Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons

2012 
Abstract Intracellular second messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca 2+ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca 2+ 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 Ca 2+ concentration ([Ca 2+ ] i ) increase depended on extracellular Ca 2+ influx as an initial trigger. The Ca 2+ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca 2+ -free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca 2+ -dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca 2+ removal, suggesting at least in part a Ca 2+ -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 Ca 2+ -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.
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