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1
Yang, Pao-Pao, Sheau-Huei Chueh, Hua-Lun Shie, Chin-Chu Chen, Li-Ya Lee, Wan-Ping Chen, Yu-Wen Chen, Li-yen Shiu, and Pei-Shan Liu. "Effects of Hericium erinaceus Mycelium Extracts on the Functional Activity of Purinoceptors and Neuropathic Pain in Mice with L5 Spinal Nerve Ligation." Evidence-Based Complementary and Alternative Medicine 2020 (May 14, 2020): 1–12. http://dx.doi.org/10.1155/2020/2890194.
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Neuropathic pain is a serious clinical problem that is difficult to treat. Purinoceptors (P2Rs) transduce pain perception from the peripheral to the central nervous system and play an important role in the transmission of neuropathic pain signals. We previously found that the crude extracts of Hericium erinaceus mycelium (HE-CE) inhibited P2R-mediated signaling in cells and reduced heat-induced pain in mice. The present study explored the effects of HE-CE on neuropathic pain. We used adenosine triphosphate (ATP) as a P2R agonist to generate Ca2+ signaling and neuronal damage in a cell line. We also established a neuropathic mouse model of L5 spinal nerve ligation (L5-SNL) to examine neuropathic pain and neuroinflammation. Neuropathic pain was recorded using the von Frey test. Neuroinflammation was evaluated based on immunohistofluorescence observation of glial fibrillary acidic protein (GFAP) levels in astrocytes, ionized calcium-binding adaptor molecule1 (iba1) levels in microglia, and IL-6 levels in plasma. The results show that HE-CE and erinacine-S, but not erinacine-A, totally counteracted Ca2+ signaling and cytotoxic effects upon P2R stimulation by ATP in human osteosarcoma HOS cells and human neuroblastoma SH-SY5Y cells, respectively. SNL induced a decrease in the withdrawal pressure of the ipsilateral hind paw, indicating neuropathic pain. It also raised the GFAP level in astrocytes, the iba1 level in microglia, and the IL-6 level in plasma, indicating neuroinflammation. HE-CE significantly counteracted the SNL-induced decrease in withdrawal pressure, illustrating that it could relieve neuropathic pain. It also reduced SNL-induced increases in astrocyte GFAP levels, microglial iba1 levels, and plasma IL-6 levels, suggesting that HE-CE reduces neuroinflammation. Erinacine-S relieved neuropathic pain better than HE-CE. The present study demonstrated that HE inhibits P2R and, thus, that it can relieve neuropathic pain and neuroinflammation.
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Popiolek-Barczyk, Katarzyna, Anna Piotrowska, Wioletta Makuch, and Joanna Mika. "Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners." Neural Plasticity 2017 (2017): 1–19. http://dx.doi.org/10.1155/2017/3829472.
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Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.
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Zhou, Feng, Xian Wang, Baoyu Han, Xiaohui Tang, Ru Liu, Qing Ji, Zhiqiang Zhou, and Lidong Zhang. "Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization." Molecular Pain 17 (January 2021): 174480692199652. http://dx.doi.org/10.1177/1744806921996520.
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Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.
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Liu, Ming, Kaijun Liao, Changxi Yu, Xuejun Li, Suhuan Liu, and Shuyu Yang. "Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord." Mediators of Inflammation 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/485927.
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Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent ofPuerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI) and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM) for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB) and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.
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Hansson, Elisabeth. "Long-term pain, neuroinflammation and glial activation." Scandinavian Journal of Pain 1, no. 2 (April 1, 2010): 67–72. http://dx.doi.org/10.1016/j.sjpain.2010.01.002.
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AbstractNociceptive and neuropathic pain signals are known to result from noxious stimuli, which are converted into electrical impulses within tissue nociceptors. There is a complex equilibrium of pain-signalling and pain-relieving pathways connecting PNS and CNS. Drugs against long-term pain are today directed against increased neuronal excitability, mostly with less success.An injury often starts with acute physiological pain, which becomes inflammatory, nociceptive, or neuropathic, and may be transferred into long-term pain. Recently a low-grade inflammation was identified in the spinal cord and along the pain pathways to thalamus and the parietal cortex. This neuroinflammation is due to activation of glial cells, especially microglia, with production of cytokines and other inflammatory mediators within the CNS. Additionally, substances released to the blood from the injured region influence the blood–brain barrier, and give rise to an increased permeability of the tight junctions of the capillary endothelial cells, leading to passage of blood cells into the CNS. These cells are transformed into reactive microglia. If the inflammation turns into a pathological state the astrocytes will be activated. They are coupled into networks and respond to substances released by the capillary endothelial cells, to cytokines released from microglia, and to neurotransmitters and peptides released from neurons. As the astrocytes occupy a strategic position between the vasculature and synapses, they monitor the neuronal activity and transmitter release. Increased release of glutamate and ATP leads to disturbances in Ca2+ signalling, increased production of cytokines and free radicals, attenuation of the astrocyte glutamate transport capacity, and conformational changes in the astrocytic cytoskeleton, the actin filaments, which can lead to formation and rebuilding of new synapses. New neuronal contacts are established for maintaining and spreading pain sensation with the astrocytic networks as bridges. Thereby the glial cells can maintain the pain sensation even after the original injury has healed, and convert the pain into long-term by altering neuronal excitability. It can even be experienced from other parts of the body. As astrocytes are intimate co-players with neurons in the CNS, more knowledge on astrocyte responses to inflammatory activators may give new insight in our understanding of mechanisms of low-grade inflammation underlying long-term pain states and pain spreading. Novel treatment strategies would be to restore glial cell function and thereby attenuate the neuroinflammation.
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Yin, Yuhua, Thuỳ Linh Phạm, Juhee Shin, Nara Shin, Dong-Wook Kang, Sun Yeul Lee, Wonhyung Lee, et al. "Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice." Journal of Clinical Medicine 9, no. 2 (January 22, 2020): 305. http://dx.doi.org/10.3390/jcm9020305.
