The mechanism of Calhm2 regulating the expression of CaMKIIα in spinal dorsal horn involved in the pathogenesis of bone cancer pain

• • Calhm2 expression is significantly upregulated in the spinal dorsal horn in a mouse model of bone cancer pain. • • Increased Calhm2 expression is accompanied by enhanced CaMKIIα signaling and neuronal activation in the spinal dorsal horn. • • Spinal knockdown of Calhm2 reduces CaMKIIα expression and mechanical allodynia in bone cancer pain mice. • • The Calhm2–CaMKIIα pathway contributes to central sensitization underlying bone cancer pain. Bone cancer pain (BCP) is one of the most common and debilitating types of pain in cancer patients, severely impairing the quality of life in advanced stages of the disease. However, its underlying mechanisms remain poorly understood, highlighting the urgent need to clarify its pathogenesis and identify novel therapeutic targets. Increasing evidence suggests that altered excitability of spinal dorsal horn neurons is a prerequisite for pain generation. The dynamic balance of intracellular and extracellular calcium ion concentrations is critical for maintaining normal neuronal excitability. In this study, we investigated the role of calcium homeostasis modulator 2 (Calhm2) in BCP. In BCP mice, the expression of Calhm2 in the spinal dorsal horn was significantly upregulated, accompanied by a concomitant increase in calcium/calmodulin-dependent protein kinase II α (CaMKIIα). Lentiviral-mediated knockdown of Calhm2 in the spinal dorsal horn reduced CaMKIIα expression, alleviated mechanical allodynia, and decreased c-fos expression. These findings suggest that Calhm2 regulates CaMKIIα to promote neuronal activation in the spinal dorsal horn, thereby contributing to the development of bone cancer pain. Calhm2 may represent a promising target for therapeutic intervention in BCP.