Дисертації з теми "Opioid activity"
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1
McFadyen, Iain James. "Structure-activity relationships of opioid ligands." Thesis, Loughborough University, 1999. https://dspace.lboro.ac.uk/2134/33189.
Повний текст джерелаАнотація:
There are three different types of opioid receptor, namely mu, delta and kappa. Morphine and related clinically useful analgesics exert their actions through the mu opioid receptor. Such compounds represent a huge structural diversity, including both peptides and alkaloids. Nevertheless, there exists a common pharmacophore comprising two critical features, namely an amine nitrogen and an aromatic ring, usually with a hydroxyl substituent; the spatial relationship between them is also vital.
2
Cavagnero, Silvia 1962. "Structure-activity studies of delta-selective opioid analogues." Thesis, The University of Arizona, 1990. http://hdl.handle.net/10150/278183.
Повний текст джерелаАнотація:
The two structurally different peptides DPDPE and Dermenkephalin show a similar remarkably high affinity and selectivity for the delta opioid receptor subtype. An effort has been made to gain some insight into the factors responsible for the recognition ability of these two molecules by synthesizing some DPDPE-Dermenkephalin peptide hybrids and some conformationally restricted Dermenkephalin analogues. The results of the binding and the in-vitro bioassays have been compared with those of the parent peptides. A general decrease in receptor affinity has been observed in the peptide hybrids while the dermenkephalin analogues have shown a wider range of affinities and selectivities. The above findings contribute to the understanding of the structural requirements of the delta receptor, provide information about the sensitivity of Dermenkephalin to enzymatic degradation, and indicate directions for future research.
3
Oakley, Sarah M. "The influence of G-protein coupling of the #delta#-opioid receptor on the activity of #delta#-opioid receptor ligands." Thesis, University of Surrey, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326816.
Повний текст джерела
4
Mathes, Wendy Foulds. "Running wheel activity attenuates the effects of exogenous opiates : implications for the endogenous opioid system /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2000.
Знайти повний текст джерелаАнотація:
Thesis (Ph.D)--Tufts University, 2000.Adviser: Robin B. Kanarek. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 109-134). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
5
Wheeler, Carly. "Understanding physical activity among individuals receiving opioid substitution treatment : a mixed methods study." Thesis, Oxford Brookes University, 2015. https://radar.brookes.ac.uk/radar/items/2a36dac0-b5ad-40ea-b821-e10a95fb5222/1/.
Повний текст джерелаАнотація:
This thesis explores the physical activity (PA) practices and experiences of a group of drug users receiving opioid substitution treatment (OST). Opioid Substitution treatment is the most widely used form of treatment for individuals with opioid dependence. Existing research in this group (and drug users in general) has tended to focus on harmful behaviours, as opposed to their everyday lives. Additionally, a recent shift in UK drugs policy has places an increased emphasis on the wider aspects of recovery from drug use, including the improvement of health, well-being and re- integration into society. Despite the numerous benefits associated with PA, little research has explored PA among individuals receiving OST. The use of a social-ecological approach to guide and understand the research findings was utilized, with both quantitative and qualitative data collected. Self- reported quantitative data was first collected on demographic information, PA participation, perceived benefits and barriers to PA and health-related quality of life from 100 participants. Objective PA data was also collected from a smaller sub- sample of participants through the use of pedometers. Secondly, semi-structured interviews were conducted with 30 participants, to gain further understanding of PA in this group, with the qualitative data analyzed using the Framework approach. Both quantitative and qualitative findings indicate that much of this population is physically active, largely through walking as a form of active transport, with participant in structured sport and exercise occurring less frequently. However, nearly all participants reported previous participation in structured PA prior to drug use and an a desire to resume participation. The benefits of PA participation were unanimously recognized, with perceived barriers to participation highlighted at multiple levels of influence in line with the social-ecological approach used to theoretically underpin the study. While many individuals receiving OST appear to be physically active through unstructured PA, increased participation in structured PA is often desired, yet prohibited through the presence of multiple barriers, some similar to the general population and others specific to this group. Participation in structured PA may yield additional benefits beyond those gained from unstructured activity, contributing to the wider aspects of individuals’ recovery from opioid dependence in line with current UK policy. However, strategies to increase participation may need to consider the multiple needs of this group in addressing barriers to participation.
6
GERHARD, GWENYTH GRAVLIN. "THE RELATIONSHIPS AMONG HABITUAL PHYSICAL ACTIVITY, ENDOGENOUS OPIOID LEVELS, AND SUBSEQUENT ACUTE SURGICAL PAIN EXPERIENCES (ENDORPHIN, VISUAL ANALOG SCALING)." Diss., The University of Arizona, 1985. http://hdl.handle.net/10150/188048.
Повний текст джерелаАнотація:
The purpose of this study was to elucidate relationships among habitual physical activity level, endogenous opioid level, postoperative opioid analgesic, and experiences of acute pain in response to the noxious stimulation of a subsequent orthopedic surgical procedure. Specifically, the study examined (1) the relationship between habitual activity and preoperative level of endogenous opioids in peripheral blood, and (2) whether habitual activity predicts perception of pain intensity or distress in response to a subsequent noxious stimulus. The study utilized a descriptive correlational design with causal modeling methodology to assess a five-stage theory. The convenience sample was comprised of 36 English-speaking adult subjects hospitalized for orthopedic surgeries. The theoretical concepts, acute pain intensity and distress, were indexed three times for each subject by visual analogue scales. Reliability and validity of the scales were assessed by correlation with concurrent pain measurements using randomized verbal descriptor lists. Multiple regression statistical techniques were used to estimate the theory; violations of causal modeling and statistical assumptions were assessed by residual analysis. For this sample, the strongest predictors of postoperative pain were the immediately preceding comparable indices of pain intensity or pain distress. Approximately 31% of the variance on postoperative analgesic was predicted by the combined effects of immediate postoperative pain and habitual activity. Although activity was not significantly related to endogenous opioid level in peripheral plasma, activity directly and positively influenced immediate postoperative pain intensity (Beta = .37), 24-hour pain distress (B = .27), and total opioid analgesic received in the initial 24 postoperative hours (Intensity B = .40; Distress B = .50). Endogenous opioid was significantly related only to immediate postoperative pain distress (B = -.26). More physically active patients reported greater immediate postoperative pain intensity and greater 24-hour pain distress; they received more postoperative exogenous analgesic. Incorporation of information about activity as a potential determinant of operative pain experiences would increase validity of nursing assessments on which pain interventions are based. Patients in acute pain would benefit from this improved scientific basis for pain assessment.
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Corder, Gregory F. "INJURY ESTABLISHES CONSTITUTIVE µ-OPIOID RECEPTOR ACTIVITY LEADING TO LASTING ENDOGENOUS ANALGESIA AND DEPENDENCE." UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/10.
Повний текст джерелаАнотація:
Injury causes increased pain sensation in humans and animals but the mechanisms underlying the emergence of persistent pathological pain states, which arise in the absence of on-going physical damage, are unclear. Therefore, elucidating the physiological regulation of such intractable pain is of exceptional biomedical importance. It is well known that endogenous activation of µ-opioid receptors (MORs) provides relief from acute pain but the consequences of prolonged endogenous opioidergic signaling have not been considered. Here we test the hypothesis that the intrinsic mechanisms of MOR signaling promote pathological sensitization of pain circuits in the spinal cord. We found that tissue inflammation produces agonist-independent MOR signaling in the dorsal horn of the spinal cord, which tonically represses hyperalgesia for months, even after complete recovery from injury and re-established normal pain thresholds. Disruption of this constitutive activity with MOR inverse agonists reinstated pain and precipitated cellular, somatic and aversive signs of physical withdrawal. This phenomenon required N-methyl-D-aspartate receptor activation of calcium-sensitive adenylyl cyclase type 1. Thus, we present a novel mechanism of long-lasting opioid analgesia that regulates the transition from acute to chronic pain while, in parallel, generates physical dependence. In conclusion we propose that the prevalence of chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control.
