Sensitization of Primary Afferent Nociceptors Induced by Intradermal Capsaicin Involves the Peripheral Release of Calcitonin Gene-Related Peptide Driven by Dorsal Root Reflexes

Abstract

Neuropeptides released from axons of primary afferent nociceptive neurons are the key elements for the incidence of neurogenic inflammation and their release is associated with dorsal root reflexes (DRRs). However, whether the release is due to the triggering of DRRs and plays a role in inflammation-induced pain still remain to be determined. The present study assessed the role of calcitonin gene-related peptide (CGRP) in sensitization of primary afferent nociceptors induced by activation of transient receptor potential vanilloid-1 (TRPV 1 ) following intradermal injection of capsaicin and determined if this release is due to activation of primary afferent neurons antidromically by triggering of DRRs. Under dorsal root intact conditions, primary afferent nociceptive fibers recorded in anesthetized rats could be sensitized by capsaicin injection, as shown by an increase in afferent responses and lowering of the response threshold to mechanical stimuli. After DRRs were removed by dorsal rhizotomy, the capsaicin-evoked sensitization was significantly reduced. In dorsal root intact rats, peripheral pretreatment with a CGRP receptor antagonist could dose-dependently reduce the capsaicin-induced sensitization. Peripheral post-treatment with CGRP could dosedependently restore the capsaicin-induced sensitization under dorsal rhizotomized conditions. Capsaicin injection evoked increases in numbers of single and double labeled TRPV 1 and CGRP neurons in ipsilateral dorsal root ganglia (DRG). After dorsal rhizotomy, these evoked expressions were significantly inhibited.Perspective-These data indicate that the DRR-mediated neurogenic inflammation enhances sensitization of primary afferent nociceptors induced by capsaicin injection. The underlying mechanism involves antidromic activation of DRG neurons via up-regulation of TRPV 1 receptors whereby CGRP is released peripherally. KeywordsInflammatory pain; dorsal root reflex; nociceptors; TRPV 1 ; neuropeptides; capsaicin Neurogenic inflammation is the process by which inflammatory mediators, such as neuropeptides, are released from primary afferent terminal (mainly nociceptors) and produce NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript inflammation in their target tissue 51,64. Pain evoked experimentally by intradermal capsaicin (CAP) injection has been well known to be inflammatory and this process is mediated by a neurogenic mechanism 21,57,58. The transient receptor potential vanilloid-1 (TRPV 1 ) located in primary afferent nociceptors plays a key role in neurogenic inflammation when activated by CAP. The underlying mechanism involves sensitization of primary afferent nociceptors due to activation of TRPV 1 receptors, which may lead to the release of neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP), from the nociceptors to initiate neurogenic inflammation that would presumably promote nociception 20,24,25,40,55,57,58. This is anatomically supported by evidence that many primary afferent nociceptive neur...

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