Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: Evidence for common genetic mechanisms in acute and chronic morphine physical dependence

Physical dependence is a widely known consequence of morphine intake. Although commonly associated with prolonged or repeated morphine administration, withdrawal symptoms call be elicited even after a single prior morphine exposure. What remains contentious is the extent to which physical dependence following acute and chronic morphine treatment is mediated by common physiological substrates and. accordingly, represent distinct syndromes. The genetic relationship between acute and chronic morphine dependence as thus presently Studied by comparing mice of I I inbred strains (129P3, A. AKR, BALB/c, C3H/He, C57BL/6. CBA, DBA/2, LP, SJL, and SWR) for naloxone- precipitated withdrawal jumping responses using three subcutaneous morphine administration paradigms: acute (single injection) or chronic (three daily morphine injections for 4 days) injection, or chronic infusion (7 days aria implanted osmotic minipumps), Although there were differences in the magnitude of withdrawal jumping between the three different morphine administration paradigms, large and significant strain differences were observed for each. In addition, the same strains were unusually sensitive re or, conversely, altogether refractory to withdrawal jumping across all morphine treatment conditions. Overall. strain jumping means between acute and chronic dependence paradigms displayed a high degree of genetic correlation (r = 0.87-0.95). The significant correlation between chronic morphine injection and continuous morphine infusion discounts the possible confounding effect of contextual learning and spontaneous withdrawal between chronic injections oil the assessment of naloxone-precipitated withdrawal Substantial heritability was also observed for acute and both paradigms of chronic dependence. with estimates ranging from h(2) = 0.53 to 0.70. The present demonstration of a strong genetic correlation between physical dependence to morphine following acute and chronic treatment implies that genes associated kith variable sensitivity ill the two traits are the same, and is suggestive of shared physiological substrates. The data also demonstrate that the differential genetic liability to morphine physical dependence begins with. and is predicted by. the first morphine exposure. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.