NITROUS-OXIDE INDUCES PREEMPTIVE ANALGESIA IN THE RAT THAT IS ANTAGONIZED BY HALOTHANE

Background: Noxious stimulation-induced sensitization of the central n ervous system has been proposed as a key element in the development of subsequent protracted pain. Accordingly, the authors used the formali n model of pain to test the hypothesis that general anesthesia can pro duce preemptive analgesia and thereby interfere with noxious stimulati on-induced central sensitization. Methods: Rats received 0.9% or 1.8% halothane, 30% or 75% nitrous oxide (N2O), or 75% N2O plus 0.9% haloth ane (n = 4 or 5 per group). Control rats (n = 5) received only 100% ox ygen. Fifteen minutes after the induction of anesthesia, formalin was injected subcutaneously into a hind paw of each rat, and anesthesia wa s maintained for 5 more min. Because the behavioral pain response to f ormalin (i.e., flinching of the injected paw) is biphasic, these treat ment groups were anesthetized only during phase 1 (acute phase). Anoth er group (n = 5) received 75% N2O only during phase 2 (delayed phase). Reversibility of the N2O effect was tested by the administration of n aloxone before phase 1 or naltrexone during phase 2 (n = 5 per group). Finally, additional rats anesthetized as described above (n = 4 or 5 per group) underwent tail-hick testing during anesthesia. Results: All anesthetics reduced phase 1 pain behavior, but only N2O produced anti nociception on tail-flick testing. Thirty percent and 75% N2O, adminis tered during phase 1, suppressed phase 2 flinching 29% and 49%, respec tively, whereas nitrous oxide administered after phase 1 did not suppr ess phase 2 pain behavior. This effect of nitrous oxide was reversed b y an opioid antagonist given during phase 1 but not phase 2. Halothane administered during phase I had no effect on phase 2 flinching, and i t antagonized the effect of 75% N2O. Conclusions: Nitrous oxide induce s dose-dependent preemptive analgesia in this model that is reversed p artially by naloxone, thus suggesting the involvement of endogenous op ioids in this action. In contrast, halothane has no preemptive analges ic properties and even antagonizes the analgesic effect of nitrous oxi de. Hence, the hypnotic potency of an anesthetic is a poor indication of its preemptive analgesic potential.