TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin

Abstract

Tissue acidosis due to ischemia occurs under several pathological conditions and is believed 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 used. Injections were performed in a prerandomized, 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 seconds. Pain was reported by volunteers on a numerical scale every 10 seconds during injections. Confirming the primary hypothesis, the combination of all 3 antagonists reduced acid-induced pain at pH 6.0. Because of the full-factorial design, it could be concluded that BCTC alone, but not A-967079 or amiloride, or any combination thereof, was 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 dorsal root ganglion 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 dorsal root ganglion neuron population, and 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.

Acid-sensing ion channel 3: An analgesic target

“…humans, recent data suggest no role for ASICs [22,239], which contrasts with older literature [21,240], but how this scenario is altered in chronic pain states associated with prolonged tissue acidosis and the presence of multiple inflammatory mediators, many of which sensitise ASIC3, remains unknown. Fundamentally, what the field really lacks is a selective ASIC3 antagonist that effectively blocks both transient and sustained phases of the current (as well as those derived from ASIC3 heteromers), which could be used in an interventional way to determine the true contribution of ASIC3 to pain and other physiology, and the quest for such a compound remains.…”

“…Also, in humans, is there a role for ASIC3 in chronic pain? At least for acute acid-evoked pain in humans, recent data suggest no role for ASICs [ 22 , 238 ], which contrasts with older literature [ 21 , 23 ], but how this scenario is altered in chronic pain states associated with prolonged tissue acidosis and the presence of multiple inflammatory mediators, many of which sensitize ASIC3, remains unknown.…”

“…Early work by Krishtal et al, in 1980, demonstrated for the first time that application of extracellular acid could evoke inward currents in sensory neurones [20], and further work has shown that localised tissue acidification (pH ≤6.0) causes pain in humans [21][22][23]. Thus, there is a clear link between acidosis, acid-evoked sensory neurone activation and pain.…”

Novel Analgesics with Peripheral Targets

“…Peptide isolation from the black mamba venom has also revealed an interesting new group of molecules, mambalgins, targeting acid sensors with analgesic effects [604,605]. Recently, it has been reinforced that in humans, TRPV1 is the main contributor to mild and pathophysiologically relevant acidosisinduced pain in the skin [276], which supports using modality-specific TRPV1 antagonists as a new tool for inflammatory pain.…”

“…This feature is also present in a variety of other channels, including TRPV1, TRPV4, TRPC4, TRPC5, TRPP2, P2X purinoceptors, inward rectifier K + channels, voltageactivated K + channels, L-type Ca2 + channels, HCN channels, gap junction channels and Cl − channels [273], and can be sensitized by inflammatory mediators [274,275]. In humans, low pH-induced pain in the range of acidosis occurrence is mediated by TRPV1 [276], whether other targets contribute substantially in inflammatory conditions is currently unknown. The most likely target for ASIC analgesia in inflammation remains ASIC3, with substantial expression in the peripheral nervous system [277,278].…”