Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine tolerance

Morphine is the drug of choice to treat intractable pain, although prolonged administration often causes undesirable side‐effects including analgesic tolerance. It is speculated that voltage‐dependent Ca2+ channels (VDCCs) play a key role in morphine analgesia and tolerance. To examine the subtype specificity of VDCCs in these processes, we analysed mice lacking N‐type (Cav2.2) or R‐type (Cav2.3) VDCCs. Systemic morphine administration or exposure to warm water swim‐stress, known to induce endogenous opioid release, resulted in greater analgesia in Cav2.3−/− mice than in controls. Moreover, Cav2.3−/− mice showed resistance to morphine tolerance. In contrast, Cav2.2−/− mice showed similar levels of analgesia and tolerance to control mice. Intracerebroventricular (i.c.v.) but not intrathecal (i.t.) administration of morphine reproduced the result of systemic morphine in Cav2.3−/− mice. Furthermore, i.c.v. administration of an R‐type channel blocker potentiated morphine analgesia in wild‐type mice. Thus, the inhibition of R‐type Ca2+ current could lead to high‐efficiency opioid therapy without tolerance.