mutations in TRPA1 channel allowing its activation by environmental factors and secretion of growth factors inducing resistance to apoptosis of prostate cancer cells. All these data suggest that TRPA1 channel constitutes a potential target for future therapies of PCa to interrupt the epithelial-stromal interactions of TME and prevent the development of these cancers
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Kellner, Bernhard [Verfasser], Jürgen [Akademischer Betreuer] Schüttler, Jürgen [Gutachter] Schüttler, and Carla [Gutachter] Nau. "Die Muskelrelaxanzien Rocuronium, Vecuronium, Pancuronium, Atracurium und Succinylcholin aktivieren TRPA1 - und TRPV1 - Rezeptoren nozizeptiver Neurone / Bernhard Kellner ; Gutachter: Jürgen Schüttler, Carla Nau ; Betreuer: Jürgen Schüttler." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1204257841/34.
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Santos, Gabriela Trevisan dos. "PARTICIPAÇÃO DO RECEPTOR TRPA1 EM MODELOS DE ATAQUE AGUDO DE GOTA EM ROEDORES." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/4484.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorGout is a prevalent form of inflammatory arthritis, which leads to patients poor quality of life. Acute gout attacks produce severe joint pain and inflammation associated with oxidative stress induction. This pathology is provoked by the accumulation of monosodium urate (MSU) crystals, but the underlying pain mechanisms in acute gout attacks are still poorly understood. The transient potential receptor ankyrin 1 (TRPA1) is a sensor for endogenous oxidant compounds, such as hydrogen peroxide (H2O2), found in peptidergic sensory fibers associated to inflammatory pain. The goal of this study was to explore the TRPA1 role in two models of monosodium urate (MSU) crystals-induced inflammation and nociception in rats and mice. We found that TRPA1 antagonism (HC-030031 or camphor), TRPA1 gene deletion or defunctionalization by capsaicin pretreatment of peptidergic TRPexpressing primary sensory neurons markedly decreased MSU-induced nociception and edema after intraplantar (i.pl.) or intra-articular (i.a.) injection. In addition to these neurogenic effects, MSU increased H2O2 levels in the injected tissue, an effect that was abolished by the H2O2-detoxifing, catalase enzyme. TRPA1 immunoreactivity in sciatic nerve and the levels of calcitonin gene related peptide (CGRP) in the synovial tissue were also increased by MSU. H2O2 i.pl. or i.a. injection mimicked MSU, causing nociception and edema prevented by TRPA1 antagonism. Moreover, TRPA1 blockage abrogated the increase in neutrophil infiltration and interleukin-1β elicited by MSU. Our results suggest that MSU-injection increases tissue H2O2 thereby stimulating TRPA1 on sensory nerve endings to produce inflammation and nociception. Thus, TRPA1 may be explored as a valuable target in acute gout management.
A gota é uma forma prevalente de artrite inflamatória que reduz a qualidade de vida dos pacientes. Os ataques agudos de gota produzem dor articular grave e inflamação que são associadas à produção de estresse oxidativo. Esta patologia é provocada pela deposição de cristais de urato monossódico (MSU), mas os mecanismos relacionados à dor observada nos ataques agudos de gota ainda são pouco esclarecidos. O receptor de potencial transitório anquirina 1 (TRPA1) é um sensor para compostos oxidantes, como o peróxido de hidrogênio (H2O2), encontrado em fibras sensoriais peptidérgicas e este está relacionado ao desenvolvimento de dor inflamatória. O objetivo deste estudo foi avaliar o papel do receptor TRPA1 em dois modelos de inflamação e nocicepção induzidos pela administração de cristais de MSU em ratos e camundongos. Observamos que o antagonismo do receptor TRPA1 (HC-030031 ou cânfora), a deleção genética deste canal, ou ainda a indução de dessensibilização dos neurônios sensoriais que expressam os receptores TRP pelo tratamento com capsaicina reduziram marcantemente a nocicepção e edema induzido pela administração intraplantar (i.pl.) ou intra-articular (i.a.) dos cristais de MSU. Além destes efeitos neurogênicos a administração de MSU aumentou o conteúdo de H2O2 nos tecidos injetados, um efeito que foi bloqueado pela enzima catalase, e também aumentou a imunoreatividade para o receptor TRPA1 no nervo ciático e no tecido sinovial, e também os níveis do peptídeo relacionado ao gene da calcitonina (CGRP) no tecido sinovial. A administração de H2O2 por via i.pl. ou i.a. induziu efeitos semelhantes àqueles induzidos pela administração de MSU, e estes foram reduzidos pela administração de antagonistas TRPA1. Ainda, o bloqueio do receptor TRPA1 reduziu a infiltração de neutrófilos e a produção de interleucina 1β induzidas pela administração de cristais de MSU. Em conclusão, os nossos resultados sugerem que a administração dos cristais de MSU é capaz de aumentar a produção de H2O2 que então poderia estimular o receptor TRPA1 expresso em neurônios sensoriais causando nocicepção e inflamação dos tecidos. Dessa maneira, o canal TRPA1 poderia ser explorado como um alvo em potencial para o tratamento dos ataques agudos de gota.
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Bodkin, Jennifer. "Investigating the role of Transient Receptor Potential Ankyrin One (TRPA1) in cardiovascular regulation." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/investigating-the-role-of-transient-receptor-potential-ankyrin-one-trpa1-in-cardiovascular-regulation(86e661c9-d299-45cd-b3d3-b23fe18f9181).html.
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TRPA1 is a member of the TRP superfamily; localised to neural and non-neuronal sites. TRPA1 is activated endogenously by products of oxidative stress, where its expression on sensory neurones leads to the release of vasoactive neuropeptides. Exogenous agonists of TRPAl, mustard oil and cinnamaldehyde, have been shown to cause concentration-dependent vasorelaxation of blood vessels via a variety of mechanisms. My PhD used TRPA1 WT and KO mice to investigate the potential for TRPA1 to alter peripheral artery tone and the implications of this on systemic blood pressure. I also studied the development of angiotensin II induced hypertension and associated pathologies. Wire myography using murine TRPA1 WT and KO mesenteric arteries showed cinnamaldehyde to cause concentration-dependent vasorelaxation comprising a TRPA1 dependent component, which was endothelial independent and mediated by CGRP and hyperpolarisaton. Basal blood pressure monitoring by both tail cuff plethysmography and telemetry showed no overall effect of TRPA1 deletion on basal hemodynamics. However, TRPAl KO mice displayed a previously unreported hyperactivity phenotype, measured by both telemetry and voluntary wheel running. 14 day infusion of angiotensin II by osmotic minipump induced similar hypertension in both TRPA1 WT and KO mice. Hypertrophy of the heart was seen in both genotypes, but of significantly increased magnitude in TRPA1 KO mice. Further analysis of associated inflammatory biomarkers by RT qPCR and MSD multiplex ELISA showed upregulation of pro-oxidative genes in hypertensive mice of both genotype. This was significantly greater in hypertensive TRPA1 KO mice than in hypertensive TRPA1 WT mice. These findings may partially explain the increase in hypertrophy in these mice. Angiotensin II infused mice of both genotypes showed increases in chemokine and cytokine expression. Striking, increases in IL6 and MCP-1 seen in hypertensive WT mice were significantly blunted in hypertensive KO mice, suggesting that TRPAl may differentially modulate inflammatory responses.
