Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain

Abstract

ObjectiveTo investigate the role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain.MethodsExperimental knee OA was induced in rats by intraarticular injection of monosodium iodoacetate (MIA) or by transection of the medial meniscus (MMT). Single-unit recordings of joint-innervating nociceptors were obtained in MIA- and saline-treated rats following administration of CGRP or the CGRP receptor antagonist CGRP 8–37. Effects of CGRP 8–37 were also examined in rats that underwent MMT and sham operations. Protein and messenger RNA (mRNA) levels of CGRP receptor components in the L3–L4 dorsal root ganglion (DRG) were investigated following MIA treatment.ResultsIn both the MIA and MMT groups, the mechanical sensitivity of joint nociceptors was enhanced compared to that in the control groups. Exogenous CGRP increased mechanical sensitivity in a greater proportion of joint nociceptors in the MIA-treated rats than in the saline-treated rats. Local blockade of endogenous CGRP by CGRP 8–37 reversed both the MIA- and MMT-induced enhancement of joint nociceptor responses. Joint afferent cell bodies coexpressed the receptor for CGRP, called the calcitonin-like receptor (CLR), and the intracellular accessory CGRP receptor component protein. MIA treatment increased the levels of mRNA for CLR in the L3–L4 DRG and the levels of CLR protein in medium and large joint afferent neurons.ConclusionOur findings provide new and compelling evidence implicating a role of CGRP in peripheral sensitization in experimental OA. Our novel finding of CGRP-mediated control of joint nociceptor mechanosensitivity suggests that the CGRP receptor system may be an important target for the modulation of pain during OA. CGRP receptor antagonists recently developed for migraine pain should be investigated for their efficacy against pain in OA.

Synovial macrophage-derived IL-1β regulates the calcitonin receptor in osteoarthritic mice

“…Consistent with this finding, higher expression of IL-1b was observed in synovial macrophages which, when depleted by the treatment of mice with liposomal clodronate, led to decreased IL-1b gene expression in ST. Taken together, these findings indicate that IL-1b is produced mainly by macrophages in synovium. Numerous studies have implicated the involvement of CGRP in the peripheral mechanisms of OA pain [6,[17][18][19][20][21][22]. For example, suppression of the expression of CGRP in the synovium of an adjuvant-induced arthritis rat model has been shown to attenuate the pain [17].…”

“…For example, suppression of the expression of CGRP in the synovium of an adjuvant-induced arthritis rat model has been shown to attenuate the pain [17]. In addition, in a monosodium iodoacetate-induced OA model, the gene expression of calcitonin receptor increased and the administration of CGRP receptor antagonist resulted in reduced pain [6]. Here, we found that CLR gene expression was increased in the synovium of STR/Ort mice, particularly in the F4/80-negative fraction of synovial cells.…”

“…Several clinical trials have shown that CGRP receptor antagonists are effective in treating acute migraine [3,4]. In addition, inhibition of CGRP receptors abolishes joint nociceptor sensitization in mouse models of OA pain [5,6]. Although CGRP/CGRP receptor signalling plays a critical role in the modulation of OA pain, the factors regulating CGRP/CGRP receptor signalling in OA remain unclear.…”

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

“…The role of CGRP in joint OA is particularly counterintuitive, as the pain associated with joint OA has been linked to an upregulation of vascular and neural tissue (with CGRP and substance P) in the vicinity of joint structures that are typically aneural [137,138]. However, given that DN has been shown to improve pain in osteoarthritic joints using traditional acupoint and non-acupoint locations, [139] most researchers believe that the general effect of DN may be due to improved blood flow.…”

Effects of Dietary Saturated Fatty Acids on the Onset and Progression of Osteoarthritis in Rat Knee Joints

“…It then unraveled the mystery that, maybe the OA patients were actually suffering from neuropathic pain, and that there could be a significant involvement of degeneration of the neurons in OA. Previous research has shown that the sensory nerves that innervate the OA joints are either 'punctate', 'contorted' or consist mainly of pain producing neuropeptides, such as calcitonin generelated peptide (CGRP) [14][15][16].…”