8
Custodio, Lilian. "SPINAL KAPPA OPIOID RECEPTOR ACTIVITY INHIBITS ADENYLYL CYCLASE-1 DEPENDENT MECHANISMS OF CHRONIC POSTOPERATIVE PAIN." UKnowledge, 2019. https://uknowledge.uky.edu/physiology_etds/42.
Повний текст джерелаАнотація:
Chronic postoperative pain impacts millions of individuals worldwide that undergo a variety of surgical procedures. Opioids remain the mainstay analgesics of acute and perioperative pain; however, prolonged opioid therapy may lead to life-threating adverse effects, tolerance, dependence, and addiction. Therefore, unraveling the cellular mechanisms that drive persistent pain states and opposing endogenous analgesia provided by opioid receptor signaling, may lead to novel analgesics. Evidence suggests that tissue injury leads to increased sensitization of the spinal cord nociceptive neurons which increases susceptibility to chronic pain via an N-methyl-D-aspartate (NMDA) receptor activation of calcium-sensitive adenylyl cyclase isoform 1 (AC1). This phenomenon, named latent pain sensitization (LS), is mediated by a compensatory response of endogenous inhibitory systems.
In this dissertation, we test the hypothesis that surgical insult promotes prolonged activation of kappa opioid receptors (KOR) which mask LS via attenuation of pro-nociceptive AC1 signaling pathways in both male and female animals. We employed a murine model of chronic postoperative pain that promotes LS in the spinal cord and closely resembles the phenotypic features of postoperative pain in human subjects. When behavioral signs of hyperalgesia resolved, we targeted spinal opioid receptor systems and pronociceptive modulators with intrathecal delivery of selective pharmacological antagonists and assessed behavioral signs of hyperalgesia and spinal nociceptive sensitization. We propose that LS is kept in remission by a long-lasting compensatory response of tonic endogenous KOR signaling that hinders a pronociceptive LS pathway that includes not only AC1 but also two downstream targets: protein kinase A (PKA) and exchange protein activated by cAMP (Epac1/2) - in a sex-dependent manner. Our results propose new therapeutic targets for the management of persistent postoperative pain and underscore the importance of tailoring sex-specific pain management strategies.
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Pettinger, Louisa. "Effects of bradykinin on [delta]-opioid receptor function and voltage-gated calcium channel activity in sensory neurons." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588749.
Повний текст джерелаАнотація:
The δ-opioid receptor (DOR) shows potential as a therapeutic target for analgesia. DOR-targeting pharmaceutics may lead to fewer side effects than conventional opioid drugs such as morphine due to relatively low expression of DOR in the central nervous system (compared to the main target for morphine, the u-opioid receptor). The analgesic efficacy of DOR agonists increases following inflammation and receptor insertion has been suggested as a possible mechanism for this. Modulation of membrane expression of functional DOR receptors may be useful in the development of analgesic drugs. Currently, expression of functional DOR at the membrane of sensory neurons is controversial. Here, patch-clamp recordings and total internal reflection fluorescence (TIRF) microscopy have been used to study functional expression and trafficking of DOR in sensory neurons from rat trigeminal ganglia (TG). In addition, the role of inflammatory mediator bradykinin (BK) in DOR membrane expression has been investigated. To determine whether neurons express functional DCR, inhibition of voltage-gated Ca2+ channels (VGCC) by DCR agonist [D-Ala2, D- Leu5]-Enkephalin (DADLE) was determined. DADLE inhibited VGCC in 23% of TG neurons by 25.3 ± 5%. Pre-treatment with BK increased the population of DCR-positive neurons to 54%, but did not significantly affect the degree of VGCC inhibition by DADLE. Real-time TIRF microscopy revealed that BK treatment caused robust trafficking of DCR to the plasma membrane in neurons transfected with GFP-tagged DOR. In contrast, DADLE and TRPV1 agonist capsaicin caused a decrease in membrane abundance of DOR, suggesting internalisation of the receptor. In Ca2+ imaging experiments 80% of cultured TG neurons responded to BK, thus, these data suggest that a majority of BK-responsive TG neurons have the potential to become DOR-positive upon inflammation, re-establishing the therapeutic potential of peripheral DOR. In a separate line of investigation, enhancement of T-type VGCC in nociceptive neurons by BK has been discovered.
10
Ramos-Colon, Cyf Nadine, and Cyf Nadine Ramos-Colon. "Design, Synthesis, and Biological Evaluation of Novel Peptide Ligands as Kappa Opioid Receptor Antagonists." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/621869.
Повний текст джерелаАнотація:
Millions of people in the US currently suffer from chronic pain but available therapeutics do not provide effective chronic pain treatment. Opiate therapy is still the gold standard for chronic pain management with detrimental side effects, such as tolerance, addiction, constipation, and respiratory depression that limit their therapeutic potential. Opiates exert their positive and negative effects by activating the μ opioid receptor (MOR). Conversely, the κ opioid receptor (KOR) has been shown to modulate the tolerance and addiction produced by MOR agonists and is also involved in mood modulation (anxiety and depression). Therefore, blocking KOR activation results in positive effects against opiate side effects and stress-related depression. Dynorphin A (Dyn A) is the endogenous opioid peptide for the KOR. Structure-activity relationship (SAR) studies were carried out to develop a KOR selective antagonist based on the Dyn A structure. A minimum Dyn A pharmacophore with improved stability, no cell toxicity, and antagonist activity was discovered. Peptidomimetic enkephalin analogues previously developed in our group as MOR and δ opioid receptor (DOR) agonists have shown multifunctional activity, with MOR/DOR agonist and KOR antagonist activities. To our knowledge, this finding is first of its class for the opioid receptors. Novel design and synthesis of KOR selective ligands based on our multifunctional enkephalin analogues was done. Successful peptide synthesis resulted in analogues with high stability in rat plasma and no cell toxicity.
11
Dalton, George D. "The Study of the Effect of Drugs of Abuse on Protein Kinase A Activity in Mouse Brain and Spinal Cord." VCU Scholars Compass, 2005. http://scholarscompass.vcu.edu/etd/1527.
Повний текст джерелаАнотація:
Morphine and Δ9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and Δ9-THC produces problematic side-effects including tolerance and physical dependence. The cellular mechanisms underlying opioid and cannabinoid antinociceptive tolerance have been studied for years. Research has demonstrated that the expression of morphine and Δ9-THC antinociceptive tolerance may be mediated through intracellular signaling pathways, such as the adenylyl cyclase /Protein Kinase A (PKA) cascade. The present study investigated the role of PKA in the expression of morphine and Δ9-THC antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or Δ9-THC and the warm-water tail-flick test was used to assess antinociception. These studies revealed that the level and the duration of morphine antinociceptive tolerance both influenced whether PKA activity was increased in mouse brain and spinal cord. Cytosolic PKA activity was increased in the thalamus of 3-day morphine-tolerant mice expressing a 45-fold level of tolerance, but not in mice that expressed a 10-fold level of tolerance. In addition, cytosolic PKA activity was increased in the lumbar spinal cord (LSC) of 15-day morphine-tolerant mice. However, chronic treatment with A9-THC had no effect on neuronal PKA activity even in mice that expressed a high level of antinociceptive tolerance. The absence of an effect of chronic treatment with A9-THC on neuronal PKA activity was supported by the development of a positive control in which the PKA activator Sp-8-Br-cAMPS was administered intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in drug-naYve mice and increases in PKA activity were observed in several brain regions and LSC. Finally, the i.c.v. injection of two peptide fragments of native Protein Kinase A inhibitor (PKI) peptide, PKI-(6-22)-amide and PKI-(Myr- 14-22)- amide, significantly reversed antinociceptive tolerance in mice treated chronically with morphine. PKI-(6-22)-amide (i.c.v.) also inhibited PKA activity in brain regions (thalamus, periaqueductal gray (PAG), and medulla) and LSC, which studies have shown play a role in morphine-induced analgesia. Moreover, PKI-(6-22)-amide reduced the increase in PKA activity in thalamus and LSC observed with chronic morphine treatment. Overall, these studies provide evidence that PKA plays a role in morphine tolerance, but not Δ9-THC tolerance at the doses and times tested.
