Electrophysiologic Analysis of Preemptive Effects of Spinal Opioids on N-methyl-D-aspartate Receptor-mediated Events

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Abstract
Spinal N-methyl-D-aspartate (NMDA) receptormediated mechanisms may contribute to reduced opiold sensitivity in conditions of pain. The effectiveness of spinal opioids in inhibiting NMDA-mediated nociceptive events was assessed with two models. In addition, oploid dose-response curves with preemptive administration were compared with early and late postadministrations. Dorsal horn nociceptive neuronal responses were recorded in the Intact halothane anesthetized rat to acute repetitive C-fiber electrical stimulation (0.1 and 0.5 Hz) and to the peripheral injection of 5% formalin. At 0.5 Hz but not at 0.1 Hz, there was an enhanced C-fiber evoked response of dorsal horn neurons elicited by repetitive C-fiber stimulation (wind-up), which is mediated by the NMDA receptor. Formalin produced a biphasic response; the late protracted inflammatory phase was NMDA receptor-mediated. With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 µg morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadminlstration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting µ opioid, D-Ala-Gly-MePHe-Gly-o1, given late postadminlstration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe- Gly-ol produced complete Inhibitions. NMDA receptor-mediated neuronal responses, such as wind-up and the established second phase of the formalin response, are poorly responsive to opioids. Dose increases and preemptive opioids effectively inhibit these NMDA receptor-mediated events.

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