Abstract
Prialt, a synthetic version of Cav2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Cav2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Cav2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.
Highlights
Neuropathic pain represents a substantial clinical challenge with many patients failing to achieve adequate relief from currently available treatments (Breivik et al, 2006)
Cav2.1 and Cav2.2 channels are present in distinct populations of neurons with the Cav2.2 channel highly expressed in substance P positive pre-synaptic terminals of primary afferents projecting to the superficial laminae (Westenbroek et al, 1998)
TROX-1 dose dependently inhibited neuronal responses to punctate mechanical stimulation of the receptive field in spinal nerve-ligated (SNL) rats (2 way repeated measures (RM) analysis of variance (ANOVA), P < 0.001) (Fig. 4A) with no effect observed in sham rats (2-way RM ANOVA, P > 0.05) (Fig. 4B)
Summary
Neuropathic pain represents a substantial clinical challenge with many patients failing to achieve adequate relief from currently available treatments (Breivik et al, 2006). Calcium channel modulators are one class of drug currently used and includes pregabalin and Cav2.2 antagonist Prialt. Cav2.3 (R-type) channels appear to be predominantly expressed in the soma of dorsal horn neurons (Westenbroek et al, 1998). The release of CGRP, often co-expressed with substance P, in the dorsal horn is sensitive to inhibition by x-conotoxin. Cav2.2 calcium channels mediate the release of noradrenaline from sympathetic neurons and are likely responsible for the potent hypotensive effect of parenteral x-conotoxin GVIA (Clasbrummel et al, 1989; Molderings et al, 2000). X-conotoxin MVIIA and GVIA blockade of Cav2.2 channels is effective both acutely and in models of neuropathy (Chaplan et al, 1994; Bowersox et al, 1996; Omote et al, 1996). In particular has been utilized to examine the back-translation of compounds such as pregabalin by recording from deep dorsal horn neurons in the spinal cord to study spinal processing of supra-threshold stimuli in uninjured and neuropathic conditions (Bee and Dickenson, 2008)
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