12
Zavala, Arturo Rubin. "The effects of lesions to the superior colliculus and ventromedial thalamus on [kappa]-opioid-mediated locomotor activity in the preweanling rat." CSUSB ScholarWorks, 2003. https://scholarworks.lib.csusb.edu/etd-project/2404.
Повний текст джерелаАнотація:
The purpose of this thesis was to determine the neuronal circuitry mediating U50,488-induced locomotion in preweanling rats. To this end, preweanling rats received bilateral electrolytic lesions of the ventromedial thalamus or superior colliculus and, two days later, the same rats received a challenge injection of U50,488. It was predicted that bilateral lesions of the ventromedial thalamus or superior colliculus would attenuate the U50,488-induced locomotor activity of 18-day-old rats.
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Maia, Juliana Lemos. "Estudo da atividade antinociceptiva e possÃveis mecanismos de aÃÃo do Ãcido oleanÃlico em modelos de nocicepÃÃo induzida por capsaicina e Ãleo de mostarda em camundongos." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4511.
Повний текст джерелаАнотація:
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoO Ãcido oleanÃlico à um triterpeno pentacÃclico largamente encontrado em vÃrias plantas medicinais. Essa substÃncia demonstrou ter uma variedade de atividades farmacolÃgicas, dentre as quais se destacam: antiinflamatÃria, hepatoprotetora, gastroprotetora e antinociceptiva. Este trabalho objetivou investigar a atividade antinociceptiva do Ãcido oleanÃlico em modelos de nocicepÃÃo aguda induzida por capsaicina (20Âl/ 1,6 μg) e Ãleo de mostarda (0,75%, 50 ÂL/animal) em camundongos, alÃm dos possÃveis mecanismos de aÃÃo envolvidos. Camundongos foram prÃ-tratados com Ãcido oleanÃlico (3, 10, 30, 100 mg/kg, v.o.) ou veÃculo, e os comportamentos de dor foram analisados. As doses de 10, 30 e 100 mg/kg, v.o., foram capazes de reduzir os comportamentos dolorosos expressos pelos animais nos modelos de nocicepÃÃo induzida por capsaicina e Ãleo de mostarda, sendo o maior nÃvel de inibiÃÃo (p<0,001) encontrado na dose de 30 mg/kg. Na tentativa de desvendar os possÃveis mecanismos de aÃÃo do Ãcido oleanÃlico no modelo de nocicepÃÃo induzido por capsaicina, avaliamos a participaÃÃo dos receptores opiÃides, α2, Ãxido nÃtrico e canais de potÃssio. O efeito antinociceptivo do Ãcido oleanÃlico (30 mg/kg, v.o.) foi significantemente revertido pelo prÃ-tratamento com antagonista opiÃide, naloxona (2 mg/kg, i.p.); pelo doador de Ãxido nÃtrico, L-arginina (600 mg/kg, i.p.) e pela glibenclamida (2 mg/kg, i.p.), um antagonista dos canais de potÃssio. Por outro lado, o prÃ-tratamento com um antagonista α2, ioimbina (2 mg/kg, i.p.), nÃo ocasionou a reversÃo da antinocicepÃÃo. Na tentativa de desvendar os possÃveis mecanismos de aÃÃo do Ãcido oleanÃlico no modelo de nocicepÃÃo visceral induzida por Ãleo de mostarda, avaliamos a participaÃÃo dos receptores opiÃides, α2 e TRPV1. O efeito antinociceptivo do Ãcido oleanÃlico (30 mg/kg, v.o.) foi significantemente revertido (p<0,05) pelo prÃ-tratamento com antagonista opiÃide, naloxona (2 mg/kg, i.p.), enquanto que o antagonista α2 , ioimbina (2 mg/kg, i.p.), nÃo teve o mesmo efeito. O prÃ-tratamento com vermelho de rutÃnio (3 mg/kg, s.c.), um antagonista nÃo competitivo do receptor TRPV1 causou inibiÃÃo significativa da nocicepÃÃo (p<0,01) induzida pelo Ãleo de mostarda, entretanto a administraÃÃo conjunta com o Ãcido oleanÃlico nÃo produziu antagonismo nem potenciaÃÃo da antinocicepÃÃo causada pelo Ãcido oleanÃlico. Para avaliar a existÃncia de um impedimento locomotor ou de uma incoordenaÃÃo motora, foram utilizados os testes do campo aberto e o teste do rota rod, respectivamente. Os dados indicaram que o tratamento com o Ãcido oleanÃlico (30 mg/kg, v.o.) nÃo induziu (p>0,05) impedimento locomotor ou incoordenaÃÃo motora nos animais, sendo ainda capaz de reverter (p<0,05) o impedimento locomotor induzido pelo Ãleo de mostarda no teste do campo aberto. Em conjunto os dados revelaram a efetividade do Ãcido oleanÃlico em modelos de nocicepÃÃo possivelmente envolvendo receptores opiÃides, TRPV1, Ãxido nÃtrico e canais de potÃssio.
Oleanolic acid is a triterpene pentacyclic widely distributed in the plant kingdom. Different biologic activities have been reported including: antiinflammatory, hepatoprotective, gastroprotective and antinociceptive. This work was aimed to evaluate the antinociceptive effect of oleanolic acid in acute nociception models induced by capsaicin (20Âl/ 1.6 μg) and mustard oil (0.75%, 50 ÂL/animal) in mice and to establish the likely mechanism(s) of action. Mice were pretreated orally with oleonolic acid (3, 10, 30 and 100 mg/kg) or vehicle, and the pain-related behavioral responses were analysed. The pain behavioral responses were significantly suppressed at doses 10, 30 and 100 mg/kg in acute nociception models induced by capsaicin and mustard oil. The maximal suppression (p<0.001) was observed at the dose of 30 mg/kg. In order to verify the possible mechanisms involved in the antinociceptive action of oleanolic acid in the capsaicin-induced nociception, the involvement of endogenous opioids, α2, nitric oxide and KATP channels were analyzed. The antinociception produced by OA (30 mg/kg, v.o.) was found to be significantly blocked in animals pre-treated with the opioid antagonist, naloxone (2 mg/kg, i.p.); the substrate for oxide nitric synthase, L-arginine (600 mg/kg, i.p.); or a KATP-channel blocker, glibenclamide (2 mg/kg, i.p.) but was unaffected by yohimbine (2 mg/kg, i.p.), an α2 -adrenoceptor antagonist. In order to verify the possible mechanisms involved in the antinociceptive action of oleanolic acid in the mustard oil-induced visceral pain model, opioid, α2 adreno and TRPV1 receptors were analyzed. The antinociceptive effect of oleanolic acid (30 mg/kg, v.o.) was significantly blocked (p<0.05) by pretreatment with the opioid antagonist, naloxone (2 mg/kg, i.p.), but the α2-adrenoceptor antagonist, yohimbine (2 mg/kg, s.c.), had no effect. Pretreatment with ruthenium red (3 mg/kg, s.c.), a non-competitive TRPV1 antagonist alone caused significant inhibition (p<0.01) of mustard oil-induced nociception but its co-administration with oleanolic acid produced neither antagonism nor potentiation of oleonolic acid antinociception. Further, to evaluate a possible motor impairment and motor incoordination effects related to oleanolic acid, open-field and rota-rod tests were performed. The data indicated that the treatment of animals with the oleanolic acid (30 mg/kg, v.o.) was unable to cause motor impairment or motor incoordination effects (p>0.05), being even able to reverse (p<0.05) a mustard oil-induced motor impairment in the open field test. The results taken together strongly suggest the therapeutic potential of oleanolic acid in oblitering nociception through the mechanisms that possibly involve the opioids, TRPV1 receptors, nitric oxide and KATP channels.
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Hall, Sara M. "Bradykinin Ligands and Receptors Involved in Neuropathic Pain." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/578606.
