Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain

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Abstract

Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to surgically-induced peripheral tissue injury. However, the potential role and molecular mechanisms of nociceptive ion channel dysregulation in acute pain conditions such as those resulting from skin and soft tissue incision remain unknown. Here, we use selective pharmacology, electrophysiology and mouse genetics to link observed increased current densities arising from Ca v3.2 isoform of T-type calcium channels (T-channels) to nociceptive sensitization using a clinically-relevant rodent model of skin and deep tissue incision. Furthermore, knockdown of the Ca v3.2-targeting deubiquitinating enzyme USP5, or the specific disruption of its binding to Ca v3.2 channel, in peripheral nociceptors resulted in a robust antihyperalgesic effect in vivo, and substantial T-current reduction in vitro. Our study provides a key mechanistic understanding of Ca v3.2 channel’s plasticity post-surgical incision and identifies novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse. Selective pharmacological antagonism of Ca v3.2 channels in peripheral nociceptors and disruption of Ca v3.2-USP5 signaling alleviate hyperalgesia post-surgery.

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The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.

L Stanfa, N Ogata, S. J. McMahon … (1999)

Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.

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Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels.

Edmund Talley, Leanne L. Cribbs, Jung-Ha Lee … (1999)

Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (alpha1G, alpha1H, and alpha1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed alpha1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (alpha1H), and thalamic reticular neurons (alpha1I and alpha1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (alpha1G), the olfactory tubercles (alpha1H and alpha1I), and the subthalamic nucleus (alpha1I and alpha1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for alpha1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for alpha1H and alpha1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.

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Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception.

John McRory, Brigitte Couette, Olivier Poirot … (2005)

Analgesic therapies are still limited and sometimes poorly effective, therefore finding new targets for the development of innovative drugs is urgently needed. In order to validate the potential utility of blocking T-type calcium channels to reduce nociception, we explored the effects of intrathecally administered oligodeoxynucleotide antisenses, specific to the recently identified T-type calcium channel family (CaV3.1, CaV3.2, and CaV3.3), on reactions to noxious stimuli in healthy and mononeuropathic rats. Our results demonstrate that the antisense targeting CaV3.2 induced a knockdown of the CaV3.2 mRNA and protein expression as well as a large reduction of 'CaV3.2-like' T-type currents in nociceptive dorsal root ganglion neurons. Concomitantly, the antisense treatment resulted in major antinociceptive, anti-hyperalgesic, and anti-allodynic effects, suggesting that CaV3.2 plays a major pronociceptive role in acute and chronic pain states. Taken together, the results provide direct evidence linking CaV3.2 T-type channels to pain perception and suggest that CaV3.2 may offer a specific molecular target for the treatment of pain.