Takahashi M, Senda T, Kaneto H
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.
Eur J Pharmacol. 1991 Aug 6;200(2-3):293-7. doi: 10.1016/0014-2999(91)90585-e.
The site of action of the kappa opioid receptor agonist, U-50,488H in suppressing the development of tolerance to morphine antinociception was examined by local application, either intrathecal (i.t., spinal) or intracerebroventricular (i.c.v., supraspinal) in mice. Mice given morphine s.c., i.c.v. or i.t. daily developed tolerance regardless of the route. Co-administration of U-50,488H i.p. at a subanalgesic dose suppressed the development of tolerance to s.c. and i.t. administered morphine without affecting the antinociceptive effect of morphine. U-50,488H did not influence the development of tolerance to i.c.v. administered morphine. The antinociceptive effect of s.c. administered morphine was not affected by co-administration of U-50,488H given i.t. or i.c.v.; however, the development of tolerance to morphine was suppressed by i.t. but not i.c.v. administered U-50,488H. The suppressive effect of U-50,488H on the development of tolerance to morphine was abolished by pretreatment with nor-binaltorphimine (nor-BNI) given i.p. or i.t. Intracerebroventricularly administered nor-BNI failed to abolish the effect of U-50,488H. We suggest that U-50,488H suppresses the development of tolerance to morphine at the spinal level by interacting with kappa opioid receptors in this area.
通过在小鼠中鞘内（i.t.，脊髓）或脑室内（i.c.v.，脊髓上）局部给药，研究了κ阿片受体激动剂U - 50,488H抑制对吗啡镇痛耐受性发展的作用部位。无论给药途径如何，每天皮下（s.c.）、脑室内或鞘内给予吗啡的小鼠都会产生耐受性。以亚镇痛剂量腹腔内（i.p.）联合给予U - 50,488H可抑制对皮下和鞘内给予吗啡耐受性的发展，而不影响吗啡的镇痛作用。U - 50,488H不影响对脑室内给予吗啡耐受性的发展。皮下给予吗啡的镇痛作用不受鞘内或脑室内给予U - 50,488H联合给药的影响；然而，鞘内而非脑室内给予U - 50,488H可抑制对吗啡耐受性的发展。腹腔内或鞘内给予诺 - 纳曲酮（nor - BNI）预处理可消除U - 50,488H对吗啡耐受性发展的抑制作用。脑室内给予nor - BNI未能消除U - 50,488H的作用。我们认为，U - 50,488H通过与该区域的κ阿片受体相互作用，在脊髓水平抑制对吗啡耐受性的发展。
