The NMDA receptor antagonist MK-801 differentially modulates μ and κ opioid actions in spinal cord in vitro

We have examined the interactions between NMDA receptors and opioid effects in isolated neonatal rat spinal cord. Electrical stimulation of a lumbar dorsal root evoked a nociceptive-related slow ventral root potential (sVRP) recorded at the corresponding ipsilateral ventral root. The κ opiate receptor agonist U69,593 (2.5 nM-1 μM) depressed sVRP area by a maximum of 80%; EC50was approximately 33 nM. Both the non-specific antagonist naloxone and the κ-specific antagonist nor-binaltorphimine (nor-BNI) antagonized the effects of U69,593. Morphine, a μ agonist, (1 nM-1 μM) depressed sVRP area with an approximate EC50of 90 nM. The effects of both μ and κ opioid agonists were selective for the very slow metabotropically mediated components of the sVRP, compared to the relatively fast NMDA receptor-mediated components. The non-competitive N-methyl- d-aspartate (NMDA) antagonist MK-801 (20 nM) had no effect on sVRP area when applied alone but co-applied with morphine significantly potentiated the depressant effects of morphine. In contrast, MK-801 either had no effect on or slightly antagonized the depressant effects of U69,593. Naloxone following morphine produced a significant increase in sVRP area above pre-morphine control 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 μ and κ receptor agonists exert similar selective depressant effects on spinal nociceptive neurotransmission; (2) μ but not κ agonists exert prolonged excitatory effects that oppose the depression; and (3) NMDA receptors play a role in determining opioid analgesic potency and naloxone-precipitated hyperresponsiveness. The results may be related to initial steps in the development of acute tolerance to μ opioids, and suggest that tolerance to κ opioids may have a different mechanism.