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Microglia, the resident macrophages, act as the first and main form of active immune defense in the central nervous system. Arginase 2 (Arg2) is an enzyme involved in L-arginine metabolism and is expressed in macrophages and nervous tissue. In this study, we determined whether the absence of Arg2 plays a beneficial or detrimental role in the neuroinflammatory process. We then investigated whether the loss of Arg2 potentiated microglia activation and pain behaviors following nerve injury-induced neuropathic pain. A spinal nerve transection (SNT) experimental model was used to induce neuropathic pain in mice. As a result of the peripheral nerve injury, SNT induced microgliosis and astrogliosis in the spinal cord, and upregulated inflammatory signals in both wild-type (WT) and Arg2 knockout (KO) mice. Notably, inflammation increased significantly in the Arg2 KO group compared to the WT group. We also observed a more robust microgliosis and a lower mechanical threshold in the Arg2 KO group than those in the WT group. Furthermore, our data revealed a stronger upregulation of M1 pro-inflammatory cytokines, such as interleukin (IL)-1β, and a stronger downregulation of M2 anti-inflammatory cytokines, including IL4 and IL-10, in Arg2 KO mice. Additionally, stronger formation of enzyme-inducible nitric oxide synthase, oxidative stress, and decreased expression of CD206 were detected in the Arg2 KO group compared to the WT group. These results suggest that Arg2 deficiency contributes to inflammatory response. The reduction or the loss of Arg2 results in the stronger neuroinflammation in the spinal dorsal horn, followed by more severe pain behaviors arising from nerve injury-induced neuropathic pain.
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Block, Linda. "Glial dysfunction and persistent neuropathic postsurgical pain." Scandinavian Journal of Pain 10, no. 1 (January 1, 2016): 74–81. http://dx.doi.org/10.1016/j.sjpain.2015.10.002.
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AbstractBackgroundAcute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosen-sory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.AimThis topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.MethodRelevant literature was searched for in PubMed.Results Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a μ–opioid receptor agonist, a μ–opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. ConclusionSurgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.ImplicationsLarger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.
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Sheng, Wen S., Priyanka Chauhan, Shuxian Hu, Sujata Prasad, and James R. Lokensgard. "Antiallodynic Effects of Cannabinoid Receptor 2 (CB2R) Agonists on Retrovirus Infection-Induced Neuropathic Pain." Pain Research and Management 2019 (July 4, 2019): 1–12. http://dx.doi.org/10.1155/2019/1260353.
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The most common neurological complication in patients receiving successful combination antiretroviral therapy (cART) is peripheral neuropathic pain. Data show that distal symmetric polyneuropathy (DSP) also develops along with murine acquired immunodeficiency syndrome (MAIDS) after infection with the LP-BM5 murine retrovirus mixture. Links between cannabinoid receptor 2 (CB2R) and peripheral neuropathy have been established in animal models using nerve transection, chemotherapy-induced pain, and various other stimuli. Diverse types of neuropathic pain respond differently to standard drug intervention, and little is currently known regarding the effects of modulation through CB2Rs. In this study, we evaluated whether treatment with the exogenous synthetic CB2R agonists JWH015, JWH133, Gp1a, and HU308 controls neuropathic pain and neuroinflammation in animals with chronic retroviral infection. Hind-paw mechanical hypersensitivity in CB2R agonist-treated versus untreated animals was assessed using the MouseMet electronic von Frey system. Multicolor flow cytometry was used to determine the effects of CB2R agonists on macrophage activation and T-lymphocyte infiltration into dorsal root ganglia (DRG) and lumbar spinal cord (LSC). Results demonstrated that, following weekly intraperitoneal injections starting at 5 wk p.i., JWH015, JWH133, and Gp1a, but not HU308 (5 mg/kg), significantly ameliorated allodynia when assessed 2 h after ligand injection. However, these same agonists (2x/wk) did not display antiallodynic effects when mechanical sensitivity was assessed 24 h after ligand injection. Infection-induced macrophage activation and T-cell infiltration into the DRG and LSC were observed at 12 wk p.i., but this neuroinflammation was not affected by treatment with any CB2R agonist. Activation of JAK/STAT3 has been shown to contribute to development of neuropathic pain in the LSC and pretreatment of primary murine microglia (2 h) with JWH015-, JWH133-, or Gp1a-blocked IFN-gamma-induced phosphorylation of STAT1 and STAT3. Taken together, these data show that CB2R agonists demonstrate acute, but not long-term, antiallodynic effects on retrovirus infection-induced neuropathic pain.
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Li, Xuyang, Guangzhi Wu, Miyang Li, and Zhan Zhang. "Oleanolic acid administration alleviates neuropathic pain after a peripheral nerve injury by regulating microglia polarization-mediated neuroinflammation." RSC Advances 10, no. 22 (2020): 12920–28. http://dx.doi.org/10.1039/c9ra10388k.
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Zou, He‐Lin, Juan Li, Jun‐Li Zhou, Xi Yi, and Song Cao. "Effects of norepinephrine on microglial neuroinflammation and neuropathic pain." Ibrain 7, no. 4 (December 2021): 309–17. http://dx.doi.org/10.1002/ibra.12001.
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Borgonetti, Vittoria, and Nicoletta Galeotti. "Rosmarinic Acid Reduces Microglia Senescence: A Novel Therapeutic Approach for the Management of Neuropathic Pain Symptoms." Biomedicines 10, no. 7 (June 21, 2022): 1468. http://dx.doi.org/10.3390/biomedicines10071468.
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The worldwide incidence of neuropathic pain is around 7–8% and is associated with significant and disabling comorbidities (sleep disturbances, depression, anxiety). It is now known that cellular ageing of microglia contributes to neurodegenerative diseases, mood disorders, and, even if with less evidence, chronic pain. The aim of this work was to investigate in vitro and in vivo the senolytic activity of rosmarinic acid (RA) to be exploited for the management of NP symptoms. BV2 cells were stimulated with LPS 500 ng/mL for 24 h. Treatment with RA 1 µM improved cell viability and reduced IL-1ß release leading to an attenuation of neuroinflammation. We then moved on to test the efficacy of RA in reducing microglial senescence. In our model, BV2 cells were stimulated with LPS 500 ng/mL every 72 h for 4 h/day, over a period of 10 days. RA 1 µM reduced the expression of the β-galactosidase enzyme, reduced the release of senescence-associated secretory phenotype (SASP) factors, increased cell viability, and reduced the presence of nuclear foci of senescence (SAHF), well-known cellular senescence markers. In the Spared Nerve Injury (SNI) model, 28 days from surgery, repeated oral administration of RA 5 mg/kg reduced hyperalgesia and NP-associated symptoms, such as anxiety and depression. A reduction of senescence markers was detected on both hippocampal and spinal samples of SNI-treated mice. This study represents a starting point for investigating the role of microglial senescence as a possible pharmacological target in controlling symptoms related to the more advanced stages of peripheral neuropathy.
