Conotoxins (conopeptides) are small
disulfide bonded
peptides from the
venom of marine cone snails. These
peptides target a wide variety of membrane receptors,
ion channels and transporters, and have enormous potential for a range of
pharmaceutical applications. Structurally related ω-
conotoxins bind directly to and selectively inhibit neuronal (N)-type voltage-gated
calcium channels (VGCCs) of nociceptive primary afferent neurones. Among these, ω-
conotoxin MVIIA (
Prialt) is approved by the Food and Drug Administration (FDA) as an alternative intrathecal
analgesic for the management of chronic
intractable pain, particularly in patients refractory to
opioids. A series of newly discovered ω-
conotoxins from Conus catus, including CVID-F, are potent and selective antagonists of N-type VGCCs. In spinal cord slices, these
peptides reversibly inhibit excitatory synaptic transmission between primary afferents and dorsal horn superficial lamina neurones, and in the rat partial sciatic nerve
ligation model of
neuropathic pain, significantly reduce allodynic behaviour. Another family of
conotoxins, the α-
conotoxins, are competitive antagonists of mammalian
nicotinic acetylcholine receptors (nAChRs). α-
Conotoxins Vc1.1 and RgIA possess two
disulfide bonds and are currently in development as a treatment for
neuropathic pain. It was initially proposed that the primary target of these
peptides is the α9α10 neuronal nAChR. Surprisingly, however, α-
conotoxins Vc1.1, RgIA and PeIA more potently inhibit N-type VGCC currents via a
GABA(B) GPCR mechanism in rat sensory neurones. This inhibition is largely voltage-independent and involves complex intracellular signalling. Understanding the molecular mechanisms of
conotoxin action will lead to new ways to regulate VGCC block and modulation in normal and diseased states of the nervous system.