Tissue acidosis due to ischemia occurs under several pathological conditions, and is thought to contribute to pain in these circumstances. TRPV1, TRPA1 and ASICs are known to be sensitive to acidic pH. Addressing their possible role in acidosis perception, the respective antagonists BCTC, A-967079 and amiloride were injected in the volar forearm skin of 32 healthy volunteers. To investigate possible redundancies between channels, a full factorial study design was employed. Injections were performed in a pre-randomized, double-blind and balanced design. Each injection included a three-step pH protocol from pH 7.0 over pH 6.5 to pH 6.0 with a step duration of 90 s. Pain was reported by volunteers on a numerical scale every 10 s during injections. Confirming the primary hypothesis, the combination of all three antagonists reduced acid-induced pain at pH 6.0. Due to the full factorial design, it could be concluded that BCTC alone, but not A-967079 or amiloride, or any combination thereof, were responsible for the observed effects, suggesting TRPV1 as primary sensor for pH 6.0-induced pain. Surprisingly, A-967079 even enhanced pain induced by pH 6.0. In cultured mouse DRG neurons, TPRV1-dependence of pH 6-induced calcium responses could be confirmed. Responses of hTRPV1 to acidic stimulation showed a maximum around pH6, providing an explanation for the pH-dependent inhibition by BCTC. A-967079 sensitizes pH responses is a TRPA1-responsive DRG neuron population, a direct effect of A-967079 on hTRPA1 and hTRPV1 was excluded. In conclusion, inhibiting TRPV1-mediated acidosis-induced pain could be a symptomatic and potentially also a disease-modifying approach.
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