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Ramesh, Geeta, Andrew G. MacLean, and Mario T. Philipp. "Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain." Mediators of Inflammation 2013 (2013): 1–20. http://dx.doi.org/10.1155/2013/480739.
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Cytokines and chemokines are proteins that coordinate the immune response throughout the body. The dysregulation of cytokines and chemokines is a central feature in the development of neuroinflammation, neurodegeneration, and demyelination both in the central and peripheral nervous systems and in conditions of neuropathic pain. Pathological states within the nervous system can lead to activation of microglia. The latter may mediate neuronal and glial cell injury and death through production of proinflammatory factors such as cytokines and chemokines. These then help to mobilize the adaptive immune response. Although inflammation may induce beneficial effects such as pathogen clearance and phagocytosis of apoptotic cells, uncontrolled inflammation can result in detrimental outcomes via the production of neurotoxic factors that exacerbate neurodegenerative pathology. In states of prolonged inflammation, continual activation and recruitment of effector cells can establish a feedback loop that perpetuates inflammation and ultimately results in neuronal injury. A critical balance between repair and proinflammatory factors determines the outcome of a neurodegenerative process. This review will focus on how cytokines and chemokines affect neuroinflammation and disease pathogenesis in bacterial meningitis and brain abscesses, Lyme neuroborreliosis, human immunodeficiency virus encephalitis, and neuropathic pain.
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Tyrtyshnaia, Anna, Anatoly Bondar, Sophia Konovalova, and Igor Manzhulo. "Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain." International Journal of Molecular Sciences 22, no. 23 (November 26, 2021): 12779. http://dx.doi.org/10.3390/ijms222312779.
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Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain.
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Tyrtyshnaia, Anna A., Evgenia L. Egorova, Anna A. Starinets, Arina I. Ponomarenko, Ekaterina V. Ermolenko, and Igor V. Manzhulo. "N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury." Marine Drugs 18, no. 10 (October 15, 2020): 516. http://dx.doi.org/10.3390/md18100516.
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Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.
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Miller, Yury I., Juliana M. Navia-Pelaez, Maripat Corr, and Tony L. Yaksh. "Lipid rafts in glial cells: role in neuroinflammation and pain processing." Journal of Lipid Research 61, no. 5 (December 20, 2019): 655–66. http://dx.doi.org/10.1194/jlr.tr119000468.
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Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.
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Olmos, Gabriel, and Jerònia Lladó. "Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity." Mediators of Inflammation 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/861231.
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Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; thisde novoproduction of TNF-αis an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-αcan potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca+2permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAAreceptors on neurons. Thus, the net effect of TNF-αis to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-αlinks the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF-αexpression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-αsignaling may represent a valuable target for intervention.
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Varrassi, Giustino. "Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis." Pain Physician 19, no. 2;2 (February 14, 2016): 11–24. http://dx.doi.org/10.36076/ppj/2016.19.11.
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Background: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors. Objective: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain. Study Design: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials. Methods: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators. Results: Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score ≤ 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain. Limitations: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies. Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation. Key words: Chronic pain, neuropathic pain, neuroinflammation, astrocytes, glia, mast cells, microglia, micronized and ultra-micronized palmitoylethanolamide
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Cairns, Brian E., Lars Arendt-Nielsen, and Paola Sacerdote. "Perspectives in Pain Research 2014: Neuroinflammation and glial cell activation: The cause of transition from acute to chronic pain?" Scandinavian Journal of Pain 6, no. 1 (January 1, 2015): 3–6. http://dx.doi.org/10.1016/j.sjpain.2014.10.002.
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AbstractBackgroundIt is unknown why an acute pain condition under various circumstances can transition into a chronic pain condition.There has been a shift towards neuroinflammation and hence glial cell activations specifically in the dorsal root ganglion and spinal cord as a mechanism possibly driving the transition to chronic pain. This has led to a focus on non-neuronal cells in the peripheral and central nervous system. Besides infiltrating macrophages, Schwann cells and satellite glial cells release cytokines and therefore important mechanisms in the maintenance of pain. Activated Schwann cells, satellite glial cells, microglia, and astrocytes may contribute to pain sensitivity by releasing cytokines leading to altered neuronal function in the direction of sensitisation.Aims of this perspective paper1) Highlight the complex but important recent achievement in the area of neuroinflammation and pain at spinal cord level and in the dorsal root ganglion.2) Encourage further research which hopefully may provide better understanding of new key elements driving the transition from acute to chronic pain.Recent results in the area of neuroinflammation and painFollowing a sciatic nerve injury, local macrophages, and Schwann cells trigger an immune response immediately followed by recruitment of blood-derived immune cells. Schwann cells, active resident, and infiltrating macrophages release proinflammatory cytokines. Proinflammatory cytokines contribute to axonal damage and also stimulate spontaneous nociceptor activity. This results in activation of satellite glial cells leading to an immune response in the dorsal root ganglia driven by macrophages, lymphocytes and satellite cells. The anterograde signalling progresses centrally to activate spinal microglia with possible up regulation of glial-derived proinflammatory/pronociceptive mediators.An important aspect is extrasegmental spreading sensitisation where bilateral elevations in TNF-α, IL-6, and IL-10 are found in dorsal root ganglion in neuropathic models. Similarly in inflammatory pain models, bilateral up regulation occurs for TNF-α, IL-1 β, and p38 MAPK. Bilateral alterations in cytokine levels in the DRG and spinal cord may underlie the spread of pain to the uninjured side.An important aspect is how the opioids may interact with immune cells as opioid receptors are expressed by peripheral immune cells and thus can induce immune signaling changes. Furthermore, opioids may stimulate microglia cells to produce proinflammatory cytokines such as IL-1.ConclusionsThe present perspective paper indicates that neuroinflammation and the associated release of pro-inflammatory cytokines in dorsal root ganglion and at the spinal cord contribute to the transition from acute to chronic pain. Neuroinflammatory changes have not only been identified in the spinal cord and brainstem, but more recently, in the sensory ganglia and in the nerves as well. The glial cell activation may be responsible for contralateral spreading and possible widespread sensitisation.ImplicationsCommunication between glia and neurons is proposed to be a critical component of neuroinflammatory changes that may lead to chronic pain. Sensory ganglia neurons are surrounded by satellite glial cells but how communication between the cells contributes to altered pain sensitivity is still unknown. Better understanding may lead to new possibilities for (1) preventing development of chronic pain and (2) better pain management.