Повний текст джерелаАнотація:
Neuropathic pain is a prevalent disease with no effective, safe treatments and limited knowledge on the mechanisms involved. One target for neuropathic pain treatment may be the blockade of Dynorphin A (Dyn A). Dyn A is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors and neuroexcitatory effects that are mediated through the bradykinin 2 receptors (B2Rs). Extensive SAR was carried out to develop a ligand for the blockade of the excitatory actions of Dyn A at the B2R. A lead ligand was able to block Dyn A-induced hyperalgesia in naïve animals and was effective in a neuropathic pain model. However, the ligand was susceptible to enzymatic degradation. In an effort to increase the stability, modifications of the ligand using non-natural amino acids were performed. Analogues substituted at or near the N-terminus with a D-isomer retained binding at the receptor as well as provided a large increase in stability. These ligands were also found to be non-toxic in a cell toxicity assay. Dyn A has been found to not activate the classical signaling of the B2R, PI hydrolysis or Ca²⁺ mobilization. In an effort to determine Dyn A's signaling, a study was done examining up-regulation of phosphorylated proteins. It was found that Dyn A did not activate; pERK, 7 PKC isoforms or PKA. A well known B2R antagonist, HOE140, was found to have low affinity at rat and guinea pig brain B2Rs but high affinity in the guinea pig ileum. Further examination revealed that this discrepancy in binding may arise from a different isoform of the B2R that has not been previously examined. To date, we have discovered Dyn A analogues that have high affinity for the B2R, are very stable, and have low toxicity. The signaling pathway is still not fully understood, but further studies are underway. Also, there is evidence that the B2R in which the analogues are interacting at may be a different form than what has previously been described. Targeting this different isoform of the B2R with our current stable ligands may provide beneficial therapeutics for the treatment of neuropathic pain without the cardiovascular liabilities.
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Benedito, Rubens Batista. "Estudo do mecanismo de ação antinociceptivo e avaliação histopatológica cerebral do (S)-(-)-álcool perílico em camundongos." Universidade Federal da Paraíba, 2013. http://tede.biblioteca.ufpb.br:8080/handle/tede/6802.
Повний текст джерелаАнотація:
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The perillyl alcohol (p-mentha-1,8-diene-7-ol) is a member of the family of monoterpenes found in plants of the genus Lavandula, Mentha, Cymbopogon, among others. It is known that perillyl alcohol (AP) has antinociceptive activity, but its mechanism of action remains unknown. In the present study was investigated the possible mechanism of action of PA using pharmacological antagonists and in vitro, and evaluated the histological level neurotoxicity in the hippocampus and striatum. The test of writhing induced by acetic acid was the protocol of choice for testing the monoterpene at a dose of 100 mg/kg against antagonists. The results show a reversal of the antinociceptive effect of PA (PA 3,4 ± 1,7 writhing) after pretreatment with naloxone (NLX+PA 10,4 ± 2,3 writhing) indicating the participation of the opioid system in its mechanism of action. Unlike naloxone, antagonists, muscarinic (atropine), adenosinergic (caffeine), dopamine (sulpiride), L-arginine - L-NNA and glibenclamide, were not able to reduce the effect of the PA front abdominal writhing. In the evaluation of in vitro antioxidant activity of the PA, three methodologies were employed, one to evaluate the effect of PA on lipid peroxidation in TBARS test and the other two to investigate its action as substance radical scavenging OH and NO. In all tests, the PA showed antioxidant activity, reducing by 70% the production of free radicals. As for histopathological evaluation, the PA did not cause significant tissue changes in both brain areas studied. Therefore, the results obtained in this study demonstrate that perillyl alcohol has an antinociceptive effect mediated by the opioid system and antioxidant mechanisms, without the direct participation of muscarinic systems, adenosinergic, dopaminergic, K+ATP channels and via L-arginine nitric oxide. The monoterpene also did not show significant neurotoxicity.
O álcool perílico (p-mentha-1,8-diene-7-ol) é um membro da família dos monoterpenos encontrado em plantas dos gêneros Lavandula, Mentha, Cymbopogon, entre outros. É sabido que o álcool perílico (AP) possui atividade antinociceptiva, porém seu mecanismo de ação ainda permanece desconhecido. No presente trabalho foi investigado o possível mecanismo de ação do AP utilizando antagonistas farmacológicos e testes in vitro, e avaliada a neurotoxicidade histológica à nível do hipocampo e corpo estriado. O teste das contorções abdominais induzidas pelo ácido acético foi o protocolo de escolha para testar o monoterpeno na dose de 100 mg/kg frente aos antagonistas. Os resultados mostram uma reversão do efeito antinociceptivo do AP (AP 3,4 ± 1,7 contorções) após o pré-tratamento com a naloxona (NLX+AP 10,4 ± 2,3 contorções) indicando a participação do sistema opioide no seu mecanismo de ação. Diferentemente da naloxona, os antagonistas, muscarínico (atropina), adenosinérgico (cafeína), dopaminérgico (sulpirida), a L-arginina - L-NNA e a Glibenclamida, não foram capazes de reduzir o efeito do AP frente às contorções abdominais. Na avaliação da atividade antioxidante in vitro do AP, foram empregadas três metodologias, uma para avaliar o efeito do AP sobre a peroxidação lipídica, no teste de TBARS, e as outras duas para investigar sua ação como substância sequestradora de radicais livres OH e NO. Em todos os testes, o AP demonstrou atividade antioxidante, reduzindo em até 70% a produção de radicais livres. Quanto à avaliação histopatológica, o AP não provocou alterações teciduais significativas nas duas áreas cerebrais estudadas. Portanto, os resultados demonstram que o álcool perílico apresenta um efeito antinociceptivo mediado pelo sistema opioide e por mecanismos antioxidantes, sem a participação direta dos sistemas muscarínico, adenosinérgico, dopaminérgico, dos canais para K+ATP e da via L-arginina óxido nítrico. O monoterpeno também não apresentou neurotoxicidade significativa.
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Al-Deeb, Omar A. A. "On the investigation of the synthesis, stereochemistry and structure-activity relationship of opioid ligands related to 4-aryl-1-methylpiperidines and phencyclidine." Thesis, University of Bath, 1989. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760592.
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Kazmierski, Wieslaw Mieczyslaw. "Synthesis and hydrogen-1 NMR conformational analysis of potent and mu opioid receptor selective cyclic peptides: Topographical design utilizing a conformationally stable template." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184454.
Повний текст джерелаАнотація:
There is a dogma in molecular biology that biological functions of peptides are determined by their structure ("function" code), coded in their primary structure ("structure" code). This work describes a new approach that attempts to elucidate these relationships by peptide topology design based on intriguing conformational properties of pipecolic acid based amino acids--like 1,2,3,4 tetrahydroisoquinoline (Tic). Opioid peptides, owing to the heterogeneity of opioid receptors, display a wide variety of physiological actions. The mu opioid receptor selective octapeptide I (D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂) is a model compound for topographical modifications induced by sequential substitutions by Tic residue. Thus, the closely related peptides I and II (Gly-D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂, obtained by coupling Gly residue to I) have contrasting affinities for the mu opioid receptor (IC₅₀ = 1.2 and 278 nM, respectively). Conformational analysis of I and II by means of 1D and 2D ¹H NMR spectroscopy allowed to determine dramatic differences in the side chain orientation of D-Tic in both peptides and to propose features of the bioactive conformation. The extended conformation of I (due to g(-) side chain conformation of D-Tic) is well recognized by the mu receptor in contrast to the folded conformation of II (due to a g(+) side chain conformation of D-Tic¹, that places the aromatic ring on the opposite side of the molecule), which is not. Peptide III (D-Phe-Cys-Tic-D-Trp-Orn-Thr-Pen-Thr-NH₂), featuring replacement of Tyr³ by Tic³, binds very weakly to the mu opioid receptor, due to rotation of the Tic aromatic side chain to the opposite side of the molecule (Tic side chain is in a g(+) conformation again). As these substitutions conserve the conformation of the backbone, constrained cyclic amino acids (picolic acid derivatives) can modify the topography of the peptide in a predictable manner, and (in conjunction with biological data) disclose structural elements of bioactive conformations. The mechanisms of pipecolic acid side chain rotamer selection, will be discussed in the context of design principles.