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Roe, Paige M. "Identifying potential agonists of TRPA1 using a heterologous expression system and transgenic mice." Winston-Salem, NC : Wake Forest University, 2009. http://dspace.zsr.wfu.edu/jspui/handle/10339/42604.
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Paumier, Adrien. "Evaluation du canal calcique TRPA1 comme cible thérapeutique potentielle dans la pathogénèse de la maladie d’Alzheimer TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV010.
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La maladie d'Alzheimer (MA) est une maladie neurodégénérative qui affecte progressivement les fonctions cognitives et la mémoire. Le cerveau des personnes atteintes de la MA est caractérisé par le dépôt extracellulaire d'amyloïde-β (Aβ), un peptide qui s'agrège au sein de structures appelées "plaques séniles". Cependant, il a été reconnu que les formes solubles oligomériques d’Aβ (Aβo) sont les formes du peptide qui déclenchent la pathologie. Elles sont impliquées dans des dysfonctionnements synaptiques qui sont considérés comme l'un des premiers événements de la MA. Des études récentes suggèrent que les astrocytes pourraient jouer un rôle majeur dans les dysfonctionnements synaptiques, mais leur implication dans les premiers stades de la MA reste peu documentée. En utilisant l'imagerie calcique, nous avons montré que l'application brève d’Aβo sur des tranches aiguës de cerveau de souris induit une hyperexcitabilité calcique astrocytaire dans l'hippocampe. Cette hyperexcitabilité est indépendante de l'activité neuronale et se produit dans les microdomaines des prolongements astrocytaires impliqués dans la formation des synapses tripartites. Dans la même échelle de temps, nous avons observé une hyperactivité au sein des neurones voisins, en utilisant des enregistrements par patch-clamp en configuration cellule entière. Cette hyperactivité dépend de la signalisation calcique dans le réseau astrocytaire. De manière intéressante, l'inhibition du canal calcique TRPA1, exprimé dans les astrocytes, bloque l'effet d’Aβo et restaure l'activité des astrocytes et des neurones à un niveau basal. Par ailleurs, l'inhibition chronique de TRPA1 dans le modèle de souris APP/PS1-21 de la MA bloque les perturbations neuronales et astrocytaires précliniques et prévient les troubles de l'apprentissage. En somme, ce travail de thèse suggère un rôle essentiel pour l'hyperexcitabilité précoce astrocytaire dans la pathogenèse de la MA, et souligne que TRPA1 est une cible thérapeutique prometteuse avec un effet neuroprotecteurAlzheimer’s disease (AD) is a neurodegenerative disorder that progressively affects cognitive functions and memory. AD brains are characterized with the extracellular deposition of amyloid-β (Aβ), a peptide that aggregates in structures named “senile plaques”. However, it has been recognized that oligomeric soluble forms of Aβ (Aβo) are the pathology-triggering form of the peptide. They are involved in synaptic dysfunctions which are thought to be one of the earliest events in AD. Recent studies suggest that astrocyte could play a major role in synaptic dysfunctions but their involvement in early stages of AD remained largely undefined. By using calcium imaging we showed that short term application of Aβo on mice acute brain slices induces astrocytic calcium hyperexcitability in the hippocampus. This hyperexcitability was independent of neuronal activity and occurred in the astrocyte processes microdomains involved in tripartite synapses formation. In the same time-scale, we observed hyperactivity in neighboring neurons, using whole-cell patch-clamp recordings, which depends on calcium signaling in astrocyte network. Strikingly, the inhibition of astrocytic calcium channel TRPA1 blocked the effect of Aβo and reversed both astrocyte and neuron activity toward physiological range. Interestingly, chronic inhibition of TRPA1 in APP/PS1-21 mouse model of AD, blocked both neuron and astrocyte dysfunctions at preclinical stages and prevented learning impairments. Overall, this thesis work suggests a critical role for early astrocyte hyperexcitability in pathogenesis of AD and highlights TRPA1 as an interesting therapeutic target with neuroprotective effect
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Haider, Georg [Verfasser]. "Effekte von TRPA1-Agonisten auf die Methacholin-induzierte Atemwegskonstriktion bei der Maus / Georg Haider." Gießen : Universitätsbibliothek, 2016. http://d-nb.info/1120270278/34.
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Stöckl, Stephanie Kerstin [Verfasser]. "Wirkung von TRPA1-Rezeptor-Agonisten bei der meningealen Nozizeption und Kopfschmerzentstehung / Stephanie Kerstin Stöckl." Gießen : Universitätsbibliothek, 2016. http://d-nb.info/110601426X/34.
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Bonet, Ivan José Magayewski 1986. "O papel do receptor TRPA1 no desenvolvimento e manutenção da hiperalgesia induzida pela carragenina." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314055.
