Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin.
BACKGROUND
Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV1) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV1 receptors initiates neurogenic inflammation via triggering DRRs.


RESULTS
Here we used pharmacological manipulations to analyze the roles of TRPV1 and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABAA receptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV1 receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30-150 mug. In contrast, pretreatment of the periphery with different doses of CGRP8-37 (a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK1 receptors were blocked by co-administration of CGRP8-37 and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.


CONCLUSIONS
Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1 receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.
Lin
Qing
Q
Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-1069, USA. qilin@utmb.edu
Li
Dingge
D
Xu
Xijin
X
Zou
Xiaoju
X
Fang
Li
L
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000209:etiology; D018756:GABA Antagonists / Q000494:pharmacology; D007271:Injections, Intradermal; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000209:etiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology*; D012018:Reflex; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000503:physiopathology*; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D050916:TRPV Cation Channels / Q000819:agonists / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D000700:Analgesics; D018756:GABA Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C058636:calcitonin gene-related peptide (8-37); D013373:Substance P; C042867:spantide; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; D001640:Bicuculline