title: Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron CaVcurrent.
abstract: 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 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) vs. 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.
  
  
  CONCLUSIONS
  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 CaVcurrent in a majority of sensory neurons.
authors.affiliation: The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, AT Still University of Health Sciences, Kirksville, MO.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Wright
authors.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University of Health Sciences, Kirksville, MO.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Norimatsu
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84148.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, AT Still University of Health Sciences, Kirksville, MO.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Elmslie