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Orientador: Cláudia Herrera TambeliDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-22T19:36:40Z (GMT). No. of bitstreams: 1 Bonet_IvanJoseMagayewski_M.pdf: 8243433 bytes, checksum: a5cdaab90bdcc5bbba66a0e5e4a1293f (MD5) Previous issue date: 2013
Resumo: O Receptor Potencial Transiente Ankiryn 1 (TRPA1) é um canal não seletivo a cátions importante na fixação do limiar nociceptivos e pertencente à superfamília de canais TRP. É expresso em fibra C-nociceptiva e células não neuronais envolvidas na liberação de mediadores pró-inflamatórios. No presente estudo, investigamos se o TRPA1 contribui para a hiperalgesia induzida pela carragenina em ratos, e se essa contribuição é mediada por mecanismos de inflamação, tais como liberação de citocinas pró-inflamatórias e migração de neutrófilos e/ou sensibilização direta do neurônio aferente primário. Avaliamos a sensibilização do nociceptor induzida pela carragenina utilizando estímulos mecânico (analgesímetro mecânico) e químico (capsaicina), com ou sem bloqueio farmacológico local do receptor TRPA1 pelo seu antagonista seletivo HC 030031. A carragenina induziu hiperalgesia com pico na terceira hora, persistindo até vigésima quarta hora. O bloqueio farmacológico do receptor TRPA1 por co-administração de HC 030031 diminuiu significativamente a hiperalgesia induzida pela carragenina na terceira hora e a pós-administração de HC 030031 (2hrs 55min) reduziu na terceira e na sexta hora. O silenciamento do gene do TRPA1, induzido por um pré-tratamento intratecal com Oligonucleotídeo antisense, preveniu a hiperalgesia induzida pela carragenina após 24 horas além de reduzir significativamente a expressão de TRPA1 em células dos gânglios da raiz dorsal (GRD) (L5-6). O tratamento com carragenina, por sua vez, não alterou a expressão do receptor TRPA1 no GRD, e tampouco afetou os níveis de citocinas e a migração de neutrófilos no tecido periférico (patas). Concluímos que TRPA1 tem papel importante no desenvolvimento e manutenção da hiperalgesia inflamatória induzida pela carragenina por contribuir diretamente na excitabilidade do nociceptor. Baseado nesses achados, sugerimos que o bloqueio de TRPA1 é uma estratégia promissora no desenvolvimento de futuras drogas para o controle e tratamento da dor
Abstract: The Transient Receptor Potential Ankiryn 1 (TRPA1) is a nonselective cation channel, important in setting nociceptive threshold belonging to the superfamily of TRP channels. It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators release. In this study, we asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and whether this contribution is mediated by mechanisms in inflammation, such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. We measured the carrageenan-induced nociceptive sensitization using a mechanical (mechanical analgesymeter) and a chemical (capsaicin) stimulus, with or without pharmacological blockade of TRPA1 by its selective antagonist HC 030031. Carrageenan-induced Hiperalgesia has peaked at the third hour and persisted until the twenty-fourth hour. Pharmacological blockade of TRPA1 receptor by co-administration of HC 030031 significantly lowered carrageenan-induced hiperalgesia at the third hour and post-administration (2hrs 55min) decreased at both third and sixth hours. The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 hours and significantly reduced TRPA1 expression in the dorsal root ganglia cells (DRG ) (L5-6). However, carrageenan treatment, did not affect the TRPA1 expression on DRG, neither affected the cytokines levels and neutrophil migration in peripheral tissue (paws). We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability. Based on these findings, we suggest that TRPA1 blockade is a promising strategy for the development of future drugs to pain treatment and control
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular
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Silva, Cássia Regina da. "ENVOLVIMENTO DO RECEPTOR TRPA1 NA RESPOSTA INFLAMATÓRIA INDUZIDA PELA ADMINISTRAÇÃO TÓPICA DE CINAMALDEÍDO EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2011. http://repositorio.ufsm.br/handle/1/11180.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCinnamaldehyde, a natural compound frequently present in cosmetic formulations, induces skin irritation when topically applied, but the mechanism by which cinnamaldehyde produces such skin reactions is unclear. Here, we showed that cinnamaldehyde induced ear edema in mice (1-6 μg/ear) with a maximum effect with 4 μg/ear (Emax of 0.18 ± 0.02 mm and an ED50 value of 2.0 (1.1- 3.4 μg/ear). Cinnamaldehyde can induce leukocyte infiltration detected by an increase in MPO activity and confirmed by histological analyses. The edema and cellular infiltration evoked by 4 μg/ear of cinnamaldehyde was prevented through topical application of ruthenium red, a non selective TRP antagonist or by camphor and HC030031, two TRPA1 receptor antagonists. In contrast, the edema and the leukocyte infiltration was unaffected by the TRPV1 receptor antagonist SB366791. Cinnamaldehydeinduced edema but not cellular infiltration was also prevented though topical application of the tachykinin NK1 antagonist aprepitant, indicating a neuropeptides release phenomenon in this process. Also, we observed that repeated topical applications of cinnamaldehyde (4 μg/ear) did not induced sensitization/desensitization alterations. Interestingly, the TRPV1 antagonist, capsaicin, repeated treatment abrogated its edematogenic response, confirming the desensitization process and decrease partially the cinnamaldehyde induced edema, suggesting the involvement of capsaicin-sensitive fibers and additional targets in cinnamaldehyde response. The present results demonstrated that cinnamaldehyde induces mouse skin inflammation through a mechanism involved the TRPA1 receptor activation and subsequent leukocyte infiltration. In addition, evidence supports the assumption that the tachykinin NK1 receptor is involved in these inflammatory responses.
O cinamaldeído é um composto natural frequentemente encontrado em formulações cosméticas, capaz de induzir irritação na pele quando aplicado topicamente, porém o mecanismo pelo qual o cinamaldeído produz estas reações ainda é desconhecido. Neste trabalho demonstramos que o cinamaldeído foi capaz de induzir edema de orelha em camundongos (1-6 μg/orelha) com um efeito máximo obtido com a dose de 4 μg/orelha (Emax de 0,18 ± 0,02 mm e um DE50 de 2,0 (1,1- 3,4) μg/orelha). O cinamaldeído foi capaz ainda de induzir infiltração leucocitária detectada por um aumento na atividade da MPO e confirmada por análise histológica. O edema e a infiltração leucocitária iniciados após aplicação tópica de 4 μg/orelha de cinamaldeído foi prevenido pela aplicação tópica de vermelho de rutênio, um antagonista TRP não seletivo, e por cânfora e HC030031, dois antagonistas seletivos TRPA1. Por outro lado, a aplicação de SB366791, um antagonista seletivo TRPV1, não alterou o edema nem a infiltração leucocitária. Ainda, o edema induzido pelo cinamaldeído foi prevenido pela aplicação tópica de aprepitant, um antagonista seletivo do receptor NK1 para taquicininas, sugerindo que a liberação de neuropeptídeos esteja envolvida neste processo. Também foi observado que a aplicação tópica repetida de cinamaldeído 4 μg/orelha não foi capaz de induzir processos de ensibilização/dessensibilização. No entanto, o tratamento repetidocom o antagonista TRPV1, capsaicina, aboliu o edema induzido pela própria capsaicina, confirmando a ocorrência de dessensibilização, e diminuiu parcialmente o edema induzido pelo cinamaldeído sugerindo o envolvimento de fibras sensíveis a capsaicina, além de outras vias, neste processo. Os resultados demonstram que o cinamaldeído induz um processo inflamatório na pele através de um mecanismo que envolve a ativação do receptor TRPA1 e consequente infiltração leucocitária.
