Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice

Clinical and experimental observations suggest that opiates can exert diffe rent influences on the perception of stimuli from distinct sensory modaliti es. Thermally-induced nociception is classically responsive to opiate agoni sts. mu-Opioid receptor-deficient transgenic mice are more sensitive to the rmal nociceptive stimuli and morphine fails to attenuate the nociceptive re sponses to thermal stimuli in these animals. To enhance our understanding o f opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice w ith normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug p retreatment or following pretreatment with morphine, the selective kappa-op ioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE, Salin e-pretreated mice of each genotype displayed similar, monotonically increas ing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal re sponses in wild type and heterozygous mice, but had no significant effect i n homozygous mice. Intraventricular administration of DPDPE also reduced th e frequency of paw withdrawal (FPW) in wild type mice, but not in homozygou s mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings su ggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in d rug-free animals, and (2) deficiency of mu-opioid receptors has no function al consequence on the response to the prototypical kappa-opioid receptor ag onist, but decreases responses to the prototypical mu- and delta-opioid rec eptor agonists. (C) 1999 Elsevier Science B.V. All rights reserved.