Importance of glial activation in neuropathic pain

Purinergic signalling, i.e. the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes 4 subtypes of the P1 (adenosine) receptor, 7 subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventicular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y¬12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y¬12 receptor-mediated platelet aggregation. Diquafasol, a long acting P2Y¬2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes and cancer.

/pdf/purinergic-signalling-therapeutic-developments-29zcy5b0n6.pdf

Purinergic Signalling: Therapeutic Developments.

Our goal is to examine the processes—both central and peripheral—that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals. Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.

Neuropathic Pain: Central vs. Peripheral Mechanisms

Spatial and temporal activation of spinal glial cells: Role of gliopathy in central neuropathic pain following spinal cord injury in rats

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

The purpose of this Special Issue is to identify the exact mechanism underlying inflammation to direct more effective strategies for inflammation management and to provide basic data for the development of anti-inflammatory and analgesic treatment methods for patients with inflammatory pain [...].

/pdf/editorial-chronic-inflammation-and-related-diseases-from-252ta26a.pdf

Editorial: Chronic Inflammation and Related Diseases: From Mechanisms to Therapies

Introduction We and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics. Methods Here, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension. Results Stimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation. Conclusion These findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats.

/pdf/attenuation-of-immobilization-stress-induced-hypertension-by-279yhfua.pdf

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms

OBJECTIVE
Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice.


METHODS
To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF).


RESULTS
Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area.


CONCLUSIONS
LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

Background The novel threadlike structure is called the primo structure, and studies are conducted through many different approaches. Although various ways of differentiation are currently used, a standard for differentiation is deemed necessary in order to identify the primo structure based on the overall form of the structure. This study aims to explore the differentiation standard through the histological common point of the threadlike structure of rat and swine by using the hematoxylin and eosin (HE (2) cavity availability; and (3) nuclei density. Results For the rat threadlike structure, the bright cell (70.5%) and nuclei density (92.6%) were mainly observed; in the swine threadlike structure, however, the bright cell (60.6%) and cavity (67.2%) were mainly observed. The bright cell was confirmed to have been observed in the threadlike structures of both rat and swine. Conclusion The bright cell is determined to be the common point in the primo structure. However, further research is deemed necessary in the future as to the functions performed by the characteristic shown by the Primo structure.

Suk Yun Kang

Papers

Editorial: Chronic Inflammation and Related Diseases: From Mechanisms to Therapies

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms

Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

Exploration of differentiation standard for primo through the histological common point of threadlike structure found in rats and swine.