Contribution of T-type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin-treated mice of both sexes

Abstract

Background and Purpose

The chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Ca_v3) contribute to OIPN.

Experimental Approach

We chronically treated mice with oxaliplatin and assessed pain responses and changes in expression of Ca_v3.2 calcium channels. We also tested the effects of T-type channel blockers on cold sensitivity in wild-type and Ca_v3.2 null mice.

Key Results

Oxaliplatin treatment led to mechanical and cold hypersensitivity in male and female mice. Mechanical hypersensitivity persisted in Ca_v3.2 null mice of both sexes. Intraperitoneal or intrathecal delivery of pan T-type channel inhibitors attenuated mechanical hypersensitivity in wild-type but not Ca_v3.2 null mice. Remarkably cold hypersensitivity occurred in female but not male Ca_v3.2 null mice even without oxaliplatin treatment. Unexpectedly, intrathecal, intraplantar or intraperitoneal delivery of T-type channel inhibitors Z944 or TTA-P2 transiently induced cold hypersensitivity in both male and female wild-type mice. Acute knockdown of specific Ca_v3 isoforms revealed that the depletion of Ca_v3.1 in males and depletion of either Ca_v3.1 or Ca_v3.2 in females triggered cold hypersensitivity. Finally, reducing Ca_v3.2 expression by disrupting the interactions between Ca_v3.2 and the deubiquitinase USP5 with the small organic molecule II-2 reversed oxaliplatin-induced mechanical and cold hypersensitivity and importantly did not trigger cold allodynia.

Conclusion and Implications

Altogether, our data indicate that T-type channels differentially contribute to the regulation of cold and mechanical hypersensitivity, and raise the possibility that T-type channel blockers could promote cold allodynia.