Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

Abstract

The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. AbstractThe large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain.3

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

“…These same α-conopeptides that minimally affected Ca V current strongly (>80%) inhibited α9α10 nAChRs expressed in Xenopus oocytes, which demonstrates the expected potency of these α9α10 nAChR antagonists. While our results fail to reproduce results reported in some previous publications (Callaghan et al, 2008; Callaghan and Adams, 2010), they do support other publications showing that RgIA and Vc1.1 do not activate GABA B receptors expressed in Xenopus oocytes (McIntosh et al, 2009) and showing that Vc1.1 does not affect excitatory neurotransmitter release from sensory nerve terminals that express GABA B receptors (Napier et al, 2012). …”

“…Two α-conopeptides, Vc1.1 and RgIA, have been shown to display antinociceptive effects in animal models; however, the mechanism responsible for analgesia remains debated (Vincler et al, 2006; McIntosh et al, 2009; Napier et al, 2012). Early studies found these α-conopeptides to be potent antagonists of heterologously expressed and native α9α10 nAChRs (Ellison et al, 2006; Vincler et al, 2006).…”

“…Neither Vc1.1 or RgIA were able to prevent the binding of a specific competitive antagonist to the human GABA B receptor and both failed to activate GABA B receptors expressed in Xenopus laevis oocytes (McIntosh et al, 2009). In addition, Vc1.1 failed to affect excitatory postsynaptic currents (eEPSCs) in the dorsal horn of rat spinal cord, which were almost completely blocked by baclofen (Napier et al, 2012). These findings are inconsistent with GABA B receptor-induced inhibition of N-type Ca V channels as the mechanism for analgesia produced by Vc1.1 and RgIA.…”

α-Conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement

“…Separately, recent evidence indicates that RgIA is able to inhibit high voltage-activated N-type calcium channel currents in rat DRG via activation of GABA B receptors [11], though this effect is not replicated in all systems [40]. GABA B agonist activity was not observed in spinal cord neurons [42]. The efficacy of the prototypical GABA B agonist baclofen in neuropathic pain is debated [27].…”

A novel 4/6-type alpha-conotoxin ViIA selectively inhibits nAchR α3β2 subtype

“…However, Bu22 and TiIA have not been characterized functionally yet. Moreover, some CTxs such as Vc1.1 and AuIB have been found to possess potent analgesic activity [17,18]. In this paper, we described the discovery, synthesis and functional characterization of a novel α4/6 CTx named ViIA which was identified from the worm-hunting cone snail, Conus virgo (C. virgo).…”