A locus and mechanism of action for associative morphine tolerance

Repeated administration of an opioid in the presence of specific environmen tal cues can induce tolerance specific to that setting (associative toleran ce). Prolonged or repeated administration of an opioid without consistent c ontextual pairing yields non-associative tolerance. Here we demonstrate tha t cholecystokinin acting at the cholecystokinin-B receptor is required for associative but not nonassociative morphine tolerance. Morphine given in th e morphine-associated context increased Fos-like immunoreactivity in the la teral amygdala and hippocampal area CA1. Microinjection of the cholecystoki nin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that cholecystokinin acting in the amygdala is nece ssary for associative tolerance to morphine's analgesic effect.