Calcitonin Gene-Related Peptide Promotes Cellular Changes in Trigeminal Neurons and Glia Implicated in Peripheral and Central Sensitization

Abstract

BackgroundCalcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal nerves, is implicated in the underlying pathology of temporomandibular joint disorder (TMD). Elevated levels of CGRP in the joint capsule correlate with inflammation and pain. CGRP mediates neurogenic inflammation in peripheral tissues by increasing blood flow, recruiting immune cells, and activating sensory neurons. The goal of this study was to investigate the capability of CGRP to promote peripheral and central sensitization in a model of TMD.ResultsTemporal changes in protein expression in trigeminal ganglia and spinal trigeminal nucleus were determined by immunohistochemistry following injection of CGRP in the temporomandibular joint (TMJ) capsule of male Sprague-Dawley rats. CGRP stimulated expression of the active forms of the MAP kinases p38 and ERK, and PKA in trigeminal ganglia at 2 and 24 hours. CGRP also caused a sustained increase in the expression of c-Fos neurons in the spinal trigeminal nucleus. In contrast, levels of P2X3 in spinal neurons were only significantly elevated at 2 hours in response to CGRP. In addition, CGRP stimulated expression of GFAP in astrocytes and OX-42 in microglia at 2 and 24 hours post injection.ConclusionsOur results demonstrate that an elevated level of CGRP in the joint, which is associated with TMD, stimulate neuronal and glial expression of proteins implicated in the development of peripheral and central sensitization. Based on our findings, we propose that inhibition of CGRP-mediated activation of trigeminal neurons and glial cells with selective non-peptide CGRP receptor antagonists would be beneficial in the treatment of TMD.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

“…Because CGRP enhances PKC-mediated signaling to increase neuronal hyperexcitability [44,58,74] and because only peripheral PKCe is upregulated after nonpainful 15 Hz WBV, it is likely that several responses sustain pain from WBV. CGRP is also proinflammatory in the dorsal horn, recruiting immune cells [15,69] and modulating cytokine release [69].…”

“…PKCe is responsible for heat and pain sensitivity in peripheral nociceptors [16,93] and, through PKC pathway signaling, also modulates spinal calcitonin gene-related peptide (CGRP) activity [69,74]. After injury, CGRP is released by nociceptive fibers in the superficial dorsal horn [56,58,74,76] and can stimulate spinal immune cell activation [15,64] and cytokine release [69]. These immune responses not only further exacerbate a host of other inflammatory cytokines and chemokines, but also regulate neuronal responses through modulation at synaptic connections [22,32,46,86].…”

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury

“…Several regions of the nociceptive pathway, including the anterior cingulate cortex (ACC), hippocampus, spinal dorsal horn (SDH) and dorsal root ganglion (DRG), are involved in the development and maintenance of neuropathic pain (4)(5)(6)(7)(8)(9). Several recent studies have shown that peripheral and central sensitization are associated with global changes in gene expression in different regions of the pain transmission pathway, and that these changes may be part of the mechanisms behind neuropathic pain (10)(11)(12)(13). In order to elucidate the molecular mechanisms underlying neuropathic pain, it is essential to determine how gene expression patterns are altered by nerve injuries and how these alterations lead to the development and maintenance of chronic pain.…”

Zmiana stężenia CGRP w osoczu u pacjentów z dysfunkcją układu ruchowego narządu żucia leczonych szynami okluzyjnymi — badanie randomizowane

“…Peripheral and central sensitisation leads to hyperalgesia and allodynia. Cady et al injected CGRP into the TMJ capsule of rats and observed the inflammation process and sensitisation [1]. Sato et al studied CGRP-positive cells in synovial connective tissues around blood vessels in TMJ and found the number to be significantly higher in the experimental group than in healthy volunteers.…”

“…Temporomandibular disorders (TMD) affect 70% of the population, but only 3-7% of these patients are aware of their disorder and seek treatment [1]. Occlusal splint therapy is a well-known and popular method for the treatment of TMD [8].…”