scholarly journals Pathophysiology of neuropathic pain

2021 ◽  
Vol 64 (7) ◽  
pp. 468-476
Author(s):  
Ohyun Kwon
Keyword(s):  
Neuropathic Pain ◽  
Central Sensitization ◽  
Research Progress ◽  
Diagnostic Tools ◽  
Afferent Neuron ◽  
Peripheral Sensitization ◽  
Best Management ◽  
Plausible Mechanism ◽  
Key Aspects ◽  
Inflammatory Milieu

Background: Neuropathic pain is notoriously difficult to manage properly, not only because of its varied nature and the absence of objective diagnostic tools but also because of extensive reciprocal neuronal interactive pathogenic mechanism from the molecular level to patient’s own psychophysical characteristics. This paper briefly reviews the pathophysiology of neuropathic pain to the level of clinicians’ interest and its potential in clinical practiceCurrent Concepts: Recent research progress now allows us to obtain a bird view of neuropathic pain pathophysiology: peripheral and central sensitization. For peripheral sensitization, a local inflammatory milieu of the injured nerve primarily drives sequential phenotypic changes, which are critical and shared by both neuropathic and inflammatory pain. Central sensitization is led either by the hyperexcitability of the second-order afferent neuron itself or loss of physiological inhibitory control of the transmission of pain signal to the higher nervous system. Peripheral and central sensitization work synergistically but can also introduce neuropathic pain alone.Discussion and Conclusion: The cause of neuropathic pain is diverse, and understanding of its pathophysiology is still insufficient to realize a mechanism-based approach to clinical phenotypes or therapeutic applications. In dealing with chronic neuropathic pain, it is highly desirable to assess key aspects of a patient’s pain based on a plausible mechanism and select the best management method accordingly.

Pain neurophysiology

2013 ◽  
Author(s):  
Hans-Georg Schaible ◽  
Rainer H. Straub
Keyword(s):  
Neuropathic Pain ◽  
Central Sensitization ◽  
Cell Activation ◽  
Warning Signal ◽  
Nociceptive Pain ◽  
Neural Function ◽  
Peripheral Sensitization ◽  
Nerve Fibres ◽  
Glial Cell Activation ◽  
Ectopic Discharges

Physiological pain is evoked by intense (noxious) stimuli acting on healthy tissue functioning as a warning signal to avoid damage of the tissue. In contrast, pathophysiological pain is present in the course of disease, and it is often elicited by low-intensity stimulation or occurs even as resting pain. Causes of pathophysiological pain are either inflammation or injury causing pathophysiological nociceptive pain or damage to nerve cells evoking neuropathic pain. The major peripheral neuronal mechanism of pathophysiological nociceptive pain is the sensitization of peripheral nociceptors for mechanical, thermal and chemical stimuli; the major peripheral mechanism of neuropathic pain is the generation of ectopic discharges in injured nerve fibres. These phenomena are created by changes of ion channels in the neurons, e.g. by the influence of inflammatory mediators or growth factors. Both peripheral sensitization and ectopic discharges can evoke the development of hyperexcitability of central nociceptive pathways, called central sensitization, which amplifies the nociceptive processing. Central sensitization is caused by changes of the synaptic processing, in which glial cell activation also plays an important role. Endogenous inhibitory neuronal systems may reduce pain but some types of pain are characterized by the loss of inhibitory neural function. In addition to their role in pain generation, nociceptive afferents and the spinal cord can further enhance the inflammatory process by the release of neuropeptides into the innervated tissue and by activation of sympathetic efferent fibres. However, in inflamed tissue the innervation is remodelled by repellent factors, in particular with a loss of sympathetic nerve fibres.

The neural basis of chronic pain, its plasticity and modulation

1997 ◽  
Vol 20 (3) ◽  
pp. 435-437 ◽  
Author(s):  
Misha-Miroslav Backonja
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Central Sensitization ◽  
Primary Afferents ◽  
Peripheral Sensitization ◽  
Neural Basis ◽  
Painful Events

Dysfunction or injury of pain-transmitting primary afferents' central pathways can result in pain. The organism as a whole responds to such injury and consequently many symptoms of neuropathic pain develop. The nervous system responds to painful events and injury with neuroplasticity. Both peripheral sensitization and central sensitization take place and are mediated by a number of biochemical factors, including genes and receptors. Correction of altered receptors activity is the logical way to intervene therapeutically. [berkley; blumberg et al.; coderre & katz; dickenson; mcmahon; wiesenfeld-hallinet al.]

