Molecular mechanisms and signaling by comenic acid in nociceptive neurons influence the pathophysiology of neuropathic pain

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

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Sortilins in neuropathic pain

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2012.05.028 ◽

2012 ◽

Vol 3 (3) ◽

pp. 183-184

Author(s):

M. Richner ◽

O.J. Bjerrum ◽

Y. De Koninck ◽

A. Nykjaer ◽

C.B. Vaegter

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Molecular Mechanisms ◽

Intrathecal Injection ◽

Ion Concentration ◽

Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

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Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820466116 ◽

2019 ◽

Vol 116 (21) ◽

pp. 10557-10562 ◽

Cited By ~ 19

Author(s):

Zhoumou Chen ◽

Timothy M. Doyle ◽

Livio Luongo ◽

Tally M. Largent-Milnes ◽

Luigino Antonio Giancotti ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Molecular Mechanisms ◽

Interleukin 10 ◽

Sphingolipid Metabolism ◽

Receptor Subtype ◽

Endogenous Opioid ◽

Major Health Problem ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

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Loss of SNHG4 Attenuated Spinal Nerve Ligation-Triggered Neuropathic Pain through Sponging miR-423-5p

Mediators of Inflammation ◽

10.1155/2020/2094948 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Xia Pan ◽

Cheng Shen ◽

Yayi Huang ◽

Long Wang ◽

Zhongyuan Xia ◽

...

Keyword(s):

Neuropathic Pain ◽

Molecular Mechanisms ◽

Thermal Hyperalgesia ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Rat Models ◽

Tnf Α ◽

Cord Injury ◽

Gene 4 ◽

Nucleolar Rna

Neuropathic pain is an intractable comorbidity of spinal cord injury. Increasing noncoding RNAs have been implicated in neuropathic pain development. lncRNAs have been recognized as significant regulators of neuropathic pain. lncRNA Small Nucleolar RNA Host Gene 4 (SNHG4) is associated with several tumors. However, the molecular mechanisms of SNHG4 in neuropathic pain remain barely documented. Here, we evaluated the function of SNHG4 in spinal nerve ligation (SNL) rat models. We observed that SNHG4 was significantly upregulated in SNL rat. Knockdown of SNHG4 was able to attenuate neuropathic pain progression via regulating behaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, knockdown of SNHG4 could repress the neuroinflammation via inhibiting IL-6, IL-12, and TNF-α while inducing IL-10 levels. Additionally, miR-423-5p was predicted as the target of SNHG4 by employing bioinformatics analysis. miR-423-5p has been reported to exert significantly poorer in several diseases. However, the role of miR-423-5p in the development of neuropathic pain is needed to be clarified. Here, in our investigation, RIP assay confirmed the correlation between miR-423-5p and SNHG4. Meanwhile, we found that miR-423-5p was significantly decreased in SNL rat models. SNHG4 regulated miR-423-5p expression negatively. As exhibited, the loss of miR-423-5p contributed to neuropathic pain progression, which was rescued by the silence of SNHG4. Therefore, our study indicated SNHG4 as a novel therapeutic target for neuropathic pain via sponging miR-423-5p.

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Microglia–Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21186834 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6834

Author(s):

Sayaka Asano ◽

Yoshinori Hayashi ◽

Koichi Iwata ◽

Akiko Okada-Ogawa ◽

Suzuro Hitomi ◽

...

Keyword(s):

Neuropathic Pain ◽

Glial Fibrillary Acidic Protein ◽

Nerve Injury ◽

Fluorescence Intensity ◽

Time Window ◽

Infraorbital Nerve ◽

Nociceptive Neurons ◽

Mechanical Hypersensitivity ◽

Injury Causes ◽

Immunohistochemical Analyses

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

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(256) Molecular mechanisms of stress exacerbated neuropathic pain in peripheral nerve injury

Journal of Pain ◽

10.1016/j.jpain.2015.01.173 ◽

2015 ◽

Vol 16 (4) ◽

pp. S40

Author(s):

J. Lerch ◽

N. Hashi ◽

A. Zawerton ◽

T. Quach ◽

P. Popovich

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms

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Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

PLoS ONE ◽

10.1371/journal.pone.0091297 ◽

2014 ◽

Vol 9 (3) ◽

pp. e91297 ◽

Cited By ~ 28

Author(s):

Karine Thibault ◽

Bernard Calvino ◽

Isabelle Rivals ◽

Fabien Marchand ◽

Sophie Dubacq ◽

...