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Mayer, Rafaela [Verfasser], and Heike [Gutachter] Rittner. "OxPAPC as an endogenous agonist of TRPA1 channels on nociceptors / Rafaela Mayer ; Gutachter: Heike Rittner." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1177686988/34.
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Kloka, Jan Andreas [Verfasser], and Heike [Gutachter] Rittner. "Endogene Lipide als neues Behandlungstarget im TRPA1-vermittelten Entzündungsschmerz / Jan Andreas Kloka ; Gutachter: Heike Rittner." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1187140473/34.
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Sulak, Michael A. "Modulation of Transient Receptor Potential Cation Channel, Subfamily A, Member 1 (TRPA1) Activity by Cdk5." Kent State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=kent1322494947.
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Kouzai, Daisuke. "Chemical biological studies on oxidation status-sensitive calcium channels." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188546.
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Sparrer, Ingo Udo Rene [Verfasser]. "Funktionelle Expression des TRPA1-Kanals in vestibulären Typ II Haarzellen des Meerschweinchens / Ingo Udo Rene Sparrer." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2012. http://d-nb.info/1021936960/34.
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Zehfuß, Franziska [Verfasser], and Harald [Akademischer Betreuer] Mückter. "Der TRPA1 Kanal als Zielstruktur bei der Zinkchlorid-Exposition in vitro / Franziska Zehfuß ; Betreuer: Harald Mückter." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1171705263/34.
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Schäfer, Eva [Verfasser], and Alexander [Akademischer Betreuer] Dietrich. "Non-neuronale Expression und Funktion des sensorischen Kationenkanals TRPA1 in Tumorzellen / Eva Schäfer. Betreuer: Alexander Dietrich." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1052015328/34.
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Andrade, Edinéia Lemos de. "Participação do receptor TRPA1 na hiperatividade urinária da bexiga urinária induzida por lesão medular em ratos." reponame:Repositório Institucional da UFSC, 2012. http://repositorio.ufsc.br/xmlui/handle/123456789/94193.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2010Made available in DSpace on 2012-10-25T07:28:16Z (GMT). No. of bitstreams: 1 281751.pdf: 2813307 bytes, checksum: 6667e18ff620b043e8f40c51f47a9a5e (MD5)
A proposta deste estudo foi avaliar a relevância do receptor TRPA1 (receptor de potencial transitório com domínios tipo anquirina 1) na hiperatividade da bexiga urinária decorrente da lesão medular em ratos. A lesão medular resultou em alterações na capacidade locomotora dos animais, em hipertrofia muscular e dano na bexiga urinária, representado pela perda de células uroteliais, formação de edema, deposição de fibrina e infiltração de neutrófilos, bem como por mudanças na contratilidade do órgão e nos parâmetros urodinâmicos envolvidos no processo de micção. Além disso, a lesão medular induziu aumento nos níveis do RNAm e da expressão do receptor TRPA1 na bexiga urinária e nos neurônios do GRD (gânglio da raiz dorsal) e da expressão do receptor TRPV1 (receptor de potencial transitório vanilóide 1) na bexiga urinária, nos neurônios do GRD (L6-S1) e na porção correspondente da medula espinhal. A exposição do KCl (agente despolarizante), carbacol (agonista de receptores muscarínicos), cinamaldeído (agonista do receptor TRPA1) ou da capsaicina (agonista do receptor TRPV1) às preparações de bexiga urinária induziu resposta contrátil, a qual foi potencializada pela lesão medular. A pré-incubação das preparações de bexiga urinária com HC-030031 (antagonista do receptor TRPA1) ou com SB-366791 (antagonista do receptor TRPV1), ou ainda o tratamento intratecal com antisense oligodeoxinucleotídeo para o receptor TRPA1 (AS-ODN TRPA1), todos reduziram significativamente a resposta contrátil da bexiga urinária induzida pelo cinamaldeído. Por outro lado, o tratamento intratecal com AS-ODN TRPA1 não interferiu com a resposta contrátil induzida pelo carbacol (agonista muscarínico). Ademais, a remoção das células uroteliais reduziu a resposta contrátil mediada pelo cinamaldeído ou pelo carbacol. A lesão medular aumentou a amplitude da atividade fásica espontânea da bexiga urinária, o número de contrações não associadas à micção (CNMs), a pressão basal, a pressão limiar, a capacidade de armazenamento da bexiga urinária, o volume residual e reduziu o intervalo entre as contrações, o volume eliminado e a eficiência do esvaziamento vesical. O tratamento sistêmico agudo com HC-030031 reduziu significativamente a amplitude e o número de CNMs, enquanto o tratamento intratecal com AS-ODN TRPA1 reduziu o número de CNMs e normalizou a atividade fásica espontânea da bexiga urinária. Além disso, o tratamento com AS-ODN TRPA1 reduziu acentuadamente a expressão do receptor TRPA1 nos neurônios do GRD (L6-S1), na porção correspondente da medular espinhal, no músculo detrusor, porém não no urotélio da bexiga urinária. Estudos realizados em cultura neuronal mostraram que a lesão medular induziu aumento na proporção de neurônios do GRD (L6-S1) responsivos e na mobilização de cálcio intracelular ao estímulo com cinamaldeído e apenas na mobilização de cálcio intracelular ao estímulo com capsaicina. A exposição dos neurônios do GRD (L6-S1) às neurotrofinas NGF (fator de crescimento derivado do nervo) ou BDNF (fator neurotrófico derivado do cérebro) induziu aumento na mobilização de cálcio intracelular ao estímulo com cinamaldeído ou capsaicina, enquanto a exposição ao BDNF induziu aumento na proporção de neurônios do GRD responsivos ao cinamaldeído. Finalmente, após a lesão medular os níveis de NGF e BDNF foram aumentados na bexiga urinária, nos neurônios do GRD (L6-S1) e na porção correspondente da medula espinhal. Em conjunto, os resultados sugerem que o modelo animal de lesão medular utilizado neste estudo reproduziu as alterações fisiopatológicas no trato urinário inferior e evidencia um papel importante do receptor TRPA1 na hiperatividade urinária causada pela lesão medular em ratos.