Mechanisms of Neuropathic Pain

2018 ◽  
pp. 17-26
Author(s):  
Jianguo Cheng
Keyword(s):  
Neuropathic Pain ◽  
Central Sensitization ◽  
Receptive Fields ◽  
Somatosensory System ◽  
Direct Consequence ◽  
Inflammatory Cells ◽  
Peripheral Sensitization ◽  
Excitatory Pathways ◽  
Processing Pathways ◽  
The Central Nervous System

Neuropathic pain arises as a direct consequence of a lesion or a disease affecting the somatosensory system. The mechanisms of neuropathic pain are often complex and difficult to study given the diversity of causes, pathology, and clinical presentation of various neuropathic pain conditions. Common mechanisms include peripheral and central sensitizations. Peripheral sensitization refers to increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields. Central sensitization refers to the augmented response of central signaling neurons. The mechanisms of peripheral and central sensitization are understood at the cellular and molecular levels. The processes of neuroplasticity involve activation of inflammatory cells, such as macrophages (and microglia in the central nervous system) and other immune cells, and release of inflammatory mediators, such as cytokines, chemokines, and a host of other mediators. Interactions of these mediators with specific receptors in the nociceptors or the spinal cord neurons may lead to phosphorylation or changes in expression of ion channels, receptors, transporters, and other effectors through specific signaling pathways. These events ultimately lead to changes in excitability, conductivity, and transmissibility of neurons in the pain processing pathways. Other factors may include disinhibition of interneurons, changes in descending inhibitory and excitatory pathways, and reorganization of the cortical areas and their interconnections.

scholarly journals Progressive Increase of Inflammatory CXCR4 and TNF-Alpha in the Dorsal Root Ganglia and Spinal Cord Maintains Peripheral and Central Sensitization to Diabetic Neuropathic Pain in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Dan Zhu ◽  
Tingting Fan ◽  
Xinyue Huo ◽  
Jian Cui ◽  
Chi Wai Cheung ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Central Sensitization ◽  
Dorsal Root ◽  
Diabetic Rats ◽  
Spinal Cord Dorsal Horn ◽  
Peripheral Sensitization ◽  
Diabetic Neuropathic Pain ◽  
Spinal Cord Dorsal

Diabetic neuropathic pain (DNP) is a common and serious complication of diabetic patients. The pathogenesis of DNP is largely unclear. The proinflammation proteins, CXCR4, and TNF-α play critical roles in the development of pain, while their relative roles in the development of DNP and especially its progression is unknown. We proposed that establishment of diabetic pain models in rodents and evaluating the stability of behavioral tests are necessary approaches to better understand the mechanism of DNP. In this study, Von Frey and Hargreaves Apparatus was used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia in streptozotocin-induced diabetic rats at different phases of diabetes. Moreover, CXCR4 and TNF-α of spinal cord dorsal and dorsal root ganglia (DRG) were detected by western blotting and immunostaining over time. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced as early as 1 week in diabetic rats and persistently maintained at lower levels during the progression of diabetes as compared to control rats that were concomitant with significant increases of both CXCR4 and TNF-α protein expressions in the DRG at 2 weeks and 5 weeks (the end of the experiments) of diabetes. By contrast, CXCR4 and TNF-α in the spinal cord dorsal horn did not significantly increase at 2 weeks of diabetes while both were significantly upregulated at 5 weeks of diabetes. The results indicate that central sensitization of spinal cord dorsal may result from persistent peripheral sensitization and suggest a potential reference for further treatment of DNP.

scholarly journals A38 TRPV1 VISCERAL AFFERENTS CONTROL CENTRAL SENSITIZATION IN IBD

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 278-279
Author(s):  
M Defaye ◽  
N Abdullah ◽  
M Iftinca ◽  
C Altier
Keyword(s):  
Chronic Pain ◽  
Central Sensitization ◽  
Microglial Activation ◽  
Visceral Pain ◽  
Purinergic Signaling ◽  
Designer Drugs ◽  
Visceral Afferents ◽  
Peripheral Sensitization ◽  
Specific Expression

Abstract Background Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease, suggesting a high level of plasticity in nociceptive circuits during acute phases. The establishment of chronic visceral pain results from neuroplasticity in nociceptors first, then along the entire neural axis, wherein microglia, the resident immune cells of the central nervous system, are critically involved. Our lab has shown that spinal microglia were key in controlling chronic pain state in IBD. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown. Aims To investigate the role of TRPV1+ visceral afferents in microglial activation and chronic visceral pain. Methods We generated DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice in which TRPV1 sensory neurons can be inhibited (TRPV1-hM4Di) or activated (TRPV1-hM3Dq) in a time and tissue specific manner using the inert ligand Clozapine-N-Oxide (CNO). To test the inhibition of TRPV1 neurons in DSS-induced colitis, TRPV1-hM4Di mice were treated with DSS 2.5% or water for 7 days and received vehicle or CNO i.p. injection twice daily. To activate TRPV1 visceral afferents, TRPV1-hM3Dq mice received vehicle or CNO daily for 7 days, by oral gavage. After 7 days of treatment, visceral pain was evaluated by colorectal distension and spinal cords tissues were harvested to measure microglial activation. Results Our data validated the nociceptor specific expression and function of the DREADD in TRPV1-Cre mice. Inhibition of TRPV1 visceral afferents in DSS TRPV1-hM4Di mice was able to prevent the colitis-induced microglial activation and thus reduce visceral hypersensitivity. In contrast, activation of TRPV1 visceral afferents in TRPV1-hM3Dq mice was sufficient to drive microglial activation in the absence of colitis. Analysis of the proalgesic mediators derived from activated TRPV1-hM3Dq neurons identified ATP as a key factor of microglial activation. Conclusions Overall, these data provide novel insights into the mechanistic understanding of the gut/brain axis in chronic visceral pain and suggest a role of purinergic signaling that could be harnessed for testing effective therapeutic approaches to relieve pain in IBD patients. Funding Agencies CCCACHRI (Alberta Children’s Hospital Research Institute) and CSM (Cumming School of Medicine) postdoctoral fellowship

