740 Selective Ablation of Nociceptive Neurons for Elimination 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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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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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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Angiotensin Type 2 Receptors: Painful, or Not?

Frontiers in Pharmacology ◽

10.3389/fphar.2020.571994 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lakshmi Pulakat ◽

Colin Sumners

Keyword(s):

Neuropathic Pain ◽

Tissue Repair ◽

Drug Target ◽

Drug Targets ◽

Acute Injury ◽

Nociceptive Neurons ◽

Inflammatory Models ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as ‘pain caused by a lesion or disease of the somatosensory nervous system’, is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (AT2R) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that AT2R activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that AT2R antagonists are anti-nociceptive and therefore AT2R is a drug target for neuropathic pain. However, AT2R expression in nociceptive neurons is lacking, indicating that neuronal AT2R is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that AT2R antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may AT2R not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.

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Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter

Cell Research ◽

10.1038/cr.2014.106 ◽

2014 ◽

Vol 24 (11) ◽

pp. 1374-1377 ◽

Cited By ~ 55

Author(s):

Xing-Jun Liu ◽

Yanli Zhang ◽

Tong Liu ◽

Zhen-Zhong Xu ◽

Chul-Kyu Park ◽

...

Keyword(s):

Neuropathic Pain ◽

Adaptive Immunity ◽

Innate And Adaptive Immunity ◽

Nociceptive Neurons

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Pathways that elicit long-term changes in gene expression in nociceptive neurons following nerve injury: contributions to neuropathic pain

Neurological Research ◽

10.1179/016164104225013761 ◽

2004 ◽

Vol 26 (2) ◽

pp. 195-203 ◽

Cited By ~ 17

Author(s):

Ying-Ju Sung ◽

Richard T. Ambron

Keyword(s):

Gene Expression ◽

Neuropathic Pain ◽

Nerve Injury ◽

Nociceptive Neurons ◽

Long Term Changes

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SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology

Neurology Genetics ◽

10.1212/nxg.0000000000000255 ◽

2018 ◽

Vol 4 (4) ◽

pp. e255 ◽

Cited By ~ 8

Author(s):

Ryan Castoro ◽

Megan Simmons ◽

Vignesh Ravi ◽

Derek Huang ◽

Christopher Lee ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Fiber ◽

Sensory Neuropathy ◽

Nociceptive Pain ◽

Missense Mutations ◽

Nociceptive Neurons ◽

Small Fiber ◽

Skin Biopsies ◽

Electrophysiologic Studies ◽

Small Nerve

ObjectiveThe SCN11A gene encodes the NaV1.9 sodium channel found exclusively in peripheral nociceptive neurons.MethodsAll enrolled participants were evaluated clinically by electrophysiologic studies, DNA sequencing, and punch skin biopsies.ResultsAll affected family members are afflicted by episodes of pain. Pain was predominantly nociceptive, but not neuropathic in nature, which led a diagnosis of fibromyalgia in some patients. All patients had normal findings in nerve conduction studies for detecting large nerve fiber neuropathies and skin biopsies for detecting small nerve fiber pathology.ConclusionsUnlike those patients with missense mutations in SCN11A, small fiber sensory neuropathy, and neuropathic pain, the Arg225Cys SCN11A in the present study causes predominantly nociceptive pain with minimal features of neuropathic pain and undetectable pathophysiologic changes of peripheral neuropathy. This finding is consistent with dysfunction of nociceptive neurons. In addition, since nociceptive pain in patients has led to the diagnosis of fibromyalgia, this justifies a future search of mutations of SCN11A in patients with additional pain phenotypes such as fibromyalgia to expand the clinical spectrum beyond painful small fiber sensory neuropathy.

