THE NMDA RECEPTOR ANTAGONIST MK-801 DIFFERENTIALLY MODULATES MU-OPIOID AND KAPPA-OPIOID ACTIONS IN SPINAL-CORD IN-VITRO

We have examined the interactions between NMDA receptors and opioid ef fects in isolated neonatal rat spinal cord. Electrical stimulation of a lumbar dorsal root evoked a nociceptive-related slow ventral root po tential (sVRP) recorded at the corresponding ipsilateral ventral root. The kappa opiate receptor agonist U69,593 (2.5 nM-1 mu M) depressed s VRP area by a maximum of 80%; EC(50) was approximately 33 nM. Both the non-specific antagonist naloxone and the kappa-specific antagonist no r-binaltorphimine (nor-BNI) antagonized the effects of U69,593. Morphi ne, a mu agonist, (1 nM-1 mu M) depressed sVRP area with an approximat e EC(50) Of 90 nM. The effects of both mu and kappa opioid agonists we re selective for the very slow metabotropically mediated components of the sVRP, compared to the relatively fast NMDA receptor-mediated comp onents. The non-competitive N-methyl-D-aspartate (NMDA) antagonist MK- 801 (20 nM) had no effect on sVRP area when applied alone but co-appli ed with morphine significantly potentiated the depressant effects of m orphine. In contrast, MK-801 either had no effect on or slightly antag onized the depressant effects of U69,593. Naloxone following morphine produced a significant increase in sVRP area above pre-morphine contro l values; the increase lasted 30 min or more. Neither naloxone nor nor -BNI was associated with an increase in sVRP area when given alone or following U69,593. MK-801 co-applied with morphine blocked the rebound increase in sVRP area following naloxone. These results suggest that (1) both mu and kappa receptor agonists exert similar selective depres sant effects on spinal nociceptive neurotransmission; (2) mu but not k appa agonists exert prolonged excitatory effects that oppose the depre ssion; and (3) NMDA receptors play a role in determining opioid analge sic potency and naloxone-precipitated hyperresponsiveness. The results may be related to initial steps in the development of acute tolerance to mu opioids, and suggest that tolerance to kappa opioids may have a different mechanism.