A Single Nitrous Oxide (N₂O) Exposure Leads to Persistent Alleviation of Neuropathic Pain in Rats

Abstract 

Using the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N₂O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10°C water bath. A single 50% N₂O exposure for 1 hour, 15 minutes not only induced potent anti-nociception during N₂O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N₂O exposure. A preadministration of naltrexone, which markedly reduced acute N₂O-induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N₂O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N₂O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N₂O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner.

Perspective

Because a single 50% N₂O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N₂O effects in patients with neuropathic pain. The ability of N₂O to potentiate analgesic effects of other drugs also must be evaluated.

Key words: Nitrous oxide, neuropathic pain, hyperalgesia, central sensitization, NMDA receptors