Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron Ca_V current

Chronic pain is very difficult to treat. Thus, novel analgesics are a critical area of research. Strong pre-clinical evidence supports the analgesic effects of α-conopeptides, Vc1.1 and RgIA, which block α9α10 nicotinic acetylcholine receptors (nAChRs). However, the analgesic mechanism is controversial. Some evidence supports the block of α9α10 nAChRs as an analgesic mechanism, while other evidence supports the inhibition of N-type Ca_V (Ca_V2.2) current via activation of GABA_B receptors. Here we reassess the effect of Vc1.1 and RgIA on Ca_V current in rat sensory neurons. Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA. We also investigated the potential involvement of GABA_B receptors in the Vc1.1 induced inhibition, and found no correlation between the size of Ca_V current inhibition induced by baclofen (GABA_B agonist) vs. that induced by Vc1.1. Thus, GABA_B receptors are unlikely to mediate the Vc1.1 induced Ca_V current inhibition. Based on the present findings, Ca_V current inhibition in dorsal root ganglia is unlikely to be the predominant mechanism by which either Vc1.1 or RgIA induce analgesia.

Better analgesic drugs are desperately needed to help physicians to treat pain. While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial. The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism. However, we show that we cannot reproduce one of the proposed analgesic mechanisms, which is an irreversible inhibition of Ca_V current in a majority of sensory neurons.