P2X7 Receptor of Microglia Mediates Neuropathic pain by Regulating Autophagy After Chronic-Constriction Injury

Abstract P2X7 receptor is a crucial receptor related to neuronal activation, neurosensitization, and pain transmission, and increasing evidences indicated that glial cells is thought to be a major contributor to the chronic neuropathic pain after nerve injury. In present study, we designed to investigate whether the P2X7R in glial plays a role in chronic neuropathic pain. We divided adult male Sprague Dawley rats were respectively into four groups:(1) vehicle group (Veh), (2) CCI (C group), (3) P2X7 inhibitor group (P group), (4) CCI+ P2X7R inhibition (CP group). Behavior test, real-time polymerase chain reaction, western blot, immunofluorescence staining, and transmission electron microscope were used to analyze the scientific hypothesis. The results of the experiment is that(i) P2X7R of microglia was downregulated by A-70003 after CCI. (ii) Downregulation of P2X7R on microglia is coincident with remission of NP after CCI. (iii) P2X7R of microglia participates in NP via regulating autophagy and apoptosis. In summary, our results support P2X7R inhibition can counteract the CCI-induced NP due to microglia activation via a modulation of autophagy and apoptosis in mPFC and spinal cord. This may provide an importantly neuroprotective mechanism for the improved NP and also help devising new therapeutic to improve chronic pain in patients.

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Chronic Oral Gabapentin Reduces Elements of Central Sensitization in Human Experimental Hyperalgesia

Anesthesiology ◽

10.1097/00000542-200412000-00021 ◽

2004 ◽

Vol 101 (6) ◽

pp. 1400-1408 ◽

Cited By ~ 70

Author(s):

Hanne Gottrup ◽

Gitte Juhl ◽

Anders D. Kristensen ◽

Robert Lai ◽

Boris A. Chizh ◽

...

Keyword(s):

Neuropathic Pain ◽

Central Sensitization ◽

Human Subjects ◽

Clinical Signs ◽

Experimental Models ◽

Human Model ◽

Chronic Neuropathic Pain ◽

Double Blind ◽

Pain Transmission ◽

Parallel Group Design

Background In chronic pain, increased activity from intact or damaged peripheral nerve endings results in an enhanced response in central pain transmission systems, a mechanism known as central sensitization. Central sensitization can also be invoked in human experimental models. Therefore, these models may be useful to characterize novel analgesics in humans. The anticonvulsant gabapentin has demonstrated efficacy in patients with neuropathic pain, but its mode of action remains unclear. This study examined the effects of gabapentin on signs of central sensitization (brush and pinprick hyperalgesia) in a human model of capsaicin-evoked pain, using a gabapentin dosing regimen similar to that used in the clinic. The aims were to determine whether gabapentin, dosed in a manner similar to that used in the clinic, affected the various components of central sensitization and to assess the utility of this model for characterizing novel analgesics. Methods Intradermal capsaicin (100 microg/20 microl) was administered in the volar forearm of 41 male human volunteers to induce pain and clinical signs of central sensitization. Gabapentin (titrated to 2,400 mg daily) or placebo was given orally for 15 days in a randomized, double-blind, parallel-group design. The capsaicin test was conducted at baseline and after gabapentin or placebo. Endpoints were the size of areas of brush-evoked allodynia (with cotton gauze) and pinprick hyperalgesia (with von Frey filament), and the intensity of ongoing brush- and pinprick-evoked pain. Results Gabapentin significantly reduced the area of brush allodynia compared with placebo (P </= 0.05) and insignificantly attenuated the area of pinprick hyperalgesia. Gabapentin had no significant effect on spontaneous and evoked pain intensity. Conclusion Oral gabapentin, administered to healthy volunteers in a regimen similar to that used in treating chronic neuropathic pain, reduces measures of central sensitization evoked by intradermal capsaicin. This suggests that the pain-relieving effect in chronic neuropathic pain condition is linked to the effect of gabapentin on central sensitization. The ability of the capsaicin model to detect the efficacy of this standard treatment of neuropathic pain suggests that it may have a predictive value for detection of efficacy in human subjects.

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ERK activation in noradrenergic and serotonergic brainstem nuclei in chronic pain upon noxious stimulation and antidepressants treatment

Microscopy and Microanalysis ◽

10.1017/s1431927609990493 ◽

2009 ◽

Vol 15 (S3) ◽

pp. 7-8

Author(s):

G. Borges ◽

E. Berrocoso ◽

A. Ortega-Alvaro ◽

J. A. Micó ◽

F. L. Neto

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Chronic Constriction Injury ◽

Noxious Stimulation ◽

Analgesic Action ◽

Chronic Neuropathic Pain ◽

Erk Activation ◽

Pain Transmission ◽

Extracellular Signal ◽

Brainstem Nuclei

AbstractChronic neuropathic pain is a pathology that affects thousands of people worldwide. Antidepressants have been prescribed for the treatment of this sort of pain but the mechanisms underlying their analgesic action remain unknown. Extracellular-signal regulated kinases (ERKs) are being implicated in pain transmission and modulation as well as in the pathophysiology of depression. In order to clarify some of the mechanisms which might be related to the analgesic effect of antidepressants, we started by evaluating possible changes in the pattern of activation of ERKs in rats with chronic constriction injury (CCI), an experimental model of chronic

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Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

Neural Plasticity ◽

10.1155/2017/2480689 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 31

Author(s):

Young S. Gwak ◽

Claire E. Hulsebosch ◽

Joong Woo Leem

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Sensory Neurons ◽

Glial Cells ◽

Intracellular Signaling ◽

Glial Activation ◽

Chronic Neuropathic Pain ◽

Pain Transmission ◽

Cord Injury

The hyperactive state of sensory neurons in the spinal cord enhances pain transmission. Spinal glial cells have also been implicated in enhanced excitability of spinal dorsal horn neurons, resulting in pain amplification and distortions. Traumatic injuries of the neural system such as spinal cord injury (SCI) induce neuronal hyperactivity and glial activation, causing maladaptive synaptic plasticity in the spinal cord. Recent studies demonstrate that SCI causes persistent glial activation with concomitant neuronal hyperactivity, thus providing the substrate for central neuropathic pain. Hyperactive sensory neurons and activated glial cells increase intracellular and extracellular glutamate, neuropeptides, adenosine triphosphates, proinflammatory cytokines, and reactive oxygen species concentrations, all of which enhance pain transmission. In addition, hyperactive sensory neurons and glial cells overexpress receptors and ion channels that maintain this enhanced pain transmission. Therefore, post-SCI neuronal-glial interactions create maladaptive synaptic circuits and activate intracellular signaling events that permanently contribute to enhanced neuropathic pain. In this review, we describe how hyperactivity of sensory neurons contributes to the maintenance of chronic neuropathic pain via neuronal-glial interactions following SCI.

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