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LI, YINGXUE. "DESIGN, SYNTHESIS, AND CHARACTERIZATION OF HELICAL OPIOID GLYCOPEPTIDE AGONISTS: THE STUDY OF THE STRUCTURE-ACTIVITY RELATIONSHIP AND TRANSPORT OF GLYCOPEPTIDES RELATED TO BETA-ENDORPHIN AND DYNORPHIN." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/203033.
Повний текст джерелаАнотація:
Structure-activity relationships (SAR) of opioid peptide analogues related to endorphin or dynorphin have provided rational and powerful approaches toward the design of peptide therapeutics. A series of glycosylated β-endorphin analogues were designed by modifying the N-terminal “message domain,” the C-terminal “address domain,” and the “linkage domain” between the two, and by altering the intrinsic helix stability of the amphipathic helix that comprises the “address domain.” Further changes were accomplished by altering the charged groups on the side chains of the “address region.” The unglycosylated peptide homologues and variations of the saccharide moieties (monosaccharides vs disaccharides) were also studied. The β- endorphin glycopeptide analogue ¹Tyr- ᵐD-Thr- ³Gly- ⁴Phe- ⁵Leu- ᴸPro- ⁷Asn- ⁸Leu- ʰAib ᶜGlu- ᶜLys- ʰAla- ¹³Leu- ᶜLys-¹⁵Ser[β-O-Glucose]- ¹⁶Leu-NH2, was modified at the indicated positions (m, h, c), and in collaboration with the Bidlack Lab at the Rochester Medical Center, binding affinities Kᵢ were measured using human opioid receptors expressed in CHO cells. All the peptides and glycopeptides were panagonists, showing low nanomolar affinity for the μ, δ and κ-opioid receptors. Helix stability was varied by substituting ʰAib, ʰAla, and ʰGly, which altered membrane affinity, which was correlated with helix stability. Charges on the address side chains were varied by substituting ᶜAsn, ᶜGlu, and ᶜLys. The 15Ser residue bore either a β- Lactoside, a β-D-glucoside or was unglycosylated. These peptides and glycopeptides were studied by circular dichroism (CD) and by 2D-NMR in H₂O buffer (pH = 5.5), in 30% trifluoroethanol in H₂O, and in H₂O containing SDS micelles as a model for biological membranes. In H₂O the glycopeptides and peptides showed only nascent helix behavior and random coil conformations. Chemical Shift Indices (CSI) and nuclear Overhauser effects (NOE) confirmed the helical nature of the “address domains” in the presence of SDS micelles (membrane mimics). Detailed backbone conformations were determined using distance constraints provided by NOE volumes. Based on the CD experiments, most of the β-endorphin analogues showed substantial amounts of helicity in the presence of membrane bilayer models. Several glycopeptides demonstrated penetration of the Blood Brain Barrier (BBB), and produced potent antinociceptive effects in mice after intravenous (i.v.) injection. The amphipathic address domain played a major role in BBB penetration, as reflected by the i.v. activities. The linker also had profound effects on the SAR, and it was possible to produce antinociceptive glycopeptides. In summary, we suggest that this biousian nature is essential for glycopeptides to maintain bioactivities, and the longer, more flexible linkages GABA and DAVA were able to mediate two interactions having lower energy, one interaction between the message segment and opioid receptor’s binding pocket, and another one between the address segment and the cell membrane, to result in higher binding affinities to all three opioid receptors, and significantly increasing analgesia after both i.c.v and i.v. administration. The cyclic linkers restricted D- and L-Pro on the orientation of message segment, relative to the membrane.
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Beane, Amber. "Health and Academic Achievement in College and University Students." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3702.
Повний текст джерелаАнотація:
The purpose of this non-experimental quantitative correlational study was to investigate the relationship between academic achievement and health in a national sample of college students using quantitative data analysis. Specifically, the researcher analyzed the relationship between three health-promoting behaviors (physical activity, strength training, and fruit and vegetable consumption), three negative health behaviors (cigarette, e-cigarette, and opioid use) and obesity with GPA.
Cross-sectional data on student health collected from the American College Health Association’s National College Health Assessment II (ACHA-NCHA-II) and completed by 426,650 college students from 650 U.S. colleges during the semesters between 2015 and 2019 formed the foundation for this research. Nine research questions were addressed using a series of chi square tests.
Results showed there was a significant positive relationship between health behaviors and grade average. Students who met the recommendations for fruit and vegetable consumption, moderate activity and vigorous physical activity were more likely to have GPAs than those who did not. Students who used cigarettes, opioids, or were obese were more likely to have GPAs.
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Herlenius, Eric. "Respiratory activity in medulla oblongata and its modulation by adenosine and opioids /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3240-9/.
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Ma, Daqing. "The effects of anaesthesia on sympathetic activity, somatosympathetic reflexes and associated haemodynamic and respiratory changes." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313600.
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Tseng, Raymond J. "Stress-induced suppression of natural killer cell activity during influenza viral infection the role of glucocorticoids and opioids /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1148586277.
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Zullig, Kelly. "THE EFFECTS OF ORPHANIN FQ/NOCICEPTIN (OFQ/N) DELETION ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS ACTIVITY AND PROLACTIN RESPONSE TO STRESS." Miami University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=miami1218130798.
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Alexander-Goreá, Trenika. "Development of a Guideline for Hospice Staff, Patients, and Families on Appropriate Opioid Use." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/4496.
Повний текст джерелаАнотація:
There is an identified problem with patients receiving suboptimal pain management at a hospice agency in the northwestern United States. At this agency, undertreatment of pain is prevalent. Evidence indicates that this may be a result of a lack of guidelines, education, and knowledge of appropriate prescribing. Known barriers to the correct prescription and administration of potent opioids in the hospice setting include prevailing beliefs, knowledge, skills, and attitudes, all of which can impact care negatively. Contextually, hospice principles mandate patient comfort and caregiver involvement in continuous quality improvement, which includes adequate and informed pain management. Moreover, hospice metrics demand requisite knowledge, skills, and attitudes for optimal care, including pain management at the end of life. The Academic Center for Evidence-Based Practice (ACE) star model was used to guide the development of an evidence-based, guideline-supported educational program that will improve pain management at the hospice agency when implemented. The purpose of this project was to use transdisciplinary expertise and team collaboration to develop the program and then to conduct a formative and summative evaluation utilizing experts to prepare the guidelines and process for implementation. Ten experts reviewed the guideline, the educational materials, the process, and the evaluation plan and conducted reviews using the AGREE II tool. The panel of experts agreed within the 6 AGREE domains. Future implementation of this guideline, translation process, and evaluation tool will impact social change through the empowerment of the clinical staff, patients, and caregivers to provide the best pain control and comfort at end of life, a vulnerable time for all patients.
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Traverse, Bastien Roger Marcel. "Activité cérébrale du système opioïde chez les sportifs d'endurance et l'anorexie mentale : Etudes TEP à la [11C]-diprénorphine." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSES003.