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Cai, Yuanxing, Jing Xu, and Qinghao Cheng. "Proto-oncogene tyrosine-protein kinase SRC (Src) inhibition in microglia relieves neuroinflammation in neuropathic pain mouse models." Bioengineered 12, no. 2 (December 1, 2021): 11390–98. http://dx.doi.org/10.1080/21655979.2021.2008694.
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Yousaf, Muhammad, Dennis Chang, Yang Liu, Tianqing Liu, and Xian Zhou. "Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders." Molecules 27, no. 15 (August 4, 2022): 4961. http://dx.doi.org/10.3390/molecules27154961.
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The lack of effective treatment for neurological disorders has encouraged the search for novel therapeutic strategies. Remarkably, neuroinflammation provoked by the activated microglia is emerging as an important therapeutic target for neurological dysfunction in the central nervous system. In the pathological context, the hyperactivation of microglia leads to neuroinflammation through the release of neurotoxic molecules, such as reactive oxygen species, proteinases, proinflammatory cytokines and chemokines. Cannabidiol (CBD) is a major pharmacologically active phytocannabinoids derived from Cannabis sativa L. CBD has promising therapeutic effects based on mounting clinical and preclinical studies of neurological disorders, such as epilepsy, multiple sclerosis, ischemic brain injuries, neuropathic pain, schizophrenia and Alzheimer’s disease. A number of preclinical studies suggested that CBD exhibited potent inhibitory effects of neurotoxic molecules and inflammatory modulators, highlighting its remarkable therapeutic potential for the treatment of numerous neurological disorders. However, the molecular mechanisms of action underpinning CBD’s effects on neuroinflammation appear to be complex and are poorly understood. This review summarises the anti-neuroinflammatory activities of CBD against various neurological disorders with a particular focus on their main molecular mechanisms of action, which were related to the downregulation of NADPH oxidase-mediated ROS, TLR4-NFκB and IFN-β-JAK-STAT pathways. We also illustrate the pharmacological action of CBD’s derivatives focusing on their anti-neuroinflammatory and neuroprotective effects for neurological disorders. We included the studies that demonstrated synergistic enhanced anti-neuroinflammatory activity using CBD and other biomolecules. The studies that are summarised in the review shed light on the development of CBD, including its derivatives and combination preparations as novel therapeutic options for the prevention and/or treatment of neurological disorders where neuroinflammation plays an important role in the pathological components.
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Varrassi, Giustino. "Chronic Pain in the Elderly: The Case for New Therapeutic Strategies." Pain Physician 5;18, no. 5;9 (September 14, 2015): E863—E876. http://dx.doi.org/10.36076/ppj.2015/18/e863.
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Background: Elderly patients in general exhibit a higher incidence of chronic and neuropathic pain conditions. This group poses a particular clinical challenge due to age-related pharmacokinetic and pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and cognitive decline. Poor control of pain has consistently been identified as an issue for older people. The identification of safe and efficacious treatments for chronic pain remains a critical public health concern, especially considering the progressive increase of the world’s elderly population. Objectives: This narrative review deals with the principal alterations of the somatosensory system together with changes in non-neuronal cells in the course of aging. The possibility to control chronic pain based on an innovative strategy which addresses non-neuronal cell dysregulation control will also be discussed. Study Design: Narrative review. Results: Peripheral nerves display functional, structural, and biochemical changes with aging that mainly involve Aδ fibers. Alteration in the responses to heat pain in the middle insular cortex and primary somatosensory cortex are also observed in the elderly. In general, pain threshold increases with age while the threshold of pain tolerance remains unchanged or decreases. Additionally, other important modifications of the pain perception system in this age group consist in a clear reduction in the descending inhibitory capacity with an associated increase in central sensitization. Furthermore, different changes concern immune system cells, such as mast cells and microglia, that with age show an increase in their sensitivity to noxious stimuli and a decreased capability to be regulated by homeostatic endogenous systems. Since these cells are the primary interlocutors for pain neurons, their alterations lead to changes that promote persistent neuroinflammation, thereby impacting pain neuronal cell functionality. Limitation: This review is not an exhaustive review for the current evidence supporting the role of immune cells in influencing pain somatosensory neuron functions. It is also important to stress the small number of studies designed to determine the efficacy and safety of anti-pain therapies in elderly patients. Conclusion: Non-neuronal cells of immune system origin such as microglia and mast cells, along with astrocytes, are capable of influencing pain somatosensory neuron functions. These nervous system non-neuronal cells may thus be viewed as innovative targets for persistent pain control. Among therapies aiming at preserving the functionality of non-neuronal cells, palmitoylethanolamide, with its high efficacy/risk ratio, may be an excellent co-treatment for the ever-growing elderly population with chronic pain. Key words: Elderly, chronic and neuropathic pain, mast cells, glial cells, neuroinflammation, micronized and ultra-micronized palmitoylethanolamide
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Gaire, Bhakta Prasad, and Ji-Woong Choi. "Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses." International Journal of Molecular Sciences 22, no. 15 (July 23, 2021): 7864. http://dx.doi.org/10.3390/ijms22157864.
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Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.
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Lim, Eun Yeong, Changho Lee, and Yun Tai Kim. "The Antinociceptive Potential of Camellia japonica Leaf Extract, (−)-Epicatechin, and Rutin against Chronic Constriction Injury-Induced Neuropathic Pain in Rats." Antioxidants 11, no. 2 (February 17, 2022): 410. http://dx.doi.org/10.3390/antiox11020410.