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Suslak, Thomas James. "There and back again : a stretch receptor's tale." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/10474.
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Mechanotransduction is fundamental to many sensory processes, including balance, hearing and motor co-ordination. However, for such an essential feature, the mechanism(s) that underlie it are poorly understood. The mechanotransducing stretch receptors that relay information on the tonicity and length of skeletal muscles have been well-defined, particularly at the gross anatomical level, in a wide variety of species, encompassing both vertebrates and invertebrates. To date, there exists a wealth of data describing them, anatomically, as well as good electrophysiological data from stretch receptors of some larger organisms. However, comparatively few studies have succeeded in identifying putative mechanotransducing molecules in such systems. Nonetheless, this class of sensory mechanotransducers perhaps offer the best means of identifying molecules that permit the stretch-sensitivity of such endings, revealing new information about the underlying mechanisms of stretch receptors, and mechanoreceptors more generally. However, a different approach is clearly needed; a theoretical approach, utilising mathematical modelling, offers a powerful means of pooling the current wealth of knowledge on the reported electrophysiological behaviour of muscle stretch receptors. This study, therefore, develops an extended theoretical model of a stretch receptor system in order to reproduce, in silico, the reported behaviour of both vertebrate and invertebrate stretch receptors, within the same modelling environment, thus enabling the first quantitative framework for comparing these data, and moreover, making predictions of the likely roles of specific molecular entities within a stretch receptor system. Subsequently, this study utilises a model in vivo system to test these theoretical predictions. The genetic toolbox of D. melanogaster offers a wide range of tools that are extremely suitable for identifying mechanotransducing molecules in stretch receptors. However, very little is currently known about such endings in this organism. This study, therefore, firstly characterises a putative stretch receptor organ in larval Drosophila, the dbd neuron, via a novel experimental approach. It is shown that this neuron exhibits known properties of stretch receptors, as previously observed in other, similar organs. Furthermore, these observations bear out the predictions of the mathematical model. Having defined the dbd neuron as a muscle stretch receptor, pharmacological and genetic assays in this system, combined with predictions from the mathematical model, identify a key role for the recently-discovered DmPiezo protein as an amiloride-sensitive, mechanically-gated sodium channel (MNaC) in dbd neurons, with TRPA1 also acting in this system in a supporting role. These data confirm the essential role of an MNaC in mechanosensory systems, but also supply important evidence that, whilst the electrophysiological mechanisms in stretch receptors are remarkably similar across taxa, different species likely employ various molecular mechanisms to achieve this.
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Hooper, Justin Shane. "Cardiovascular Effects Evoked by Airway Nociceptive Reflexes in Healthy and Cardiovascular Diseased Rats." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6258.
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Acute inhalation of airborne pollutants alters cardiovascular function and has been shown to have its greatest affects on individuals with pre-existing cardiovascular disease. Evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the cardiovascular responses evoked by inhalation of AITC (TRPA1 agonist) and capsaicin (TRPV1 agonist) in healthy Sprague Dawley (SD) and Wistar Kyoto (WKY) rats, and cardiovascular diseased Spontaneously Hypertensive (SH) rats. Inhalation of the agonists by healthy SD and WKY rats caused significant bradycardia, atrio-ventricular (AV) block and prolonged PR-Intervals. Inhalation of TRP agonists caused differential cardiovascular responses in the cardiovascular diseased SH rats, such that the TRP agonists evoked brady-tachy with AV block and premature ventricular contractions (PVCs). Bradycardic responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine, but atropine did not prevent the tachycardic responses seen in the SH rats. Adrenergic inhibition with atenolol prevented the tachycardic responses, but did not prevent the bradycardic responses evoked by AITC in the SH rats. In healthy rats, AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase, while evoking hypertension in the SH rats. Atropine accentuated the hypertensive phase in all animals, while preventing the hypotension in the healthy animals. In all animals, AITC-evoked heart rate responses were not abolished by terazosin, the [U+F061]1 adrenoceptor inhibitor, which prevented the hypertensive responses. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following pre-collicular decerebration. In conclusion, we provide evidence that activation of TRP channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in healthy rats via reflex modulation of the autonomic nervous system (ANS), and that these effects are exacerbated in cardiovascular diseased rats.
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Shang, Ye. "Mechanisms Regulating Transient Receptor Potential Cation Channel A1 (TRPA1) and Their Roles in Nociception and Nociceptive Sensitization." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1092.
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Nociception is the sensory nervous system that detects harmful stimuli including excessive heat, cold, toxic chemicals, and noxious mechanical stimulations. Transient receptor potential (TRP) channels are a group of evolutionarily conserved ion channels consisting of 4 subunits, each with 6 transmembrane spans, and detect a variety of external and internal nociceptive stimuli. Due to their critical roles in nociception, it is essential to understand the mechanisms that regulate TRP channels and subsequent nociception. Here, I investigated two distinct types of regulation of Drosophila transient receptor potential cation channel A1 (TrpA1): regulation via the expression of different TrpA1 isoforms, and via its binding with associated proteins. I found that one of the TrpA1 isoforms, TrpA1(E), inhibits the thermal responses of other TrpA1 isoforms in vitro. I also identified potential TrpA1 binding partners through Co- immunoprecipitation (Co-IP) and mass spectrometry analysis. These binding partners need further validation and characterization through biochemical, cellular, and behavioral assays to illustrate their roles in nociception, and may serve as potential drug targets for chronic pain.
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Kannler, Martina [Verfasser], and Alexander [Akademischer Betreuer] Dietrich. "TRPA1-Kationenkanäle : Expression und Funktion als Sauerstoffsensoren in Epithelzellen des respiratorischen Systems / Martina Kannler ; Betreuer: Alexander Dietrich." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1206096330/34.