Повний текст джерелаАнотація:
Le travail présenté dans cette thèse s’attache à démontrer le rôle central joué par le système opioïde dans le développement et le maintien de deux modèles d’addictions comportementales : l’anorexie mentale et l’addiction au sport.Il présente une approche originale, multidisciplinaire et transverse utilisant des techniques modernes et novatrices, avec pour procédé central une imagerie cérébrale TEP/TDM utilisant de la [11C]-diprénorphine comme traceur. Cherchant à obtenir une imagerie en densité de récepteurs opioïdes, une modélisation SRTM a été utilisée. Les images en densité de récepteurs ainsi obtenues ont été exploitées par analyse voxel à voxel sous SPM12. Ces comparaisons statistiques paramétriques ont également intégré plusieurs variables, covariables et paramètres de régressions issus d’analyses complémentaires (tests psychométriques, mesures anthropométriques et analyses biologiques, notamment des dosages d’opioïdes en circulation périphérique mesurés par une technique ELISA).Ces analyses ont démontré la complexité du mécanisme addictif dans ces deux modèles, avec un rôle indirect du système opioïde probablement par modulation du circuit dopaminergique de la boucle méso limbique du circuit de la récompense. Cependant les nombreuses divergences entre ces deux addictions comportementales et les hétérogénéités retrouvées entre les individus montre aussi l’existence d’une sensibilité et de mécanismes variables d’une personne à l’autre, posant la question du phénotypage et de la génétique, et ouvrant le champ à de nouvelles études, avec à terme de possibles répercussions cliniques voire thérapeutiquesThis thesis aims to demonstrate the central role of opioid system in developing and maintaining addiction in two behavioural addiction models: sport addiction and anorexia nervosa.It presents an original, multidisciplinary and transversal approach using modern and innovative tools, with a brain imagery using [11C]-diprenorphine PET-scan as main process. We attempt to get receptor density mapping using a SRTM model. Images obtained by this way were then exploited by voxel-based analysis using SPM12. Statistical parametric comparisons include several variables, covariables and regression parameters extracted from complementary exams (psychometric tests, anthropometric measurements, biological samplings especially peripheric circulating opioids assessment by ELISA technic).These analyses demonstrate the complexity of addictive mechanisms in these two models, with an indirect role of opioid system which seems to work by modulation of dopaminergic mesolimbic reward system. However, we also find several differences and inhomogeneities in these two behavioural addictions which indicate existence of various sensitivity and different mechanisms among subjects. This asks the question of phenotyping and genetics underlying these phenomena, needing new studies with a long-term perspective of clinical and therapeutic possibilities
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Robichon, Alain. "Photoaffinité des récepteurs opioides U et D et du récepteur au VIP (vasoactive intestinal peptide)." Paris 6, 1987. http://www.theses.fr/1987PA066605.
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Kulkarni, Sandhya N. "Synthesis and opioid activity of dynorphin analogues with the modifications in the message sequence." Thesis, 1995. http://hdl.handle.net/1957/34920.
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Snyder, Kristin Renee. "Synthesis and opioid activity of dynorphin a analogues." Thesis, 1993. http://hdl.handle.net/1957/35936.
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Hall, Arleen Martha. "Opioid involvement in epileptogenic activity and gastrointestinal pathogenesis." 1990. http://hdl.handle.net/1993/17025.
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Wu, Yng-Ching, and 吳盈清. "Structure-Activity Relationships of Opioid Ligands:A Molecular Dynamics Study." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/53403459960181750717.
Повний текст джерелаАнотація:
博士國立成功大學
工程科學系碩博士班
96
The dissertation directs on studying the structure-activity relationships of the various opioid ligands using molecular dynamics simulations and AM1 calculations in order to understand the mechanisms of the active binding interactions between opioid receptors and ligands. It is clear known that morphine is widely used in medicine as strong analgesics for relief of severe pain. Yet, it may cause addiction and withdrawal symptoms as well as other harmful effects. Therefore, since the endogenous opioid peptide of the enkephalin was discovered corresponding to the opioid receptor, the efforts of developing the new analgesic drugs have been toward minimizing a risk of addiction and reducing adverse side effects. Due to the existence of the opioid system in humans, in terms of its functions not only possess analgesia, sedation, and euphoria, but influence of the psychological and physiological levels involve the emotion, memory, and recognition. All of the above-mentioned functions result from a series of biochemical regulations after the binding interactions between opioid receptors and their ligands. Because opioid receptors are large membrane proteins, difficult to study by standard structural techniques. Thus, conformational studies of opioid peptides are still important for drug design and also for indirect receptor mapping. We first introduce a number of backgrounds for opioid receptors and opioid ligands. Subsequently, the structure-activity relationships of δ-, κ- and μ-selective opioid ligands are studied. We hope such investigations can let us more understand the structure-activity relationships of opioid system. In this dissertation, we have well defined the pharmacophore model of κ- and μ-opioid receptor, respectively. These significant results have compared to δ pharmacophore model. Finally, the results of this dissertation will provide some valuable information for drug design and clinical therapy.
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Cai, Ya-Jing, and 蔡雅菁. "Synthesis and Opioid Activity of 1', 3'-Disubstituted Spiro[7-." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/74468078105288578008.
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Tsai, Ya-Ching, and 蔡雅菁. "Synthesis and Opioid Activity of 1', 3'-Disubstituted Spiro[7-." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/83781498713901352434.
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Cheung, Pak Ho Paul. "The antiarrhythmic activity of ±-opioid agonist RSD 939 is unrelated to ±-agonism." Thesis, 1994. http://hdl.handle.net/2429/5201.
Повний текст джерелаАнотація:
Cumulating evidence have indicated that various opioid agonists
and antagonists, especially kappa (ic) agonists, can exhibit a variety of
cardiovascular and antiarrhythmic actions. Two important questions
arise. First, are these cardiovascular and antiarrhythmic actions mediated
by the opioid receptors? Second, what is the underlying mechanism of
actions if these effects are not mediated by opioid receptors? Previous
studies have shown that some of the cardiac and cardiovascular actions of
ic agonists are a result of direct actions on cardiac ionic channels and are
independent of ic agonism. RSD 939 is structurally related to ic agonists
and in binding studies appears to be a potent and selective ic agonist. The
present study is an attempt to study the involvement of opioid-receptors
in the cardiovascular and antiarrhythmic activity of ic agonists and to
determine the underlying mechanism of such activities using RSD 939.
The cardiovascular and antiarrhythmic actions of RSD 939 were
investigated in a series of studies. Firstly, the initial profile of acute
cardiovascular and toxic actions of RSD 939 were investigated. RSD 939
was given as cumulative i.v. bolus doses to anaesthetised rats whose
blood pressure, heart rate and ECG were measured. It was found that at 8
jimole/kg, RSD 939 decreased both blood pressure and heart rate by 25%. At 5
tmole/kg, it also prolonged the P-R interval and increased RSh of
the ECG. However, at a
higher dose of 16 jtmole/kg, it also produced
changes in the Q-T interval.
Since opioid receptors are found in the vagus nerve, in several
sympathetic ganglia as well as the heart, opioid peptides can influence the
cardiovascular system both centrally and peripherally. Therefore, in
order to determine the direct cardiac effects of RSD 939, it is necessary
to examine the drug effects in the absence of neuronal and humoral
influence on hearts. In isolated rat hearts, over the concentration range
0.1 to 3.0 riM, RSD 939 concentration-dependently prolonged the P-R and
QRS intervals of the ECG.
The antiarrhythmic activity of RSD 939 was determined in terms of
its ability to prevent both electrically-induced and ischaemia-induced
arrhythmias. For electrical stimulation, two silver electrodes were
implanted into the rat’s left ventricle and the ability of the drug to raise
the ventricular fibrillation threshold (VFt) was determined. In the
ischaemia model, the left anterior decending coronary artery (LAD) of the
rat was ligated. Occlusion of the LAD results in the production of acute
myocardial ischaemia and ventricular arrhythmias in a
predictable and
reproducible manner that mimics conditions found clinically in
myocardial ischaemia and infarction. At a
dose of 1.5 jtmole/kg/min, RSD 939 significantly increased the threshold voltage needed to induce
ventricular fibrillo-flutter. At the same dose, the incidence of ventricular
arrhythmias produced by occlusion was also significantly reduced
(reduction of arrhythmia score from 7.0 in control groups to 3.2 in RSD
939 group).
Naloxone at a dose which had no cardiovascular or ECG actions,
but blocked opioid receptors, was used to differentiate between opioid
and nonopioid receptor-mediated actions of RSD 939. In a random and
double-blind manner, either control vehicle or 8 j.imole/kg(1 tM in vitro)
naloxone was given to rats or infused into isolated rat hearts. RSD 939 or
control vehicle was administered 5 mm later. The cardiovascular and
antiarrhythmic actions of RSD 939 in naloxone pre-treated preparations
and untreated rats were also compared. It was found that the ECG and
antiarrhythmic effects of RSD 939 were not antagonized by naloxone.
