title: Electrophysiologic analysis of preemptive effects of spinal opioids on N-methyl-D-aspartate receptor-mediated events.
abstract: BACKGROUND
  Spinal N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms may contribute to reduced opioid sensitivity in conditions of pain. The effectiveness of spinal opioids in inhibiting NMDA-mediated nociceptive events was assessed with two models. In addition, opioid dose-response curves with preemptive administration were compared with early and late postadministrations.
  
  
  METHODS
  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.
  
  
  RESULTS
  With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 micrograms morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadministration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting mu opioid, D-Ala-Gly-MePHe-Gly-ol, given late postadministration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe-Gly-ol produced complete inhibitions.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, University College London, United Kingdom.
authors.forename: V
authors.initials: V
authors.lastname: Chapman
authors.forename: J E
authors.initials: JE
authors.lastname: Haley
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005557:Formaldehyde / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013116:Spinal Cord
chemical_list: D000700:Analgesics; D004745:Enkephalins; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005557:Formaldehyde; D009020:Morphine