Opiate withdrawal-induced place aversion lasts for up to 16 weeks

Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown.

The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal.

Morphine-dependent rats were tested in a three-chamber place-aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 microg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests).

A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points.

In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.