The antiarrhythmic action of naloxone alone was also evaluated and
compared in the two groups. Naloxone alone had no effect on any of the
ECG variables except for P-R interval which was prolonged slightly.
However, naloxone alone reduced the incidence and severity of
ischaemia-induced arrhythmia. This action of naloxone was not
synergistic with RSD 939 since no difference in antiarrhythmic potency
was found between the naloxone pre-treated and nonnaloxone pre-treated groups. From the above observations, it can be concluded that the cardiac
and cardiovascular actions of RSD 939 were not mediated through opioid
receptors.
Effects of RSD 939 on the ECG parameters such as P-R, QRS, RSh
and Q-T intervals and electrical stimulation parameters such as threshold
current (iT), threshold duration (tT), and effective refractory period
(ERP) were used to establish the underlying mechanism of actions of its
antiarrhythmic activities. RSD 939 dose-dependently prolonged P-R,
QRS, RSIi, iT, and tT without significant effects on Q-T and ERP until
higher doses. Since most sodium channels blockers will increase P-R,
QRS, RSh, iT, and tT and most potassium channel blockers will prolong
Q-T and ERP, we concluded that RSD 939 mediated its cardiac and
cardiovascular effects by direct cardiac sodium and potassium channel
blockade.
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Sherman, Patrick James. "The isolation, structure, and membrane interactions of biologically active peptides." Thesis, 2013. http://hdl.handle.net/2440/82703.
Повний текст джерелаАнотація:
The host-defence secretions of amphibians and the venoms of arachnids are an abundant source of biologically active peptides with a great potential for use in therapeutic pharmacology. Over millions of years of evolution, the chemical arsenals of a multitude of species have produced a vast collection of peptides that have potent and selective activities. The research presented in this thesis details the isolation, structure determination and mechanistic pathways of a selection of biologically active peptides. The southern brown tree frog Litoria ewingi occupies areas of the southeastern coast of Australia and Tasmania. Over a twelve month period, the peptide skin profile of a population of L. ewingii from Penola (South Australia) was determined using a combination of chromatography, tandem mass spectrometry and Edman degradation techniques. The peptide profiles of a L. ewingi from Penola show surprising differences relative to a population previously studied from the Adelaide hills, despite appearing to be morphologically identical. A total of six skin peptides were identified, four of which were unique; showing peptide sequence homology with peptides from Adelaide hills population. The evidence showed how a species can evolve separately after long periods of geographical isolation, how peptide profiling can be used to trace the migration of a species, and how new peptides can be discovered from different populations of a species. The antimicrobial meucin peptides were first identified using cDNA cloning of DNA from the venom gland of the ‘Lesser Asian scorpion’ Mesobuthus eupus mongolicus. These peptides exhibit cytolytic effects against a number of eukaryotic and prokaryotic cells at micromolar concentrations, and their peptide sequences share similarities with other antimicrobial peptides from scorpions, arthropods and amphibian species. The secondary structures of the meucin peptides were determined using 2-D NMR and molecular dynamics calculations. Both meucin peptides exhibit α-helical structure, and are amphipathic in nature. The study further shows how the length of the α-helical structure can as an antibiotic affect the cytolytic activity of the peptide, since meucin-18 is more potent than meucin-13. The C-terminal amide analogue of the peptide fallaxidin 4.l (fallaxidin 4.1a) isolated from the dermal secretions of Litoria fallax, is partially α-helical in nature, and shows potent activity against a wide range of yeast and bacteria (both Gram-positive and Gramnegative). This thesis uses solid-state NMR to detail the dynamic interactions of fallaxidin 4.1a with artificial lipid bilayers, and to explore the surface interactions of the peptides with eukaryotic (neutral) and prokaryotic (anionic) membranes. The solid state NMR and analysis using a quartz crystal microbalance indicated that the peptide acts via a surface interaction with neutral membranes and forms pores within anionic membranes at micromolar concentrations, indicating the specific pore forming mechanism by which the peptide interacts with anionic (prokaryotic) membranes. Rothein 1, an 11 residue neuropeptide from the dermal secretions of Litoria rothii, and two alanine substituted analogues, rothein 1.4 and 1.5; show differing activities via binding to CCK2 receptors. The structures of rothein 1.4 and 1.5 were determined using 2-D NMR and molecular dynamics calculations. Each peptide has a largely extended structure, with similarities to the structure of rothein 1. Two 10 residue, disulfidecontaining neuropeptides signiferin 1 and riparin 1 from dermal secretions of frogs of the Crinia genus, show potent smooth muscle and splenocyte activities. The dynamics of the interaction of signiferin 1, riparin1 and rothein 1 with artificial eukaryotic (neutral) lipid bilayer suspensions were probed using solid-state NMR, to emulate how a neuropeptide interacts with a cellular membrane surface prior to receptor binding. Solid-state NMR showed that rothein 1 had little effect on the mobility and orientation of the lipids, signiferin 1 interacted largely at the surface of the bilayers, and riparin 1 was partially inserted into the membrane. Rothein 1 is significantly less active than the disulphide peptides and more hydrophilic in nature; this is reflected in the interactions with bilayers. The disulphide peptides are more hydrophobic in character and the solid-state NMR indicated that they adhere to membranes.Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2013
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Javid, Farideh A., and Robert J. Naylor. "Opioid receptor involvement in the adaptation to motion sickness in Suncus murinus." 2001. http://hdl.handle.net/10454/3601.
Повний текст джерелаАнотація:
NoThe aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of I Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, ip) or morphine (0.1 mg/kg, ip) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, ip) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, ip) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.
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Liou, Jing Ping, and 劉景平. "1. Syntheses and Opioid Activity of Spiro[benzofuran-3(2H),4’-piperidines] : A Conformation-activity Study and Novel Synthesis of Isoneopine : A Formal Total Synthesis of Morphine." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/61170371995587220133.
