ASSOCIATIVE AND NONASSOCIATIVE MECHANISMS OF MORPHINE ANALGESIC TOLERANCE ARE NEUROCHEMICALLY DISTINCT IN THE RAT SPINAL-CORD

Opiate tolerance involves both associative and non-associative changes . However, procedures designed to distinguish between these two proces ses have rarely been employed when investigating the physiological bas is of such plasticity. The present experiments assessed some of the me chanisms contributing to both associative and non-associative decrease s in morphine analgesic potency following repeated IV morphine adminis tration (4 days, 5 mg/kg per day). For one group of rats, testing for morphine analgesia (tailflick) occurred in a context that had been rep eatedly paired with morphine administration. Another group of rats, ex posed equally to the testing context, handling procedures and morphine , was tested for morphine analgesia in a context that was specifically unpaired with prior drug. Although both of these groups showed a decr ease in the drug effect following repeated administrations, those rats tested in the morphine-associated context were significantly more tol erant than the unpaired group. We evaluated the spinal cord involvemen t of NMDA receptors, as well as the peptide neurotensin in these two t ypes of tolerance. NMDA receptors appeared to mediate non-associative changes in drug potency, as rats tested in either context were less to lerant when morphine administration was preceded with the non-competit ive NMDA antagonist, MK-801 (2.5 and 5 nmol). Spinal neurotensin antag onism with [D-Trp(11)]neurotensin (3 pmol) selectively abolished assoc iative tolerance. These findings provide information about the mechani sms of opiate tolerance and support the distinction between associativ e and non-associative processes underlying these changes.