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The Role of TMEM16A/ERK/NK-1 Signaling in Dorsal Root Ganglia Neurons in the Development of Neuropathic Pain Induced by Spared Nerve Injury (SNI)

Molecular Neurobiology ◽

10.1007/s12035-021-02520-9 ◽

2021 ◽

Author(s):

Qinyi Chen ◽

Liangjingyuan Kong ◽

Zhenzhen Xu ◽

Nan Cao ◽

Xuechun Tang ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Dorsal Root ◽

Electrophysiological Recording ◽

Erk Pathway ◽

Spared Nerve Injury ◽

Positive Interaction ◽

Nociceptive Neurons ◽

Nociceptive Responses

AbstractIncreasing evidence suggests that transmembrane protein 16A (TMEM16A) in nociceptive neurons is an important molecular component contributing to peripheral pain transduction. The present study aimed to evaluate the role and mechanism of TMEM16A in chronic nociceptive responses elicited by spared nerve injury (SNI). In this study, SNI was used to induce neuropathic pain. Drugs were administered intrathecally. The expression and cellular localization of TMEM16A, the ERK pathway, and NK-1 in the dorsal root ganglion (DRG) were detected by western blot and immunofluorescence. Behavioral tests were used to evaluate the role of TMEM16A and p-ERK in SNI-induced persistent pain and hypersensitivity. The role of TMEM16A in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. The results show that TMEM16A, p-ERK, and NK-1 are predominantly expressed in small neurons associated with nociceptive sensation. TMEM16A is colocalized with p-ERK/NK-1 in DRG. TMEM16A, the MEK/ERK pathway, and NK-1 are activated in DRG after SNI. ERK inhibitor or TMEM16A antagonist prevents SNI-induced allodynia. ERK and NK-1 are downstream of TMEM16A activation. Electrophysiological recording showed that CaCC current increases and intrathecal application of T16Ainh-A01, a selective TMEM16A inhibitor, reverses the hyperexcitability of DRG neurons harvested from rats after SNI. We conclude that TMEM16A activation in DRG leads to a positive interaction of the ERK pathway with activation of NK-1 production and is involved in the development of neuropathic pain after SNI. Also, the blockade of TMEM16A or inhibition of the downstream ERK pathway or NK-1 upregulation may prevent the development of neuropathic pain.

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Effects of a Cannabinoid Agonist on Spinal Nociceptive Neurons in a Rodent Model of Neuropathic Pain

Journal of Neurophysiology ◽

10.1152/jn.00498.2006 ◽

2006 ◽

Vol 96 (6) ◽

pp. 2984-2994 ◽

Cited By ~ 25

Author(s):

Cheng Liu ◽

J. Michael Walker

Keyword(s):

Neuropathic Pain ◽

Receptive Field ◽

Nerve Injury ◽

Dynamic Range ◽

Rodent Model ◽

Field Size ◽

Neural Basis ◽

Noxious Heat ◽

Nociceptive Neurons ◽

Wdr Neurons

The effects of the synthetic cannabinoid WIN 55,212–2 on heat-evoked firing of spinal wide dynamic range (WDR) neurons were examined in a rodent model of neuropathic pain. Fifty-eight WDR neurons (1 cell/animal) were recorded from the ipsilateral spinal dorsal horns of rats with chronic constriction injury (CCI) and sham-operated controls. Relative to sham-operated controls, neurons recorded in CCI rats showed elevations in spontaneous firing, noxious heat-evoked responses, and afterdischarge firing as well as increases in receptive field size. WIN 55,212–2 (0.0625, 0.125, and 0.25 mg/kg, intravenous) dose-dependently suppressed heat-evoked activity and decreased the receptive field areas of dorsal horn WDR neurons in both nerve injured and control rats with a greater inhibition in CCI rats. At the dose of 0.125 mg/kg iv, WIN 55,212–2 reversed the hyperalgesia produced by nerve injury. The effect of intravenous administration of WIN 55,212–2 appears to be centrally mediated because administration of the drug directly to the ligated nerve did not suppress the heat-evoked neuronal activity in CCI rats. Pretreatment with the cannabinoid CB1 receptor antagonists SR141716A or AM251, but not the CB2 antagonist SR144528, blocked the effects. These results provide a neural basis for reports of potent suppression by cannabinoids of the abnormal sensory responses that result from nerve injury.

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