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Andrade, Edinéia Lemos de. "Caracterização farmacológica in vitro e in vivo de substâncias naturais como ativadoras do receptor TRPA1 em roedores." Florianópolis, SC, 2006. http://repositorio.ufsc.br/xmlui/handle/123456789/88968.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pos-Graduação em Farmacologia.Made available in DSpace on 2012-10-22T15:25:17Z (GMT). No. of bitstreams: 0
O presente estudo avaliou através do emprego de abordagens farmacológicas in vitro e in vivo, alguns dos mecanismos envolvidos na ativação do receptor TRPA1 (receptor de potencial transitório com domínios anquirina 1), um membro da família de canais catiônicos TRP (receptor de potencial transitório). De forma semelhante ao agonista do receptor TRPV1 (receptor de potencial transitório vanilóide 1), a capsaicina, os agonistas do receptor TRPA1, o isotiocianato de alila e o cinamaldeído, causaram contração da bexiga isolada de rato dependente de cálcio externo. Esta resposta foi susceptível a dessensibilização. O vermelho de rutênio, um antagonista não-seletivo dos receptores TRP, reduziu de forma significativa a resposta contrátil induzida pela capsaicina, pelo isotiocianato de alila ou pelo cinamaldeído. O antagonista seletivo do receptor TRPV1, o SB 366791, foi capaz de inibir completamente a resposta contrátil induzida pela capsaicina, enquanto reduziu parcialmente o efeito produzido pelos agonistas do receptor TRPA1. Ademais, a contração induzida pelo isotiocianato de alila foi significativamente reduzida pelos antagonistas dos receptores taquicinérgicos NK1, NK2 e NK3, tetrodotoxina e indometacina, mas não pela atropina ou suramina. Por outro lado, a contração causada pelo cinamaldeído foi inibida pelos antagonistas de receptores NK1 e NK2, tetrodotoxina ou indometacina. Em contraste à capsaicina, o isotiocianato de alila e o cinamaldeído não interferiram com a união específica do agonista [3H]-resiniferatoxina em membranas de medula espinhal de rato. A exposição da bexiga isolada de rato ao isotiocianato de alila causou aumento dos níveis de prostaglandina E2 e de substância P na solução nutritiva. A resposta contrátil induzida pela capsaicina ou pelo cinamaldeído na bexiga isolada de rato foi significativamente aumentada em ratos com cistite, em relação aos animais controle. Os resultados in vivo mostraram que, da mesma forma que a capsaicina, a injeção intraplantar de isotiocianato de alila ou cinamaldeído causou nocicepção espontânea dependente da dose em camundongos. A nocicepção induzida pela capsaicina ou pelo isotiocianato de alila foi reduzida pelo vermelho de rutênio ou pela capsazepina, antagonistas não seletivos do receptor TRPV1, mas não pelo antagonista seletivo de receptores NK1, o FK 888. O antagonista seletivo do receptor TRPV1, o SB 366791, inibiu somente a resposta nociceptiva provocada pela capsaicina, mas não aquela provocada pelo isotiocinato de alila. O tratamento neonatal de camundongos com capsaicina atenuou a nocicepção induzida pelo isotiocianato de alila ou pelo cinamaldeído. A degranulação prévia de mastócitos pelo composto 48/80 ou o tratamento com o antagonista de receptores histaminérgico H1 para a histamina, pirilamina, também inibiram de maneira significativa a resposta nociceptiva causada pela capsaicina ou pelo isotiocianato de alila. Em conjunto, estes resultados mostram que o isotiocianato de alila e o cinamaldeído induzem contração da bexiga isolada de ratos e nocicepção espontânea em camundongos. A resposta contrátil da bexiga é dependente de cálcio extracelular e da liberação de taquicininas e prostaglandina E2. Por outro lado, a nocicepção espontânea parece depender da ativação de fibras sensíveis à capsaicina e da liberação de histamina de mastócitos. The present study evaluated by use in vitro e in vivo pharmacological approaches some mechanisms involved in the activation of TRPA1 receptor (transient receptor potential ankyrin-like 1), a member of the TRP (transient potential receptor) ion channel family. Similar to the TRPV1 receptor agonist (transient receptor potential vanilloid 1) capsaicin, the agonists for TRPA1 receptor, allyl isothiocyanate and cinnamaldehyde, caused a external calcium-dependent contraction of rat isolated urinary bladder. This response was susceptible to desensitization. Ruthenium red, a non-selective TRP receptor antagonist, significantly reduced the contractile response induced by capsaicin, allyl isothiocyanate or cinnamaldehyde. The selective TRPV1 receptor antagonist SB 366791 was able to completely inhibit capsaicin-induced contractile response, whereas it partially reduced the effect produced by TRPA1 receptor agonists. In addiction, the contraction induced by allyl isothiocyante was significantly reduced by NK1, NK2 and NK3 tachykinin receptor antagonists, tetrodotoxin, and indomethacin, but not by atropine or suramin. On the other hand, the contraction caused by cinnamaldehyde was inhibited by NK1, NK2 receptors antagonists, tetrodotoxin or indomethacin. In contrast to capsaicin, allyl isothiocyanate and cinnamaldehyde did not interfere with [3H]-resiniferatoxin specific binding sites in membranes of rat spinal cord. The rat isolated urinary bladder exposition to allyl isothiocyanate caused an increase of prostaglandin E2 and substance P levels in nutritive solution. The contractile response induced by capsaicin or by cinnamaldehyde in rat isolated urinary bladder was significantly enhanced in rats with cystitis in relation to control animals. Our in vivo results showed that, similarly to capsaicin, intraplantar injection of allyl isothiocyanate or cinnamaldeyde caused spontaneous and dose-dependent nociception. Capsaicin or allyl isothiocyanate-induced nociception was reduced by ruthenium red or capsazepine, but not by NK1 receptor antagonist FK 888. The selective TRPV1 receptor antagonist SB 366791 inhibited capsaicin-evoked nociceptive response, but not that triggered by allyl isothiocyanate. Neonatal treatment of mice with capsaicin attenuated either allyl isothiocyanate- or cinnamaldehyde-induced nociception. Previous mast cells degranulation by compound 48/80 or the treatment with the H1 histaminergic receptor antagonist pyrilamine also significantly inhibited the nociceptive response caused by capsaicin or by allyl isothiocyanate. Taken together, these results shows that allyl isothiocyanate and cinnamaldehyde induced contraction of rat isolated urinary bladder and spontaneous nociception in mice. The bladder contractile response is dependent on extracellular calcium, tachykinin and prostaglandin E2 release. On the other hand, the spontaneous nociception appears to be dependent on capsaicin-sensitive fibers activation and histamine release from mast cells.
