title: 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)) after 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 dose-dependently 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.
  
  
  CONCLUSIONS
  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 upregulation of TRPV(1) receptors whereby CGRP is released peripherally.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
authors.forename: Dingge
authors.initials: D
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.forename: Xijin
authors.initials: X
authors.lastname: Xu
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Zou
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019051:Rhizotomy / Q000009:adverse effects / Q000379:methods; D018689:Sensory System Agents / Q000008:administration & dosage / Q000494:pharmacology; D013126:Spinal Nerve Roots / Q000503:physiopathology*; D050916:TRPV Cation Channels / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D010446:Peptide Fragments; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin