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Papers of the Week

Papers: 2 Feb 2019 - 8 Feb 2019

Animal Studies, Pharmacology/Drug Development

2019 Aug

J Pain



Blockade of NMDA receptors and nitric oxide synthesis potentiated morphine-induced anti-allodynia via attenuating pain-related amygdala pCREB/CREB signaling pathway.


The present study investigated the role of the amygdala NMDA receptors/NOS pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala (CeA), chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was intraperitoneally administered to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (0.05-0.1 µg/rat) or L-NAME, the NO synthase inhibitor, (0.1-0.5 µg/rat) were microinjected into the CeA, the higher doses potentiated an ineffective dose of morphine (3 mg/kg). Microinjection of the same doses of D-AP5 and L-NAME without morphine had no effect. Co-microinjection of the ineffective doses of L-NAME (0.1 µg/rat) and D-AP5 (0.05 µg/rat) with a 5-min interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cAMP-response element-binding protein (CREB) and phosphorylated CREB (pCREB) in the amygdala tissues. Our results showed that neuropathic pain increased the pCREB/CREB ratio in the amygdala, while this ratio was decreased following morphine-induced anti-allodynia. The potentiative effect of the co-administration of D-AP5/L-NAME on an ineffective dose of morphine also decreased the amygdala pCREB/CREB levels. Therefore, it seems that the amygdala pCREB/CREB signaling pathway plays a critical role in processing neuropathic pain. Moreover, the glutamate NMDA receptors and NO system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is hard to treat and the exact mechanisms are still unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. The findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.