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Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. Currently, prescribed treatments are still unsatisfactory or have limited effectiveness. Camellia japonica leaves are known to have antioxidant and anti-inflammatory properties.; however, their antinociceptive efficacy has not yet been explored. We examined the antinociceptive efficacy and underlying mechanism of C. japonica leaf extract (CJE) in chronic constriction injury (CCI)-induced neuropathic pain models. To test the antinociceptive activity of CJE, three types of allodynia were evaluated: punctate allodynia using von Frey filaments, dynamic allodynia using a paintbrush and cotton swab, and cold allodynia using a cold plate test. CCI rats developed neuropathic pain representing increases in the three types of allodynia and spontaneous pain. In addition, CCI rats showed high phosphorylation levels of mitogen-activated protein kinases (MAPKs), transcription factors, and nociceptive mediators in dorsal root ganglion (DRG). The ionized calcium-binding adapter molecule 1 levels and neuroinflammation also increased following CCI surgery in the spinal cord. CJE and its active components have potential antinociceptive effects against CCI-induced neuropathic pain that might be mediated by MAPK activation in the DRG and microglial activation in the spinal cord. These findings suggest that CJE, (−)-epicatechin, and rutin could be novel candidates for neuropathic pain management.
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Bian, Jiang, Ying Zhang, Yan Liu, Qun Li, Hai-bin Tang, and Qing Liu. "P2Y6 Receptor-Mediated Spinal Microglial Activation in Neuropathic Pain." Pain Research and Management 2019 (June 3, 2019): 1–10. http://dx.doi.org/10.1155/2019/2612534.
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Objective. To explore the role of purine family member P2Y6 receptors in regulating neuropathic pain (NP) via neuroinflammation in the spinal cord. Methods. Chronic constriction injury of the sciatic nerve (CCI) of NP was classic in setting up models on Sprague-Dawley (SD) rats. Experiments were performed on rats with sham surgery, CCI, CCI + MRS2578 (a P2Y6 receptor antagonist), and UDP (a P2Y6 receptor agonist). The hyperalgesia intensity was mirrored by paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL). Immunofluorescence staining and western blot were used to evaluate activated microglial marker Iba-1. Enzyme-linked immunosorbent assay (ELISA) was used to access levels of IL-6. Conventional reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis were used to detect the expression of P2Y6 mRNA and activation of JAK/STAT signaling. Results. Among all groups, CCI caused decreased PWT and TWL compared to sham surgery, meaning a successful establishment of the NP model. These decreased values of PWT and TWL tests could be prevented by intraperitoneally injected MRS2578 and enhanced by UDP administration. Similarly, CCI induced increase of Iba-1 protein, P2Y6 mRNA expression, and circulating IL-6 secretion, as well as increased JAK2/STAT3 mRNA expression and phosphorylating modification in spinal cord tissues could also be diminished by MRS2578 treatment and exacerbated by UDP. Conclusions. These findings indicated the crucial role of the P2Y6 receptor in modulating the microglial and inflammatory responses in the process of NP in vivo. Results from this study would provide insights into targeting the P2Y6 receptor to treat NP in the near future.
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Cheng, Kuang-I., Yu-Chin Chang, Li-Wen Chu, Su-Ling Hsieh, Li-Mei An, Zen-Kong Dai, and Bin-Nan Wu. "The Iridoid Glycoside Loganin Modulates Autophagic Flux Following Chronic Constriction Injury-Induced Neuropathic Pain." International Journal of Molecular Sciences 23, no. 24 (December 14, 2022): 15873. http://dx.doi.org/10.3390/ijms232415873.
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Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on the autophagic–lysosomal pathway in the rat CCI model. Sprague–Dawley rats were divided into sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was intraperitoneally injected once daily, and rats were sacrificed on day 7 after CCI. This study focused on the mechanism by which loganin modulates autophagic flux after CCI. CCI enhanced the autophagic marker LC3B-II in the ipsilateral spinal cord. The ubiquitin-binding protein p62 binds to LC3B-II and integrates into autophagosomes, which are degraded by autophagy. CCI caused the accumulation of p62, indicating the interruption of autophagosome turnover. Loganin significantly attenuated the expression of Beclin-1, LC3B-II, and p62. Double immunofluorescence staining was used to confirm that LC3B-II and p62 were reduced by loganin in the spinal microglia and astrocytes. Loganin also lessened the CCI-increased colocalization of both proteins. Enhanced lysosome-associated membrane protein 2 (LAMP2) and pro-cathepsin D (pro-CTSD) in CCI rats were also attenuated by loganin, suggesting that loganin improves impaired lysosomal function and autophagic flux. Loganin also attenuated the CCI-increased apoptosis protein Bax and cleaved caspase-3. Loganin prevents CCI-induced neuropathic pain, which could be attributed to the regulation of neuroinflammation, neuronal autophagy, and associated cell death. These data suggest autophagy could be a potential target for preventing neuropathic pain.
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Skaper, Stephen D., and Laura Facci. "Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide." Philosophical Transactions of the Royal Society B: Biological Sciences 367, no. 1607 (December 5, 2012): 3312–25. http://dx.doi.org/10.1098/rstb.2011.0391.
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Communication between the immune and nervous systems depends a great deal on pro-inflammatory cytokines. Both astroglia and microglia, in particular, constitute an important source of inflammatory mediators and may have fundamental roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Glial cells respond also to pro-inflammatory signals released from cells of immune origin. In this context, mast cells are of particular relevance. These immune-related cells, while resident in the CNS, are able to cross a compromised blood-spinal cord and blood-brain barrier in cases of CNS pathology. Emerging evidence suggests the possibility of mast cell–glia communication, and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization—both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of glia, neuro-immune interactions involving mast cells and the possibility that glia–mast cell interactions contribute to exacerbation of acute symptoms of chronic neurodegenerative disease and accelerated disease progression, as well as promotion of pain transmission pathways. Using this background as a starting point for discussion, we will consider the therapeutic potential of naturally occurring fatty acid ethanolamides, such as palmitoylethanolamide in treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.
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Carniglia, Lila, Delia Ramírez, Daniela Durand, Julieta Saba, Juan Turati, Carla Caruso, Teresa N. Scimonelli, and Mercedes Lasaga. "Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases." Mediators of Inflammation 2017 (2017): 1–23. http://dx.doi.org/10.1155/2017/5048616.
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Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
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Lopes, Flavia S. R., Aline C. Giardini, Morena B. Sant’Anna, Louise F. Kimura, Michelle C. Bufalo, Hugo Vigerelli, Vanessa O. Zambelli, and Gisele Picolo. "Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems." International Journal of Molecular Sciences 23, no. 19 (September 30, 2022): 11571. http://dx.doi.org/10.3390/ijms231911571.
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Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for β-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.
