We developed the fibromyalgia-like chronic pain model in mice by usingintermittent cold stress. This model mouse was found to have similarity to fibromyalgia patients in terms of pathophysiology and pharmacotherapy, which includes the loss of sensitivity to morphine. Based on the speculation that excess amounts of endogenous opioids induced by repeated stress may cause a type of opioid analgesic tolerance, we attempted to use anti-opioid NMDA receptor (NR2A subunit)-deficient mice to see the recovery of morphine analgesia. ICS-treated NR2A-KO mice successfully demonstrated the complete recovery of morphine analgesia, when given intracerebroventricularly (i.c.v.), without any change in the basal nociception threshold. The i.c.v. pre-administration of siRNA for NR2A or NR2A antagonist, (R)-CPP recovered the potency of morphine analgesia under the established pain state. Similar results were also observed with systemic (i.p.) dextromethorphan, which has NMDA receptor antagonist activity. Lastly, we found that the single administration of methadone, which has opioid agonist activity and NMDA receptor antagonist activity, showed potent analgesic actions, as seen in the case with naïve mice.

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