Role of spinal kappa opioid receptors in the blockade of the development of antinociceptive tolerance to morphine.

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.