scholarly journals Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 450
Author(s):  
Magdalena Kocot-Kępska ◽  
Renata Zajączkowska ◽  
Joanna Mika ◽  
David J. Kopsky ◽  
Jerzy Wordliczek ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Management ◽  
Clinical Studies ◽  
Neuronal Cells ◽  
Case Series ◽  
Narrative Review ◽  
Peripheral Sensitization ◽  
Cellular Mechanisms ◽  
Peripheral Neuropathic Pain ◽  
Topical Treatments

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients’ quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were “topical AND pain”, “topical AND neuropathic”, “topical AND treatment”, “topical AND mechanism”, “peripheral neuropathic”, and “mechanism”. The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

scholarly journals What do general neurologists need to know about neuropathic pain?

2009 ◽  
Vol 67 (3a) ◽  
pp. 741-749 ◽  
Author(s):  
Pedro Schestatsky ◽  
Osvaldo José M. Nascimento
Keyword(s):  
Neuropathic Pain ◽  
Somatosensory System ◽  
Relevant Information ◽  
Diagnostic Tools ◽  
Post Herpetic Neuralgia ◽  
Therapeutic Approaches ◽  
Pain Syndromes ◽  
Cord Injury ◽  
Common Causes ◽  
Nociceptive Pathway

Neuropathic pain (NP) is defined as pain caused by lesion or dysfunction of the somatosensory system, as a result of abnormal activation of the nociceptive pathway (small fibers and spinothalamic tracts). The most common causes of this syndrome are the following: diabetes, post-herpetic neuralgia, trigeminal neuralgia, stroke, multiple sclerosis, spinal cord injury, HIV infection, cancer. In the last few years, the NP has been receiving special attention for two main reasons: (1) therapeutical refractoriness of a variety of pain syndromes with predominant neuropathic characteristics and (2) the development of diagnostic tools for neuropathic pain complaints. The present review article provides relevant information on the understanding and recognition of NP, as well as evidence-based therapeutic approaches.

scholarly journals Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain

2019 ◽  
Vol 20 (1) ◽  
pp. 155 ◽  
Author(s):  
Marina Arribas-Blázquez ◽  
Luis Alcides Olivos-Oré ◽  
María Victoria Barahona ◽  
Mercedes Sánchez de la Muela ◽  
Virginia Solar ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Chromaffin Cells ◽  
Transient Receptor Potential ◽  
Synaptic Activity ◽  
Cholinergic Innervation ◽  
Cell Junction ◽  
Transient Receptor Potential Vanilloid ◽  
Peripheral Sensitization ◽  
Trpv1 Channels

We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve–chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca2+ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain.

scholarly journals Peripheral and central sensitization and neuropathic pain are present in both osteoarthritis and rheumatoid arthritis

2019 ◽  
Vol 27 ◽  
pp. S414 ◽  
Author(s):  
J. Chua ◽  
S. Ishihara ◽  
M. Riad ◽  
I. Castrejon ◽  
R. Miller ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Neuropathic Pain ◽  
Central Sensitization

scholarly journals A critical review of the possible benefits associated with homeopathic medicine

2003 ◽  
Vol 58 (6) ◽  
pp. 324-331 ◽  
Author(s):  
Renan Moritz V. Rodrigues Almeida
Keyword(s):  
Critical Review ◽  
Scientific Research ◽  
Research Progress ◽  
Reference Source ◽  
Ample Evidence ◽  
Negative Results ◽  
Plausible Mechanism ◽  
Meta Analyses ◽  
Positive Results

OBJECTIVE: To evaluate the recent scientific research progress on homeopathy. METHODOLOGY: Homeopathy was evaluated in terms of its clinical research; in vitro research, and physical foundations. The Medline database was the main reference source for the present research, concerning data of approximately the last 10 years. Secondary references (not available in this database) were obtained by means of direct requests to authors listed in the primary references. RESULTS: Clinical studies and in vitro research indicate the inefficacy of homeopathy. Some few studies with positive results are questionable because of problems with the quality and lack of appropriate experimental controls in these studies. The most recent meta-analyses on the topic yielded negative results. One of the few previous meta-analyses with positive results had serious publication bias problems, and its results were later substantially reconsidered by the main authors. The sparse in vitro homeopathic research with positive results has not been replicated by independent researchers, had serious methodological flaws, or when replicated, did not confirm the initial positive results. A plausible mechanism for homeopathic action is still nonexistent, and its formulation, by now, seems highly unlikely. CONCLUSIONS: As a result of the recent scientific research on homeopathy, it can be concluded that ample evidence exists to show that the homeopathic therapy is not scientifically justifiable.

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