We have developed an experimental fibromyalgia (FM)-like mouse model using intermittent cold stress (ICS), where chronic pain is generalized, female-predominant and abolished in type 1 lysophosphatidic acid receptor-KO (LPA1-/-) mice, but is not reversed by systemic or brain treatment with morphine. In the present study, we investigated two issues whether both chronic pain mechanisms and lack of brain morphine analgesia are associated to each other in the ICS model, and what mechanisms are involved in the lack of morphine analgesia. The hyperalgesia was not affected in μ-opioid receptor-KO (MOPr-/-) mice, while the lack of brain morphine analgesia remained unchanged in LPA1-/- mice, which completely abolish the hyperalgesia in the ICS model. On the other hand, the lack of morphine analgesia was abolished in NR2A-NMDA receptor-KO (NR2A-/-) mice, and blocked by intracerebroventricular (i.c,v,) injection of (R)-CPP, an NR2A antagonist or by microinjection of siRNA for NR2A into PAG region, while no change was observed with Ro 04-5595, an NR2B antagonist (i.c.v.). The lack of morphine analgesia was also reversed by the concomitant treatment with 1 mg/kg (i.p.) of dextromethorphan possessing NMDA receptor antagonist activity, which has no analgesic activity. Finally, the hyperalgesia was completely reversed by methadone possessing MOPr agonist and NMDA receptor antagonist activity. Indeed, the methadone analgesia was abolished in MOPr-/- mice. All these results suggest that chronic pain status and lack of morphine analgesia are independent to each other, and the lack of morphine analgesia is mediated by an activation of NR2A-NMDA receptor system. SIGNIFICANCE STATEMENT: This study describes that a type of stress-induced wide-spread pain has chronic pain independent of endogenous opioid-mediated pain inhibitory system and lack of morphine analgesia independent of chronic pain status. This study describes that the lack of morphine analgesia is possibly mediated by endogenous opioid-induced analgesic tolerance and thereby reversed by anti-opioid NMDA receptor system. The latter view is evidenced by the findings that NMDA receptor blockades recover the morphine analgesia.