Physical dependence is a widely known consequence of
morphine intake. Although commonly associated with prolonged or repeated
morphine administration,
withdrawal symptoms can 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 was thus presently studied by comparing mice of 11 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 via 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 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 on 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 with variable sensitivity in 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.