Pronociceptive role of spinal Cav2.3 (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 Ca_v2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Ca_v2.3 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. Ca_v2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Ca_v2.3 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 Ca_v2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Ca_v2.3, 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 Ca_v2.3 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 Ca_v2.3 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.