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Teixeira-Santos, Luísa, Eduardo Veríssimo, Sandra Martins, Teresa Sousa, António Albino-Teixeira, and Dora Pinho. "Effects of NADPH Oxidase Isoform-2 (NOX2) Inhibition on Behavioral Responses and Neuroinflammation in a Mouse Model of Neuropathic Pain." Biomedicines 11, no. 2 (January 31, 2023): 416. http://dx.doi.org/10.3390/biomedicines11020416.
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NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment with the NOX2-selective inhibitor (NOX2i) GSK2795039 on behavioral responses and spinal neuroinflammation in spared nerve injury (SNI)-induced NP in male and female mice. Mechanical sensitivity was evaluated with the von Frey test, while general well-being and anxiety-like behavior were assessed with burrowing and light/dark box tests. Spinal microglial activation and cytokines IL-1β, IL-6, and IL-10, as well as macrophage colony-stimulating factor (M-CSF) were evaluated by immunofluorescence and multiplex immunoassay, respectively. NOX2i treatment reduced SNI-induced mechanical hypersensitivity and early SNI-induced microglial activation in both sexes. SNI-females, but not males, showed a transient reduction in burrowing activity. NOX2i treatment did not improve their burrowing activity, but tendentially reduced their anxiety-like behavior. NOX2i marginally decreased IL-6 in females, and increased M-CSF in males. Our findings suggest that NOX2-selective inhibition may be a potential therapeutic strategy for NP in both male and female individuals, with particular interest in females due to its apparent favorable impact in anxiety-like behavior.
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Tajti, János, Délia Szok, Anett Csáti, Ágnes Szabó, Masaru Tanaka, and László Vécsei. "Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain." International Journal of Molecular Sciences 24, no. 4 (February 18, 2023): 4114. http://dx.doi.org/10.3390/ijms24044114.
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Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP.
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Hansson, Elisabeth, Linda Block, Johan Forshammar, Christopher Lundborg, and Björn Biber. "Na+/K+-ATPase dependent regulation of astrocyte Ca2+ signalling: A novel mechanism for modulation of long-term pain?" Scandinavian Journal of Pain 3, no. 3 (July 1, 2012): 185. http://dx.doi.org/10.1016/j.sjpain.2012.05.032.
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Abstract Background Long-term or chronic pain represents a major health problem and is associated with significant socio-economic costs. During injury, pain can be dissociated from its normal physiological role. It can persist for a longer period of time, even after the primary noxious stimulus has more or less subsided. Analgesic drugs, with predominant neuronal sites of actions, seem to be relatively ineffective. Chronic pain is probably partly a consequence of ongoing neuroinflammation. The mechanisms behind these phenomena, and how the neuronal and non-neuronal activities evoked by painful stimuli and inflammation are processed in the brain and throughout the CNS, are not well understood. Methods Primary cultures, calcium imaging, immunocyto-chemistry, Western blotting, cytokine release. Results Following pain stimuli increased activity of inflammatory receptors and shifts in intra- and extracellular ion concentrations occur within the CNS. One signalling pathway in astrocytes propagates Ca2+ waves, which initially decrease and then increase in form of oscillations in the astrocyte networks. This causes dysfunction in the astrocytic Ca2+ signalling resulting in down-regulation of Na+ transporters, and increased release of pro-inflammatory cytokines. The neurons will then increase their excitability and, hypothetically, also increase the sensitivity for development or potentiation of neuropathic pain states. Low-dose of potential anti-inflammatory and analgesic drugs restore the disturbed astrocytic Ca2+ signalling, and modulate the activity of inflammatory receptors and Na+/K+-ATPase. We recently report, in patients with long-term pain, changes in neurotrophic factors and pro-inflammatory cytokines in blood and CSF. Conclusions Dysfunction in downregulation of Na+ transporters, changed Ca2+ signalling in the astrocyte networks and release of cytokines from glial cells can lead to pathogenic chronic neuroinflammation. Modulation of the Na+/K+-ATPase activity and restoration with anti-inflammatory substances will lead to a balance between inflammatory and anti-inflammatory mediators in inflammatory reactive cells. The pharmacological treatment of today is directed towards neuronal over-excitability, unfortunately with less success. A novel pharmacological treatment strategy would thus be directed towards the activated astrocytes and microglial cells, being the source of the neuroinflammation. This will be an important knowledge for treatment in clinical therapy.
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Thakur, Vikram, Jayanarayanan Sadanandan, and Munmun Chattopadhyay. "High-Mobility Group Box 1 Protein Signaling in Painful Diabetic Neuropathy." International Journal of Molecular Sciences 21, no. 3 (January 30, 2020): 881. http://dx.doi.org/10.3390/ijms21030881.
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Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.
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Hsieh, Yueh-Ling, Nian-Pu Yang, Shih-Fong Chen, Yu-Lin Lu, and Chen-Chia Yang. "Early Intervention of Cold-Water Swimming on Functional Recovery and Spinal Pain Modulation Following Brachial Plexus Avulsion in Rats." International Journal of Molecular Sciences 23, no. 3 (January 21, 2022): 1178. http://dx.doi.org/10.3390/ijms23031178.
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Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS could promote functional recovery and pain modulation through the reduction of neuroinflammation and microglial overactivation in dorsal horn neurons at the early-stage of BPA. After BPA surgery was performed on rats, they were assigned to CWS or sham training for 5 min twice a day for two weeks. Functional behavioral responses were tested before and after BPA surgery, and each week during training. Results after the two-week training program showed significant improvements in BPA-induced motor and sensory loss (p < 0.05), lower inflammatory cell infiltration, and vacuole formation in injured nerves among the BPA–CWS group. Moreover, BPA significantly increased the expression of SP and IBA1 in dorsal horn neurons (p < 0.05), whereas CWS prevented their overexpression in the BPA–CWS group. The present findings evidenced beneficial rehabilitative effects of CWS on functional recovery and pain modulation at early-stage BPA. The beneficial effects are partially related to inflammatory suppression and spinal modulation. The synergistic role of CWS combined with other management approaches merits further investigation.
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ABSTRACT BOOK, Anonymes. "Abstract Book of 7th Brain Research School (2022-BRS), 27 June and 3 July 2022, Isparta, Turkey (http://2022.brs.org.tr/)." Journal of Cellular Neuroscience and Oxidative Stress 14, no. 2 (Supplement 1) (July 14, 2022): 1–24. http://dx.doi.org/10.37212/jcnos.1143834.
