Pronociceptive role of spinal Ca2.3 (R-type) calcium channels in a mouse model of postoperative pain.

Background: More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Ca2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Ca2.3 as a potential target to treat postoperative pain and to reduce opioid-related side effects.

Experimental Approach: A plantar incision model was established in adult male and female C57BL/6 mice. Ca2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Ca2.3 blocker-alone or together with morphine-was also assessed after surgery.

Key Results: Paw incision in female and male mice caused acute nociception and increased Ca2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Ca2.3, but not with a scrambled siRNA, prevented the development of surgery-induced nociception in both male and female mice, with female mice experiencing long-lasting effects. High doses of i.t. SNX-482, a Ca2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX-482 mediated a long-lasting reversal of postsurgical pain in female and male mice.

Conclusion: Our results demonstrate that Ca2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.