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Objective  To investigate the role of the sensory neuropeptide calcitonin gene‐related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain.    Methods  Experimental 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.    Results  In 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.    Conclusion  Our 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.

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