Abstract
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 CaV current in a majority of sensory neurons.
Highlights
Severe pain reduces the quality of life of millions of people each year (Cousins et al, 2004)
We investigated the potential involvement of GABAB receptors in the Vc1.1-induced inhibition, and found no correlation between the size of CaV current inhibition induced by baclofen (GABAB agonist) versus that induced by Vc1.1
Inhibition of CaV current is one mechanism that has been proposed for analgesia induced by the ␣-conopeptides Vc1.1 and RgIA (Callaghan et al, 2008; Cuny et al, 2012)
Summary
Severe pain reduces the quality of life of millions of people each year (Cousins et al, 2004). Two ␣-conopeptides, Vc1.1 and RgIA, have been shown to display antinociceptive effects in animal models; the mechanism responsible for analgesia remains debated (Vincler et al, 2006; McIntosh et al, 2009; Napier et al, 2012). Studies found these ␣-conopeptides to be potent antagonists of heterologously expressed and native ␣9␣10 nAChRs (Ellison et al, 2006; Vincler et al, 2006). Mice lacking ␣9 nAChRs have reduced mechanical hyperalgesia in both neuropathic and inflammatory pain models, supporting a role for ␣9␣10 nAChRs as a target for treatment of chronic pain (Mohammadi and Christie, 2014)
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