• Kazuaki Yokoyama, Takashi Kurihara, Hironao Saegusa, Shuqin Zong, Koshi Makita, and Tsutomu Tanabe.
• Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
• Eur. J. Neurosci. 2004 Dec 1;20(12):3516-9.

AbstractMorphine 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 Ca(2+) 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 (Ca(v)2.2) or R-type (Ca(v)2.3) VDCCs. Systemic morphine administration or exposure to warm water swim-stress, known to induce endogenous opioid release, resulted in greater analgesia in Ca(v)2.3(-/-) mice than in controls. Moreover, Ca(v)2.3(-/-) mice showed resistance to morphine tolerance. In contrast, Ca(v)2.2(-/-) 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 Ca(v)2.3(-/-) 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 Ca(2+) current could lead to high-efficiency opioid therapy without tolerance.

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