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7th Brain Research School (2022-BRS) was performed in Isparta, Turkey between 27 June and 3 July 2022 (http://2022.brs.org.tr/). There were abstracts of 8 speakers, 11 oral presentations, and 3 poster presentations in the 2022-BRS. Titles of speakers; 1- Mustafa NAZIROĞLU. Fluorescent Ca2+ stains for imaging the mice microglia. 2- Beatrice Mihaela RADU. Low-energy accelerated protons irradiation inhibits DNA repair and diminishes cell proliferation, migration and calcium signaling in brain microvascular endothelial cells. 3- Nashat ABUMARIA. Behavioral assays and animal models of psychiatric disorders. 4- Ferah YILDIRIM. Mapping genome-wide DNA methylation changes in alcohol use disorder (No abstrcat). 5- Marco CANEPARI. Principles of Ca2+ imaging using low-affinity indicators. 6- Denis ROUSSEAU. Western blot analyses in the mitochondria. 7- Xinhua SHU. Protection of p-Coumaric acid against depression and memory impairment via inhibition of neuroinflammation 8- Simon HEBEISEN. State dependent block of voltage gated sodium and calcium channels as modern treatment for epilepsy. Titles of oral presentations (OPs); OP1. Bünyamin AYDIN. Diabetic neuropathic pain and TRPM2 Channel: Focus on selenium. OP2. Agomelatine attenuates calcium signaling and apoptosis via the inhibition of TRPV1 channel in the hippocampal neurons of rats with chronic mild stress depression model. OP3. Hatice DALDAL. An interaction between cisplatin-induced optic nerve injury and TRPM2 channel. OP4. Kemal ERTİLAV. Recent developments on the traumatic brain injury models in the experimental animals. OP5. Kaan ERBAKAN. Involvement of TRPV1 channel in the etiology of epilepsy. OP6. Ramazan ÇINAR. Does GSH depletion induce TRPM2 activation in neuronal cells? OP7. Esin AKBAY ÇETİN. TRP ion channels and approaches in COVID-19. OP8. Gülin ÖZDAMAR ÜNAL. Early life stress and neuroinflammation. OP9. Adem AHLATCI. Investigation of TRPM2 cation channel activation in PTZ-induced SH-SY5Y cells by patch-clamp technique: Regulatory role of valproic acid. OP10. Yener YAZĞAN. Orthodontic teeth movement-induced pain and TRPV1 channel. OP11. Evaluation of the role of Radish (Raphanus sativus) extract in movement tests in MPTP induced experimental Parkinson's model in Balb/C mice. Titles of poster presentations (P); P1- Esin AKBAY ÇETİN. Probable pathways of SARS-CoV-2 to central nervous system. P2. Yusuf DAL. Low molecular weight heparin treatment reduced apoptosis, oxidative stress, and calcium signaling in the thrombocytes of patients with recurrent pregnancy loss and thrombophilia: Involvements of TRPM2 and TRPV1 channels. P3. Ferruh KARAMANGİL. Investigation of frequency and diversity of experimental animal models of schizophrenia.
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Wu, Zong-Sheng, Jing-Jou Lo, Sheng-Hua Wu, Chau-Zen Wang, Rong-Fu Chen, Su-Shin Lee, Chee-Yin Chai, and Shu-Hung Huang. "Early Hyperbaric Oxygen Treatment Attenuates Burn-Induced Neuroinflammation by Inhibiting the Galectin-3-Dependent Toll-Like Receptor-4 Pathway in a Rat Model." International Journal of Molecular Sciences 19, no. 8 (July 27, 2018): 2195. http://dx.doi.org/10.3390/ijms19082195.
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Hyperbaric oxygen (HBO) treatment has been proven to decrease neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague-Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment; (2) sham burn with HBO treatment; (3) burn with one-week sham HBO treatment; (4) burn with two-week sham HBO treatment; (5) burn with one-week HBO treatment; and (6) burn with two-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting. A behavior test was also conducted, which revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared to the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor α (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis showed that the expression of Gal-3, TLR-4, CD68 and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia and macrophage activation in a rat model.
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Aldskogius, Håkan, and Elena Kozlova. "Microglia and Neuropathic Pain." CNS & Neurological Disorders - Drug Targets 12, no. 6 (August 31, 2013): 768–72. http://dx.doi.org/10.2174/18715273113126660168.
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Inoue, Kazuhide, and Makoto Tsuda. "Microglia and neuropathic pain." Glia 57, no. 14 (November 1, 2009): 1469–79. http://dx.doi.org/10.1002/glia.20871.
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Beggs, Simon, Tuan Trang, and Michael W. Salter. "P2X4R+ microglia drive neuropathic pain." Nature Neuroscience 15, no. 8 (July 26, 2012): 1068–73. http://dx.doi.org/10.1038/nn.3155.
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Ward, Harry, and Steven J. West. "Microglia: sculptors of neuropathic pain?" Royal Society Open Science 7, no. 6 (June 2020): 200260. http://dx.doi.org/10.1098/rsos.200260.
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Neuropathic pain presents a huge societal and individual burden. The limited efficacy of current analgesics, diagnostic markers and clinical trial outcome measures arises from an incomplete understanding of the underlying mechanisms. A large and growing body of evidence has established the important role of microglia in the onset and possible maintenance of neuropathic pain, and these cells may represent an important target for future therapy. Microglial research has further revealed their important role in structural remodelling of the nervous system. In this review, we aim to explore the evidence for microglia in sculpting nervous system structure and function, as well as their important role in neuropathic pain, and finally integrate these studies to synthesize a new model for microglia in somatosensory circuit remodelling, composed of six key and inter-related mechanisms. Summarizing the mechanisms through which microglia modulate nervous system structure and function helps to frame a better understanding of neuropathic pain, and provide a clear roadmap for future research.
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Inoue, Kazuhide. "Microglia activation in neuropathic pain." Neuroscience Research 68 (January 2010): e32. http://dx.doi.org/10.1016/j.neures.2010.07.384.
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Widyadharma, Putu Eka, Aurelia Vania, Jimmy FA Barus, Yudiyanta ., and Thomas Eko Purwata. "Biomarkers for microglia activation in neuropathic pain." Anaesthesia, Pain & Intensive Care 24, no. 1 (May 7, 2020): 87–93. http://dx.doi.org/10.35975/apic.v24i1.1229.