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Bicca, Maíra Assunção. "A participação do receptor TRPA1 na toxicidade induzida por oligômeros de beta-amilóide em diferentes modelos experimentais." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/169100.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2016.Made available in DSpace on 2016-10-11T04:06:44Z (GMT). No. of bitstreams: 1 342201.pdf: 27655060 bytes, checksum: e348dc3bbb9dab5d42edf25140ff44b7 (MD5) Previous issue date: 2016
O receptor TRPA1 pertence à superfamília dos receptores de potencial transitório (TRPs) e está expresso na medula espinhal e em outros tecidos, sendo reconhecido por mediar uma diversidade de processos dolorosos e inflamatórios. A doença de Alzheimer (DA) é uma doença neurodegenerativa caracterizada por acúmulo da proteína Tau e dos peptídeos Aß. A progressão desta doença incurável é diretamente afetada pelos processos de estresse oxidativo e neuroinflamação. Os produtos resultantes do processo inflamatório e oxidativo - como as espécies reativas de oxigênio (EROS) e o Ca+2 em excesso - apresentam-se elevados no início, e durante, a progressão da DA. Destaca-se o fato de que estas moléculas endógenas, também são comprovados agonistas do receptor TRPA1. No entanto, o possível papel do TRPA1 na DA ainda é desconhecido. O objetivo deste trabalho de tese, portanto, foi investigar o possível papel do receptor TRPA1 em diferentes modelos animais relacionados a DA. Utilizamos neste trabalho diferentes abordagens experimentais: cultura de células primárias tratada com AßOs, administração i.c.v. de AßOs em camundongos Swiss, camundongos transgênicos (TG) 5XFAD e cérebros de humanos diagnosticados com a DA, e também, preparações distintas do peptídeo Aß (AßOs40 e AßOs42). Foram realizadas avaliações comportamentais de aprendizado e memória em animais, através do teste do reconhecimento de objetos, e do teste de esquiva passiva step down. Além de, uma variedade de técnicas moleculares e bioquímicas, como por exemplo, a avaliação da formação de EROS, determinação do potencial de membrana mitocondrial, imunocitoquímica, imunofluorescência em fatias de cérebro, western blotting, coimunoprecipitação, microscopia eletrônica de transmissão, entre outras. Os resultados demonstram a ampla expressão de TRPA1 em neurônios e nas microglias no encéfalo de camundongos, destacando ainda, a relevância do TRPA1 para a ligação de AßOs às sinapses, e para a indução do estresse oxidativo e morte neuronal. Os achados evidenciam ainda, a relação entre o acúmulo dos AßOs e a distribuição do TRPA1, em todas as abordagens experimentais utilizadas. Ademais, o aumento da expressão de TRPA1 na microglia e seu possível papel no processo inflamatório. O tratamento por via oral com o antagonista seletivo do TRPA1 (HC030031) apresenta efeito benéfico sobre a perda da memória, nos diferentes modelos animais utilizados neste trabalho, além de, reduzir a quantidade de placas e oligômeros de Aß e consequente melhoria do dano sináptico induzido por AßOs. Baseados nestes dados, sugerimos que o receptor TRPA1 é relevante para a toxicidade induzida por AßOs, sendo este receptor crucial para a patogênese DA e apresentando-se como um potencial novo alvo para o desenvolvimento de fármacos para o tratamento da doença.
Abstract : TRPA1 is a member of the transient receptor potential (TRP) superfamily well known to be expressed in the spinal horn and other tissues, and recognized to mediate a diversity of pain and inflammatory states. Alzheimer's disease (AD) is a degenerative disease characterized by accumulation of both tau and Aß peptides, and for having the disease course affected by progressive oxidative stress and brain inflammation. Products of inflammation, notably reactive oxygen species (ROS) and Ca2+ are augmented during AD initiation and progression. Intriguingly, these are endogenous molecules known to be able to activate TRPA1. However, the possible role of TRPA1 in AD pathogenesis is still unknown and we aimed to investigate it. We used different approaches (primary cell culture treated with AßOs, AßOs-injected Swiss mice, 5XFAD TG AD mouse model and AD human brains; including respective controls to each) and also two distinct preparations AßOs40 and AßOs42. Besides behavioral assessments, a variety of molecular and biochemical techniques, namely the evaluation of ROS formation, mitochondrial membrane potential determination, immunocytochemistry, immunofluorescence in brain slices, western blotting, co-immunoprecipitation, electron microscopy, and others. Here we report TRPA1 is largely expressed in neurons and microglia in the brain. TRPA1 is relevant to AßOs binding and AßOs-induced oxidative stress/death in neuronal cells. We demonstrated the correlation between the up-regulation and spreading of both AßOs and TRPA1, in all the approaches used. Herein, we are also reporting TRPA1 augmented expression in the microglia and its possible role in the inflammation process. Of note, TRPA1 selective antagonist (HC030031) oral treatment improved memory deficits in the different mouse models of approach. Besides, reduced Aß burden in plaques and oligomers with consequent improvement on AßOs-induced synaptic loss. We propose TRPA1 as novel potential target to AßOs-induced toxicity and further memory impairment, being essential to AD pathogenesis.
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Schwarz, Matthias [Verfasser], Peter [Akademischer Betreuer] Reeh, Peter [Gutachter] Reeh, and Michael [Gutachter] Fischer. "Der Einsatz von Antagonisten der TRPA1 und TRPV1 Rezeptoren an menschlichen Probanden zeigt keinen hemmenden Effekt auf durch Säure ausgelösten Schmerz. / Matthias Schwarz ; Gutachter: Peter Reeh, Michael Fischer ; Betreuer: Peter Reeh." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/120463775X/34.
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Pinheiro, Francielle de Vargas. "ENVOLVIMENTO DO RECEPTOR DE POTENCIAL TRANSITÓRIO A1 (TRPA1) EM UM MODELO DE DOR NEUROPÁTICA MANTIDA PELO SIMPÁTICO EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2012. http://repositorio.ufsm.br/handle/1/8981.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorSome forms of neuropathic pain are maintained by sympathetic fibers, but the underlying mechanisms are poorly understood. Thus, the aim of this study was to investigate the possible involvement of the TRPA1 receptor as well as the role of the sympathetic nervous system (involved in sympathetically maintained neuropathic pain) in a model of neuropathic pain induced by chronic sciatic nerve constriction injury (CCI) in mice. The systemic injection of the selective TRPA1 antagonist HC-030031 reversed both mechanical and cold allodynia induced by chronic sciatic nerve constriction injury. Nerve injury also sensitizes mice to the nociception induced by the intraplantar injection of a low dose of the TRPA1 agonist allyl isothiocyanate without changing TRPA1 immunoreactivity in the injected paw. Furthermore, the chemical sympathectomy produced by guanethidine largely prevented CCI-induced mechanical and cold allodynia. CCI also induced a norepinephrine-trigged nociception that was inhibited by α-adrenoceptor antagonism and norepinephrine transporter and monoamine oxidase inhibition. Finally, the peripheral injection of HC-030031 also largely reduced CCI-induced nociception by norepinephrine and mechanical or cold allodynia. Taken together, the present findings reveal the critical role of TRPA1 in mechanical and cold hypersensitivity as well as in hypersensitivity to norepinephrine following nerve injury. This article presents the role of TRPA1 receptor on the sympathetically-maintained nociception induced by nerve injury in mice. Our results suggest that TRPA1 antagonists may be useful to treat neuropathic patients that present sympathetically maintained pain.
