Morphine modulates excitatory amino acid-induced activity in the mouse spinal cord: short-term effects on N-methy-D-aspartate (NMDA) and long-term effects on kainic acid

Excitatory amino acid (EAA) antagonists and phenycyclidine (PCP) ligands inhibit the development of morphine tolerance and dependence. The present study tested the hypothesis that opioids increase EAA-induced activity by monitoring morphine's effect on the caudally-directed biting and scratching behaviors produced in mice by intrathecal (i.t.) injections of either N-methyl-D-aspartate (NMDA) or kainic acid (KA). A single injection of 10 mg/kg of morphine i.p. had no effect on the intensity of behaviors induced 2 h later by KA but inhibited NMDA-induced activity. Pretreatment with 100 mg/kg of morphine i.p. 24 h before testing did not alter NMDA-induced behaviors, but attenuated sensitization to repeated injections of KA, which is thought to reflect activation of primary afferent C-fibers. Coadministration of 0.1 μg of naloxone with EAAs did not alter responses to either NMDA or KA in control mice, however, 2 h after 10 mg/kg of morphine, inclusion of naloxone potentiated NMDA-induced activity without altering responses to KA. 24 h after 100 mg/kg of morphine, naloxone, coadministered with KA, was also able to reverse the inhibitory effect of morphine pretreatment on KA-induced activity. In summary, morphine produces short-term inhibitory and excitatory effects on NMDA-induced activity, the latter of which is unmasked by naloxone. Morphine has no immediate effect on KA-induced activity but is able to bring about a long-term inhibition of sensitization to KA, an effect that is reversed by naloxone. Activity along pathways activated by NMDA and KA may, therefore, contribute to different aspects of opioid tolerance or withdrawal.