Limited Efficacy of α-Conopeptides, Vc1.1 and RgIA, To Inhibit Sensory Neuron CaVCurrent

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Abstract
Chronic pain is very difficult to treat. Thus, novel analgesics are a critical area of research. Strong preclinical 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 CaV(CaV2.2) current via activation of GABABreceptors. Here, we reassess the effect of Vc1.1 and RgIA on CaVcurrent 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 GABABreceptors in the Vc1.1-induced inhibition, and found no correlation between the size of CaVcurrent inhibition induced by baclofen (GABABagonist) versus that induced by Vc1.1. Thus, GABABreceptors are unlikely to mediate the Vc1.1-induced CaVcurrent inhibition. Based on the present findings, CaVcurrent inhibition in dorsal root ganglia is unlikely to be the predominant mechanism by which either Vc1.1 or RgIA induce analgesia.
Funding Information
  • NIH NIGMS (GM48677)
  • NIH NIGMS (GM103801)
  • NIH NIAMS (AR59397)

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