Algumas formas de dor neuropática são mantidos por fibras simpáticas, contudo os mecanismos subjacentes são pouco compreendidos. Assim, o objetivo deste estudo foi investigar o possível envolvimento do receptor TRPA1, bem como o papel do sistema nervoso simpático num modelo de dor neuropática induzido pela constrição crônica do nervo ciático (CCI) em camundongos. A administração sistêmica do antagonista seletivo do receptor TRPA1, HC-030031, reverteu a alodinia mecânica e ao frio induzida pela CCI. A injeção de uma baixa dose do agonista do receptor TRPA1, isotiocianato de alila, induziu uma resposta nociceptiva nos animais que sofreram a lesão no nervo, sem alterar a imunorreatividade do TRPA1 na pata injetada. Além disso, a simpatectomia química produzida pela guanetidina amplamente previniu a alodínia mecânica e ao frio induzida pela CCI. Ainda, a injeção intraplantar de norepinefrina induziu nocicepção espontânea, a qual foi reduzida pelo antagonista α-adrenérgico, inibidor do transportador de norepinefrina e inibidor da enzima monoamina oxidase. Finalmente, a administração periférica do HC-030031 reduziu a nocicepção espontânea induzida pela norepinefrina e também a alodínia mecânica e térmica de animais neuropáticos. Assim, nossos resultados revelam o papel crítico do receptor TRPA1 na alodínia mecânica e ao frio, bem como na hipersensibilidade à norepinefrina após lesão do nervo em um modelo de dor neuropática mantida pelo simpático. Dessa forma, o receptor TRPA1 poderá ser um alvo para o desenvolvimento de novos tratamentos para esse tipo de dor.
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Perfoll, Ronaldo. "Envolvimento do receptor de potencial transitório anquirina 1 (TRPA1) na nocicepção e inflamação causadas por lesão térmica em ratos." reponame:Repositório Institucional da UNESC, 2016. http://repositorio.unesc.net/handle/1/4364.
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Dissertação de Mestrado apresentada ao Programa de Pós-Graduação em Ciências da Saúde, da Universidade do extremo Sul Catarinense, UNESC, para obtenção do título de Mestre em Ciências da Saúde.A lesão térmica (queimadura) pode ser causada pela ação direta ou indireta do calor sobre um organismo. Este processo causa o desenvolvimento de inflamação tecidual, levando a hipersensibilidade dolorosa e redução da qualidade de vida dos pacientes. Até o momento, os tratamentos utilizados para tratar esta patologia dolorosa não apresentaram eficácia significativa. Desta maneira, a procura por novos tratamentos baseados em mecanismos inovadores é relevante. O receptor de potencial transitório anquirina 1 (TRPA1) é um canal iônico ativado por substâncias oxidantes (peróxido de hidrogênio) produzidas após lesão tecidual e compostos irritantes naturais (óleo de mostarda). Este canal tem sido estudado como um alvo para a descoberta de novos analgésicos e anti-inflamatórios. No entanto, mesmo que o TRPA1 já tenha sido estudado em diferentes modelos de dor e inflamação, a sua participação em modelos causados por lesão térmica carece de maiores estudos. Assim, o objetivo desta dissertação foi avaliar a participação deste receptor na nocicepção e inflamação provocadas por modelo de lesão térmica em ratos. Para isso foram utilizados ratos Wistar machos (150-300 g). Primeiramente, para escolher a melhor dose do creme não iônico contendo o antagonista TRPA1 (HC-030031, concentrações de 0,5; 0,05 e 0,005%) foi utilizado o modelo de nocicepção causado pela administração subcutânea na pata traseira direita traseira de alil isotiocianato (AITC, 10 nmol/pata, agonista TRPA1). Observou-se que as concentrações de 0,05 e 0,5% mostraram efeito antinociceptivo, então se escolheu a concentração de 0,05% do creme não iônico contendo HC-030031 para desenvolver o modelo de lesão térmica (causado por banho-maria, 70 ºC, 5 segundos, na pata traseira direita). O controle positivo do estudo para o modelo de lesão térmica foi a sulfadiazina de prata a 1%. Os animais foram divididos em Grupo 1 (controle sem tratamento), Grupo 2 (lesão térmica sem tratamento), Grupo 3 (queimadura e aplicação tópica de veículo, creme não iônico), Grupo 4 (queimadura e aplicação tópica de sulfadiazina de prata a 1%), Grupo 5 (lesão térmica e aplicação tópica de HC-030031 a 0,05%). Assim, após aplicação por 6 dias dos tratamentos (1 vez ao dia por via tópica na pata traseira direita) foram avaliadas medidas de nocicepção (alodínia mecânica, estática e dinâmica, alodinia ao calor, dor espontânea, escore facial de nocicepção e edema). No 6º dia foram retiradas amostras da pele da pata traseira direita para determinar parâmetros de inflamação (análise histológica e atividade das enzimas mieloperoxidase e NAGase ), estresse oxidativo (dosagem de peróxido de hidrogênio e medida atividade de enzimas oxidantes - superóxido dismutase e NADPH oxidase) e a imunoreatividade para o receptor TRPA1. Os resultados obtidos mostraram que o creme não iônico contendo HC-030031 apresentou efeito antinociceptivo em relação aos diferentes parâmetros de nocicepção avaliados, semelhantes aos detectados para o creme contendo sulfadiazina de prata. Ainda, o creme não iônico contendo HC-030031 reduziu o edema e a infiltração de células inflamatórias e a atividade das enzimas mieloperoxidase e NAGase . Assim, esta preparação reduziu parâmetros associados à atividade de enzimas oxidantes e a concentração de peróxido de hidrogênio, bem como a expressão do receptor TRPA1 na pele da pata após a queimadura. O creme contendo sulfadiazina de prata apresentou efeito anti-inflamatório, antioxidante, e reduziu a imunoreatividade do receptor TRPA1 no tecido da pele da pata. Dessa forma, o presente estudo buscou determinar no receptor de TRPA1 novas formas de tratamento da dor e inflamação observadas após lesão térmica.