Повний текст джерелаАнотація:
博士國立臺灣大學
藥學研究所
88
Approaches based on simplification of the pentacyclic morphine skeleton towards the discovery of novel analgesics have been adopted by generations of medicinal chemists. However, the tricyclic spiro[benzofuran-3(2H),4’-piperidines], morphine ANO fragments, have never been developed for clinical use, due to inefficiency in their synthesis and inadequate structure-activity relationship data. In this study, a novel synthesis of the morphine ANO fragments via intramolecular radical cyclization was developed. Thus, 4-(2-bromo-6-methoxyphenoxy-methyl)-1,2,5,6-tetrahydropyridine (13) derived from guaiacol in 4 steps, underwent facile 5-exo-trig radical cyclization upon treatment with Bu3SnH /AIBN (cat.) to afford spiro[7-methoxybenzofuran-3(2H),4''-l''-methylpiperidine] (14) in 96% yield as the sole product. Its O-demethylation product, compound 15, was found to maintain weak binding affinity towards the opioid receptor (Ki, = 1654 nM) A conformational analysis on 15 and related compounds was carried out. It reveled that, unlike morphine, compound 15 prefers to have its phenyl ring in the equatorial position. Besides, analogs of 15 with alkyl substitents on C2-position of the furan ring or on C3’ of the piperidine and cis to the phenyl ring such as ()-20, ()-21, and ()-22 would have their phenyl rings locked in an axial position. Spiro[2-methyl-7-hydroxybenzofuran-3(2H),4’-1’-methylpiperidine] (()-20), the 2-methyl analog of 15, and its 2-ethyl analog 21 were synthesized by our radical route starting from 4-acetylpyridine (24), and 4-pyridylcarboxyaldehyde (28) respectivity; while the C3’-methyl analogs of 15, namely the (3’R’, 4’S’)- or cis- 22 and its trans isomer 23, were prepared similarly from 3,4-lutidine. NMR noesy experiments demonstrated that the phenyl rings in compound 20, 21, and 22, adopt an axial orientation; while the phenyl groups in 15 and 23 adopt an equatorial position. The results are in agreement with the conformational analysis. It was then gratifying to find that compounds 20, 21 and 22, with their phenyl rings situated preferentially in an axial position, showed potent -affinity (Ki, = 124, 102, 54 nM) as comparable to that of (-)-morphine (Ki, = 38 nM), which has its phenyl ring locked in an axial position. On the other hand, compound 15, compound 23, and meperidine, with their phenyl rings in an equatorial orientation, showed only weak -affinity (Ki, = 1015 nM). Our strategy towards a synthesis of morphine can be divided into three parts : the construction of morphine C13- quaternary benzylic center (synthesis of ACNO fragments), formation of morphine B ring (synthesis of desoxycodeine-D), and incorporation of the C6-hydroxy group (the synthesis of Isoneopine). We first extended our radical synthesis of morphine ANO fragments to the synthesis of morphine ACNO fragments. Thus, 5-(2-Bromo-6-methoxyphenoxy)-2-methyl-1,2,3,4,5,6, 7,8-octahydroisoquinoline (43) underwent radical reaction to provide the desired C/N trans ACNO fragments 9-methoxy-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e] isoquinoline (44) as the major product (25%), with its cis isomer 45 and a debrominated rearrangement product 46 also obtained in 16% and 17% respectively. When intermediate 43 was modified with an electron-withdrawing carbonyl function at its C-1 (55), the same radical reaction provided the desired trans isomer 56 in higher yield (30%) in the absence of its cis isomer. However, the debrominated rearrangement product 57 was also obtained in higher yield (26%). Since the intermediates used in radical cyclization can often be subjected to palladium-catalyzed reactions or the Heck reaction in the synthesis of polycyclic compounds, we then turned our attention to the construction of morphine C13 quaternary benzylic center via intramolecular Heck reaction. Intermediate 55 described above was treated with Pd(OAc)2, PPh3, and Et3N in acetonitrile at 130 oC in a sealed vessel, and afforded the desired 9-methoxy-3methyl-4-oxo-2,3,4,6,7,7a-hexahydro-lH-benzofuro(2,2-e]isoquinoline (60) in 39% yield as the major product. When intermediate 43 and its iodo-analog 61 were subjected to the same reaction condition for 55, the desired cyclization product 62 was obtained in 48% and 72% yield respectively. In order to extend the methodology to the construction of the complete morphine ABCNO skeleton, a benzylic carbon (C10) had to be added to the intermediate for the Heck cyclization. Thus, 12-(Chloromethyl)-3-ethoxycarbonyl-9-methoxy-2,3,5,6,7,7a-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (72) was prepared from 5,6,7,8-tetrahydroisoquinoline and isovanillin. Our original plan for the construction of ring B (C9-C10) was to utilize the documented Pd-catalyzed intramolecular cyclization of benzyl halides to alkene moieties. However, when compound 72 was subjected to Heck conditions (Pd(PPh3)4, Et3N, CH3CN, 120 oC), instead of giving the anticipated compound 75, an intramolecular N-benzylation occurred and provided the tertiary amine 73 as the major product. Prompted by literature reports of Stevens rearrangement of quaternary tetrahydroisoquinoline alkaloids, compound 73 was first converted to the corresponding N-methylammonium iodide 89, which was then treated with PhLi in ether. To our gratification, compound 89 underwent the anticipated Stevens rearrangement, and provided Desoxycodeine-D (93) in 83% yield, thus establishing a facile route to the morphine skeleton. (ABCNO) To complete a total synthesis of morphine, 2-(ethoxycarbonyl)-5-oxo-1,2,3,4,5,6,7,8-octahydroisoquinoline (99) was subjected to oxidation with Pb(OAc)4 in toluene, and provided the 6-acetoxy derivative compound 102. When compound 102 was treated with NaBH4 in the presence of CeCl3, stereospecific reduction of the 5-oxo group occurred, and the cis-diol acetate 104 was obtained. Compound 104 was subjected to basically the same sequence of reactions descibed above, including a mitsunobu coupling reaction, two consecutive Pd-catalyzed cyclizations and a stevens rearrangement to afford the desired Isoneopine (111), whose conversion to morphine has been documented.
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Doyon, William Maurice. "The effect of ethanol consumption on dopamine and ethanol concentrations in the nucleus accumbens during the development of reinforcement and the involvement of the k-Opioid receptor in the modulation of dopamine activity during ethanol self-administration." Thesis, 2005. http://hdl.handle.net/2152/2416.
Повний текст джерела
38
Dobrutska, Iana. "Drug addiction prevention by physical exercise." Master's thesis, 2018. http://hdl.handle.net/10316/81989.
Повний текст джерелаАнотація:
Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaEsta revisão tem como objetivo descrever o conhecimento atual sobre o exercício físico no tratamento da adicção a drogas de abuso, principalmente na prevenção. Foram utilizados os seguintes termos de pesquisa no PubMed: [“drug addiction” AND “physical exercise” AND “prevention”] ou [“drug addiction prevention” AND “physical exercise]. Referências relevantes de publicações importantes e literatura cinzenta também foram procuradas para identificar citações adicionais para inclusão. Além disso, as referências dos artigos também foram revistas. Foram pesquisada evidências clínicas e pré-clínicas. De um modo geral pode-se afirmar que os utilizadores frequentes de drogas de abuso demonstraram melhorar a sua capacidade ou fitness, incluindo melhor aptidão e medidas emocionais, menores taxas de recaída e abstinência sustentada quando comparados com indivíduos que não fazem exercício. No que diz respeito à prevenção, o número de estudos é escasso e geralmente de má qualidade, nomeadamente ao nível clínico. Em geral, pode-se dizer que o exercício pode ajudar a prevenir a adicção com estimulantes, como as anfetaminas, ou depressivos, como os opióides. Os mecanismos neurobiológicos do exercício físico no tratamento da adicção parecem refletir uma interação de vários agentes, incluindo mediadores neuroquímicos, estresse oxidativo, neurogénese, gliogénese e disfunção da barreira hematoencefálica, conforme se deduz dos dados pré-clínicos e de alguns resultados clínicos. As intervenções baseadas no exercício, isoladamente ou como terapia adicional, podem ser uma ferramenta útil para tratar a dependência ou adicção a drogas de abuso.
This review aims to describe the current knowledge about physical exercise use on drug addiction management, principally in prevention. The following searching terms in PubMed were used: [“drug addiction” AND “physical exercise” AND “prevention”] or [“drug addiction prevention” AND “physical exercise]. Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Also the references of articles were also reviewed. Preclinical and clinical evidence were searched. Overall, drug abusers demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to non-exercised individuals. Regarding prevention, the number of studies is scarce and generally of bad quality, namely at the clinical level. In general it could be said that exercise may help to prevent drug addiction with stimulants, like amphetamines, or depressants, like opioids. The neurobiological mechanisms of physical exercise in drug abusers management seem to reflect an interplay of several agents, including neurochemical mediators, oxidative stress, neurogenesis, gliogenesis, and blood-brain barrier dysfunction as disclosed by preclinical data and some clinical results. Exercise-based interventions alone or as an additional therapy may be a useful tool for managing drug addiction.This review aims to describe the current knowledge about physical exercise use on drug addiction management, principally in prevention. The following searching terms in PubMed were used: [“drug addiction” AND “physical exercise” AND “prevention”] or [“drug addiction prevention” AND “physical exercise]. Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Also the references of articles were also reviewed. Preclinical and clinical evidence were searched. Overall, drug abusers demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to non-exercised individuals. Regarding prevention, the number of studies is scarce and generally of bad quality, namely at the clinical level. In general it could be said that exercise may help to prevent drug addiction with stimulants, like amphetamines, or depressants, like opioids. The neurobiological mechanisms of physical exercise in drug abusers management seem to reflect an interplay of several agents, including neurochemical mediators, oxidative stress, neurogenesis, gliogenesis, and blood-brain barrier dysfunction as disclosed by preclinical data and some clinical results. Exercise-based interventions alone or as an additional therapy may be a useful tool for managing drug addiction.