CaV3.2 T-Type Calcium Channels in Peripheral Sensory Neurons Are Important for Mibefradil-Induced Reversal of Hyperalgesia and Allodynia in Rats with Painful Diabetic Neuropathy

Abstract

We recently showed that streptozotocin (STZ) injections in rats lead to the development of painful peripheral diabetic neuropathy (PDN) accompanied by enhancement of CaV3.2 T-type calcium currents (T-currents) and hyperexcitability in dorsal root ganglion (DRG) neurons. Here we used the classical peripherally acting T-channel blocker mibefradil to examine the role of CaV3.2 T-channels as pharmacological targets for treatment of painful PDN. When administered intraperitoneally (i.p.), at clinically relevant doses, mibefradil effectively alleviated heat, cold and mechanical hypersensitivities in STZ-treated diabetic rats in a dose-dependent manner. We also found that CaV3.2 antisense (AS)-treated diabetic rats exhibit a significant decrease in painful PDN compared with mismatch antisense (MIS)-treated diabetic rats. Co-treatment with mibefradil (9 mg/kg i.p.) resulted in reversal of heat, cold and mechanical hypersensitivity in MIS-treated but not in AS-treated diabetic rats, suggesting that mibefradil and CaV3.2 AS share the same cellular target. Using patch-clamp recordings from acutely dissociated DRG neurons, we demonstrated that mibefradil similarly blocked T-currents in diabetic and healthy rats in a voltage-dependent manner by stabilizing inactive states of T-channels. We conclude that antihyperalgesic and antiallodynic effects of mibefradil in PDN are at least partly mediated by inhibition of CaV3.2 channels in peripheral nociceptors. Hence, peripherally acting voltage-dependent T-channel blockers could be very useful in the treatment of painful symptoms of PDN.

Inhibition of Cav3.2 calcium channels: A new target for colonic hypersensitivity associated with low‐grade inflammation

“…The Ca V 3.2 isoform is expressed along nociceptive pathways, including peripheral nociceptive nerve endings, the dorsal root ganglia (DRG; François et al, ), and presynaptic (Jacus, Uebele, Renger, & Todorovic, ) and postsynaptic terminals of nociceptive fibres in the spinal cord. In addition, Ca V 3.2 channels have emerged as a relevant target for chronic pain states, such as painful post‐traumatic or diabetic neuropathy (Bourinet et al, ; García‐Caballero et al, ; Obradovic et al, ). These channels also contribute to butyrate‐induced CHS in rats (Marger et al, ).…”

Analgesic transient receptor potential vanilloid‐1‐active compounds inhibit native and recombinant T‐type calcium channels

“…It has been shown that up‐regulation of Ca v 3 expression is a common feature of various conditions that involve hyperexcitability such as chronic pain. For example, Ca v 3 channels are up‐regulated in dorsal root ganglion (DRG) neurons of various animal models of pain (Jagodic et al, ; Kang et al, ; Wen et al, ; Yue, Liu, Liu, Shu, & Zhang, ), visceral hypersensitivity (Marger et al, ), and experimental models of diabetes (Cao, Byun, Chen, & Pan, ; Jagodic et al, ; Obradovic et al, ). Moreover, their abundance in peripheral nociceptors has attracted much attention to Ca v 3 channels as analgesic targets for the treatment of pain with numerous novel drugs being developed targeting Ca v 3 channels that show promising potent analgesic effects (for recent review, see Snutch & Zamponi, ).…”

Melatonin‐mediated inhibition of Cav3.2 T‐type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C‐eta isoform

“…Adult mouse TG neurons were sorted by soma diameter into small (soma diameter <30 μm) and medium (soma diameter 30 to 40 μm) groups. Patch clamp recording was restricted to cells <30 μm because most of these neurons are nociceptors …”

“…Aberrant T‐type channel function is associated with pathological conditions such as slow‐wave sleep, the absence of epilepsy, and pain perception . In addition, as evidenced by genetic, pharmacological, and functional analyses, specific T‐type channel isoforms both facilitate and amplify peripheral pain signaling. This accumulating evidence has promoted T‐type channels as potential therapeutic targets for the treatment of pain conditions .…”