Modulation of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY274614: assessment of opioid receptor changes.

Recent reports have demonstrated that the coadministration of morphine with an N-methyl-D-aspartate (NMDA) receptor antagonist can attenuate and/or reverse the development of morphine tolerance. In the present study we used an experimental tolerance paradigm using morphine pellets (75 mg) to produce an 1-fold shift in the morphine dose-response curve in rats. Coadministration of the competitive NMDA receptor antagonist LY274614 [(+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid] via continuous s.c. infusion (24 mg/kg/24 hr) significantly attenuated the development of morphine tolerance. In addition, animals made tolerant to morphine and then infused with LY274614 (24 mg/kg/24 hr) regained their analgesic sensitivity to morphine more rapidly than morphine-tolerant animals given a saline infusion. To determine whether LY274614 treatment modifies the subsequent development of tolerance, LY274614 was administered to nontolerant animals for 1 week. One week after LY274614 treatment was discontinued the animals were challenged with morphine and then implanted with morphine pellets. Neither the expression of morphine analgesia nor the development of morphine tolerance differed when LY274614- and saline-treated animals were compared. The infusion of LY274614 for 7 days did not increase the affinity or density of mu, delta, kappa-1 or kappa-3 opioid receptors in rat brain homogenates as measured by ligand binding assays. Additionally, the IC50 values for LY274614 in mu-1, mu-2, delta, kappa-1 or kappa-3 ligand binding assays were greater than 10 microM. Taken together these results demonstrate that the competitive NMDA receptor antagonist LY274614 can both attenuate and reverse the development of morphine tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)