Keyword(s):

Neuropathic Pain ◽

Analgesic Effect ◽

Molecular Mechanisms

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740 Selective Ablation of Nociceptive Neurons for Elimination of Neuropathic Pain

Neurosurgery ◽

10.1227/00006123-200408000-00076 ◽

2004 ◽

Vol 55 (2) ◽

pp. 465-466

Author(s):

Gabriel C. Tender ◽

Stuart Walbridge ◽

Zoltan Olah ◽

Laszlo Karai ◽

Michael Iadarola ◽

...

Keyword(s):

Neuropathic Pain ◽

Nociceptive Neurons ◽

Selective Ablation

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Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK-Induced Anti-Opioid Effects

Pain Research and Management ◽

10.1155/2000/347212 ◽

2000 ◽

Vol 5 (1) ◽

pp. 49-57 ◽

Cited By ~ 1

Author(s):

Catherine M Cahill ◽

Terence J Coderre

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Nerve Injury ◽

Postnatal Period ◽

Spontaneous Pain ◽

Pain Mechanisms ◽

Nociceptive Neurons ◽

Nociceptive Transmission ◽

Chronic Pain Conditions ◽

Injury Models

The breadth of peripheral effects produced by nerve growth factor (NGF) in nociceptive processing has been well documented. However, less is known about the functional significance of central NGF in nociceptive transmission. The effect of NGF on the nervous system is dependent on the developmental stage. During the prenatal developmental period, NGF is critical for survival of nociceptors; in the postnatal period it regulates the expression of nociceptor phenotype, and in the adult it contributes to pain following an inflammatory insult. The implications for central NGF in the expression and regulation of spinal neuropeptides that are involved in pain mechanisms are reviewed. Knowledge has been gained by studies using peripheral nerve injury models that cause a deprivation of central NGF. These models also give rise to the development of pain syndromes, which encompass spontaneous pain, hyperalgesia and allodynia, routinely referred to as neuropathic pain. These models provide an approach for examining the contribution of central NGF to nociceptive transmission. Chronic pain emanating from a nerve injury is typically refractory to traditional analgesics such as opioids. Recent evidence suggests that supplementation of spinal NGF restores morphine-induced antinociception in an animal model of neuropathic pain. This effect appears to be mediated by alterations in spinal levels of cholecystokinin. The authors hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.

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Identification and integrated analysis of neuropathic pain-related circular RNA signature

10.21203/rs.3.rs-87121/v1 ◽

2020 ◽

Author(s):

Kun Wang ◽

Zhimin Zhou ◽

Junping Bao ◽

Dong Liu ◽

Yuanbin Hu ◽

...

Keyword(s):

Neuropathic Pain ◽

Molecular Mechanisms ◽

Circular Rna ◽

Gene Expression Omnibus ◽

Circular Rnas ◽

Integrated Analysis ◽

Biological Processes ◽

Non Coding Rnas ◽

Microarray Datasets ◽

Competitive Endogenous Rna

Abstract Background: More and more evidences show that non-coding RNAs are involved in neuropathic pain, however, there are few reports on the regulatory mechanism of competitive endogenous RNA (ceRNA) in neuropathic pain. The purpose of this study is to explore the possible molecular mechanisms of neuropathic pain. Methods: We collected neuropathic pain-related microarray datasets providing expression profile of circular RNAs (circRNAs) and mRNAs from the Gene Expression Omnibus (GEO) and then performed bioinformatics analysis on them. Results: The present study has identified that up-regulated circRNAs primarily regulate the activity of focal adhesion-associated biological processes and down-regulated primarily regulate the activity of metabolic-associated biological processes by means of ceRNAs. Conclusions: Our data suggest that circRNAs may be candidates for pathogenesis in neuropathic pain and may be considered as promising therapeutic targets in the future.

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