Disparate spinal and supraspinal opioid antinociceptive responses in beta-endorphin-deficient mutant mice

The role of endogenous opioid systems in the analgesic response to exogenou s opiates remains controversial. We previously reported that mice lacking t he peptide neurotransmitter beta -endorphin, although unable to produce opi oid-mediated stress-induced antinociception, nevertheless displayed intact antinociception after systemic administration of the exogenous opiate morph ine. Morphine administered by a peripheral route can activate opioid recept ors in both the spinal cord and brain. However, beta -endorphin neuronal pr ojections are confined predominantly to supraspinal nociceptive nuclei. The refore, we questioned whether the absence of beta -endorphin would differen tially affect antinociceptive responses depending on the route of opiate ad ministration. Time- and dose-response curves were obtained in beta -endorph in-deficient and matched wild-type C57BL/6 congenic control mice using the tail-immersion/withdrawal assay. Null mutant mice were found to be more sen sitive to supraspinal (i.c.v.) injection of the mu -opioid receptor-selecti ve agonists, morphine and D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin. In contra st, the mutant mice were less sensitive to spinal (i.t.) injection of these same drugs. Quantitative receptor autoradiography revealed no differences between genotypes in the density of mu, delta, or kappa opioid receptor bin ding sites in either the spinal cord or pain-relevant supraspinal areas. Th us we report that the absence of a putative endogenous ligand for the mu -o pioid receptor results in opposite changes in morphine sensitivity between discrete areas of the nervous system, which are not simply caused by change s in opioid receptor expression. (C) 2000 IBRO. Published by Elsevier Scien ce Ltd. All rights reserved.