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

Background And Purpose: The chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Ca3) contribute to OIPN.

Experimental Approach: We chronically treated mice with oxaliplatin and assessed pain responses and changes in expression of Ca3.2 calcium channels. We also tested the effects of T-type channel blockers on cold sensitivity in wild-type and Ca3.2 null mice.

Key Results: Oxaliplatin treatment led to mechanical and cold hypersensitivity in male and female mice. Mechanical hypersensitivity persisted in Ca3.2 null mice of both sexes. Intraperitoneal or intrathecal delivery of pan T-type channel inhibitors attenuated mechanical hypersensitivity in wild-type but not Ca3.2 null mice. Remarkably cold hypersensitivity occurred in female but not male Ca3.2 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 Ca3 isoforms revealed that the depletion of Ca3.1 in males and depletion of either Ca3.1 or Ca3.2 in females triggered cold hypersensitivity. Finally, reducing Ca3.2 expression by disrupting the interactions between Ca3.2 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.