D-Valine methyl ester hydrochloride

The present study investigated the role of the amygdala N-methyl-d-aspartate (NMDA) receptors/nitric oxide synthase pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala, chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was administered intraperitoneally to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (.05-.1 µg/rat) or NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), the nitric oxide synthase inhibitor (.1-.5 µg/rat), were microinjected into the central amygdala, 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. Comicroinjection of the ineffective doses of L-NAME (.1 µg/rat) and D-AP5 (.05 µg/rat) with a 5-minute interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cyclic adenosine monophosphate-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, and this ratio was decreased after morphine-induced anti-allodynia. The potentiative effect of the coadministration 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 nitric oxide system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is difficult to treat and the exact mechanisms remain unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. These findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.

The modulatory effect of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway on sympathetic preganglionic neurons still deserves further investigation. The present study was designed to examine the role of the spinal cord NO/cGMP pathway in controlling mean arterial pressure and heart rate. We observed that intrathecal administration of the NO synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) causes an increase in mean arterial pressure but does not affect heart rate. Intrathecal administration of the soluble guanylyl cyclase inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) does not change mean arterial pressure and heart rate. The precursor for NO synthesis, L-arginine, reduces both mean arterial pressure and heart rate while administration of ODQ before L-arginine impaired decreases in mean arterial pressure and heart rate. Administration of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) after L-NAME does not affect increases in mean arterial pressure promoted by NO synthase inhibition. Although the hypotensive and bradycardic responses induced by intrathecal administration of L-arginine depend on cGMP, our results indicate that NO acts to tonically inhibit SPNs, independent of either cGMP or NMDA receptors.