Abstract

N-Methyl-D-aspartate (NMDA) antagonists attenuate morphine tolerance and dependence. To test the hypothesis that morphine increases NMDA activity, generating conditions necessary for withdrawal, we examined the role of NMDA receptors in the action of morphine in the guinea pig ileum (GPI). Glutamate produced contractions of the GPI with an EC50 of 24.6 microM. Morphine inhibited contractions induced by glutamate (10-500 microM) with a Ke of 10.2 nM. Naloxone, which produced no effect alone, prevented the inhibitory effects of morphine on glutamate-induced contractions (Ke = 19.3 nM) as well as on electrically induced contractions (Ke = 18.0 nM), suggesting that opioid receptors with similar affinities mediate both inhibitory effects of morphine. Exposure to morphine for 10 to 50 min resulted in acute dependence, characterized by contractions induced by 0.1 to 4 microM naloxone. Responses to naloxone were maximal after a 20-min incubation with 50 nM morphine. Increasing the concentration of morphine or the incubation time did not further increase the degree of dependence. Competitive ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and R(-)-2 amino-5-phosphonovaleric acid) and noncompetitive (MK-801) antagonists of NMDA inhibited naloxone-induced contractions. After 20 min of incubation with morphine followed by naloxone challenge, the EC50 for glutamate was decreased by a factor of 3.2, reflecting an enhanced sensitivity to NMDA. These data show that activation of NMDA receptors and enhanced sensitivity to glutamate are important components of naloxone-precipitated contractions of the GPI after incubation with morphine.