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

2004 ◽  
Vol 101 (6) ◽  
pp. 1400-1408 ◽  
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.

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

2021 ◽  
Author(s):  
Qi Zhong ◽  
Yifei Huang ◽  
Bo Zhang ◽  
Tingting Li ◽  
Peng Fang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
P2x7 Receptor ◽  
Group Behavior ◽  
Vehicle Group ◽  
Sprague Dawley ◽  
Chronic Neuropathic Pain ◽  
Group 4 ◽  
Pain Transmission ◽  
Transmission Electron ◽  
Scientific Hypothesis

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.

scholarly journals mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Lucia Lisi ◽  
Paola Aceto ◽  
Pierluigi Navarra ◽  
Cinzia Dello Russo
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Mammalian Target Of Rapamycin ◽  
Public Health Problem ◽  
Experimental Models ◽  
Major Public Health Problem ◽  
Major Mechanism ◽  
Mtor Kinase ◽  
Pain Transmission ◽  
Pharmacological Target

Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40–60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.

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

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

scholarly journals The Neuropeptide Cortistatin Alleviates Neuropathic Pain in Experimental Models of Peripheral Nerve Injury

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 947
Author(s):  
Clara P. Falo ◽  
Raquel Benitez ◽  
Marta Caro ◽  
Maria Morell ◽  
Irene Forte-Lago ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Clinical Manifestations ◽  
Somatosensory System ◽  
Experimental Models ◽  
Protective Capacity ◽  
Chronic Neuropathic Pain ◽  
Inflammatory Conditions

Neuropathic pain is one of the most severe forms of chronic pain caused by the direct injury of the somatosensory system. The current drugs for treating neuropathies have limited efficacies or show important side effects, and the development of analgesics with novel modes of action is critical. The identification of endogenous anti-nociceptive factors has emerged as an attractive strategy for designing new pharmacological approaches to treat neuropathic pain. Cortistatin is a neuropeptide with potent anti-inflammatory activity, recently identified as a natural analgesic peptide in several models of pain evoked by inflammatory conditions. Here, we investigated the potential analgesic effect of cortistatin in neuropathic pain using a variety of experimental models of peripheral nerve injury caused by chronic constriction or partial transection of the sciatic nerve or by diabetic neuropathy. We found that the peripheral and central injection of cortistatin ameliorated hyperalgesia and allodynia, two of the dominant clinical manifestations of chronic neuropathic pain. Cortistatin-induced analgesia was multitargeted, as it regulated the nerve damage-induced hypersensitization of primary nociceptors, inhibited neuroinflammatory responses, and enhanced the production of neurotrophic factors both at the peripheral and central levels. We also demonstrated the neuroregenerative/protective capacity of cortistatin in a model of severe peripheral nerve transection. Interestingly, the nociceptive system responded to nerve injury by secreting cortistatin, and a deficiency in cortistatin exacerbated the neuropathic pain responses and peripheral nerve dysfunction. Therefore, cortistatin-based therapies emerge as attractive alternatives for treating chronic neuropathic pain of different etiologies.

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