N-Methyl-d-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((±)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in NMDA-induced behaviors. CPP also failed to inhibit withdrawal jumping. Together these data indicate that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.
Bibliographical noteFunding Information:
This research was supported by US Public Health Service Grants DA04090 and DA00124 to A.A.L. and ADHAMA training Grant T32 DA07234 and K20 DA 00177 to J.S.K.
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