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 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.
Yokoyama
Kazuaki
K
Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Kurihara
Takashi
T
Saegusa
Hironao
H
Zong
Shuqin
S
Makita
Koshi
K
Tanabe
Tsutomu
T
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020908:Calcium Channels, R-Type / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D009020:Morphine