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Neuropathic pain (NP) is a result of direct disturbances of somatosensory pathways. Its pathophysiology includes various mechanisms. Recent studies have reported an important role of microglia in the NP mechanism. There are several chemical molecules which are involved in microglia activation. The activated microglia will, in turn, enhance some receptors expression that can be used as markers of its activation. Though we still need future studies about precise microglia role in NP mechanism, the chemical mediators that initiate microglia activation and the alteration of some receptors in the activated microglia which have been found from previous studies can be the interesting future research materials and the promising target for a new therapy for NP.
Citation: Widyadharma PE, Vania A, Barus JFA, Yudiyanta, Purwata TE. Biomarkers for microglia activation in neuropathic pain. Anaesth pain intensive care 2020;24(1):___
DOI: https://doi.org/10.35975/apic.v24i1.
Received – 12 June 2019,
Reviewed – 15 September 2019, 29 February 2020,
Accepted – 2 March 2020;
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Trang, Tuan, Simon Beggs, and Michael W. Salter. "Purinoceptors in microglia and neuropathic pain." Pflügers Archiv - European Journal of Physiology 452, no. 5 (April 22, 2006): 645–52. http://dx.doi.org/10.1007/s00424-006-0074-5.
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Tsuda, Makoto, Hidetoshi Tozaki-Saitoh, and Kazuhide Inoue. "Purinergic system, microglia and neuropathic pain." Current Opinion in Pharmacology 12, no. 1 (February 2012): 74–79. http://dx.doi.org/10.1016/j.coph.2011.10.014.
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Smith, Howard. "Activated Microglia in Nociception." Pain Physician 3;13, no. 3;5 (May 14, 2010): 295–304. http://dx.doi.org/10.36076/ppj.2010/13/295.
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Microglial cells appear to play a vital role in the initiation of certain neuropathic pain states. In order to initiate neuropathic pain, microglia need to be activated. Microglia activation in the spinal cord involves both hypertrophy as well as hyperplasia, progressing through a hypertrophic morphology, with thickened and retracted processes (observed within the first 24 hours after nerve injury), and an increase in cell number (observed around 2–3 days after nerve injury). There seems to be at least 5 major paths to activate microglia. These 5 pathways will be discussed and are identified by their main signaling mediator and/or receptor which include fractalkine, interferon-gamma, monocyte chemoattractant protein-1, TLR4, and P2X4. Thus, one or more of these mediators/pathways which lead to microglial activation might contribute to neuropathic pain. A greater appreciation of the roles of various mediators/paths which activate microglia might help lead to future novel therapeutic targets in efforts to ameliorate severe symptoms of neuropathic pain. Key words: microglial cells, glia, C-fiber nociceptors, neuropathic pain, hypertrophy, hyperplasia
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Ellis, A., and D. L. H. Bennett. "Neuroinflammation and the generation of neuropathic pain." British Journal of Anaesthesia 111, no. 1 (July 2013): 26–37. http://dx.doi.org/10.1093/bja/aet128.
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Damo, Elisa, Amit Agarwal, and Manuela Simonetti. "Activation of β2-Adrenergic Receptors in Microglia Alleviates Neuropathic Hypersensitivity in Mice." Cells 12, no. 2 (January 11, 2023): 284. http://dx.doi.org/10.3390/cells12020284.
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Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.
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Inoue, Kazuhide, and Makoto Tsuda. "P2X4 Receptors of Microglia in Neuropathic Pain." CNS & Neurological Disorders - Drug Targets 11, no. 6 (October 1, 2012): 699–704. http://dx.doi.org/10.2174/187152712803581065.
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Masuda, Takahiro, Makoto Tsuda, and Kazuhide Inoue. "Transcriptional regulation in microglia and neuropathic pain." Pain Management 6, no. 2 (April 2016): 91–94. http://dx.doi.org/10.2217/pmt.15.34.
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Inoue, Kazuhide. "A state-of-the-art perspective on microgliopathic pain." Open Biology 8, no. 11 (November 2018): 180154. http://dx.doi.org/10.1098/rsob.180154.
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Acute nociceptive pain is an undesirable feeling but has a physiological significance as a warning system for living organisms. Conversely, chronic pain is lacking physiological significance, but rather represents a confusion of nerve functions. The neuropathic pain that occurs after peripheral nerve injury (PNI) is perhaps the most important type of chronic pain because it is refractory to available medications and thus remains a heavy clinical burden. In recent decades, studies have shown that spinal microglia play a principal role in the alterations in synaptic functions evoking this pain. It is also clear that the P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, is upregulated exclusively in spinal microglia after PNI and plays a key role in evoking neuropathic pain. Neuropathic pain is caused by several conditions associated with activated microglia without nerve damage. ‘Microgliopathic pain’ is a new concept indicating such abnormal pain related to activated microglia.
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Hasriadi, Peththa Wadu Dasuni Wasana, Opa Vajragupta, Pornchai Rojsitthisak, and Pasarapa Towiwat. "Mechanistic Insight into the Effects of Curcumin on Neuroinflammation-Driven Chronic Pain." Pharmaceuticals 14, no. 8 (August 7, 2021): 777. http://dx.doi.org/10.3390/ph14080777.
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Chronic pain is a persistent and unremitting condition that has immense effects on patients’ quality of life. Studies have shown that neuroinflammation is associated with the induction and progression of chronic pain. The activation of microglia and astrocytes is the major hallmark of spinal neuroinflammation leading to neuronal excitability in the projection neurons. Excessive activation of microglia and astrocytes is one of the major contributing factors to the exacerbation of pain. However, the current chronic pain treatments, mainly by targeting the neuronal cells, remain ineffective and unable to meet the patients’ needs. Curcumin, a natural plant product found in the Curcuma genus, improves chronic pain by diminishing the release of inflammatory mediators from the spinal glia. This review details the role of curcumin in microglia and astrocytes both in vitro and in vivo and how it improves pain. We also describe the mechanism of curcumin by highlighting the major glia-mediated cascades in pain. Moreover, the role of curcumin on inflammasome and epigenetic regulation is discussed. Furthermore, we discuss the strategies used to improve the efficacy of curcumin. This review illustrates that curcumin modulating microglia and astrocytes could assure the treatment of chronic pain by suppressing spinal neuroinflammation.