Extinction of tolerance to the analgesic effect of morphine: intracerebroventricular administration and effects of stress.

Previous research demonstrated that tolerance to the analgesic effect of morphine in rats is attenuated by administrations of a placebo in the context of drug-associated cues. Such apparent extinction of tolerance has been interpreted as support for a Pavlovian conditioning model of tolerance. Recently, it has been suggested that these findings are attributable to stress, induced during placebo sessions and augmenting the analgesic effect of morphine (rather than to Pavlovian extinction). Our results indicate that placebo sessions actually attenuate tolerance by extinguishing the association between predrug cues and the systemic effects of the drug. In addition, the results indicate that conditioning contributes to analgesic tolerance when morphine is administered intracerebroventricularly, which suggests that conditional alterations within the central nervous system mediate such tolerance. This contrasts with alternative suggestions that conditional alterations in drug distribution or metabolism mediate the effects of conditioning manipulations on tolerance.