Conotoxin modulation of ion channels in pain pathways

Pain which is an unpleasant sensory and emotional experience incorporating substantial tissue damage, remains quite unexplored in terms of chronic pain treatment due to availability and over prescription of opioid analgesics. These opioid drugs modulate the inhibitory signaling through coupling with G protein-coupled receptors (GPCR) (-opioid receptor), modulating a variety of ion channels and thus, resulting in inhibition of neurotransmitter release at the primary afferent nerve terminals in the spinal cord producing anti-nociception. However, the desired outcomes cannot outweigh the resultant adverse effects such as tolerance and dependency, limiting opioids’ therapeutic effectiveness. Therefore, with the aim to discover an alternative drug effective in anti-nociception, my current approach is to investigate novel conopeptides derived from the venom of marine cone snails that modulate membrane receptors and ion channels in the pain pathways. I have primarily focused on -conotoxin Vc1.1 which was originally proposed to be anti-nociceptive through inhibition of neuronal nicotinic acetylcholine receptors (nAChRs). However, the disparity in its functional activity between human and rat 910 nAChR resulted in its withdrawal from phase II clinical trial (Metabolic Discontinues ACV1 Trial, 2007). Nevertheless, the extension of this study in α9α10 knockout mice producing effective analgesia elevated curiosity of the researchers to explore more thoroughly. Interestingly, this led to the discovery of Vc1.1 activity at the GABAB receptor (GABABR) that intensified the need for their preclinical development as an effective pharmacophore. Concurrently, development of a truncated version of full length -conotoxinVc1.1, with the aim to make the compound faster, serum stable and target specific, Vc1.1(1-8) from “loop” 1 was synthesized and shown analgesic for chronic visceral hypersensitivity (CVH)