title: Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons.
abstract: Intracellular second messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca²⁺ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca²⁺ dependency in the signal transduction of capsaicin-induced desensitization. On the average, capsaicin increased cAMP, cGMP concentration and SP release in bell-shaped concentration-dependent manner, with the maximal responses at concentrations around 1 μM, suggesting acute desensitization of TRPV1 receptor activation. Capsaicin-induced intracellular Ca²⁺ concentration ([Ca²⁺](i)) increase depended on extracellular Ca²⁺ influx as an initial trigger. The Ca²⁺ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca²⁺-free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca²⁺-dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca²⁺ removal, suggesting at least in part a Ca²⁺-independent pathway is involved. Further study showed that cAMP increase was totally abolished by G-protein and adenylate cyclase (AC) antagonist, suggesting a G-protein-dependent pathway in cAMP increase. However, SP release was blocked by inhibiting PKC, but not G-protein or AC, suggesting a G-protein independent pathway in SP release. These results suggest that both Ca²⁺-dependent and independent mechanisms are involved in the regulation of capsaicin on second messengers systems, which could be a novel mechanism underlying distinct desensitization of capsaicin and might provide additional opportunities in the development of effective analgesics in pain treatment.
authors.affiliation: Department of Dermatology, Henan Provincial People's Hospital, Weiwu Road 7, Zhengzhou, Henan, China.
authors.forename: Yu-ping
authors.initials: YP
authors.lastname: Xu
authors.forename: Jie-wen
authors.initials: JW
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Zeng-you
authors.initials: ZY
authors.lastname: Ye
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.forename: Xi-sheng
authors.initials: XS
authors.lastname: Yan
authors.forename: Zhi-guo
authors.initials: ZG
authors.lastname: Liu
authors.forename: Lie-ju
authors.initials: LJ
authors.lastname: Liu
authors.forename: Xue-hong
authors.initials: XH
authors.lastname: Cao
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013373:Substance P; D000242:Cyclic AMP; D011493:Protein Kinase C; D006152:Cyclic GMP; D002211:Capsaicin; D002118:Calcium