Involvement of excitatory amino acid receptors and nitric oxide in the rostral ventromedial medulla in modulating morphine pain-inhibitory signals from the periaqueductal gray matter in rats

Supraspinal opioid analgesia is mediated in part by connections between the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Morphine analgesia from the PAG is decreased by serotonin, Nmethyl- D-aspartate (NMDA) and opioid receptor antagonists administrated into the RVM. Since in the RVM, the brain isoform of nitric oxide synthase (NOS) is also prominent this study was designed to evaluate the effects of non-selective NOS inhibitor (L-NAME) and noncompetitive NMDA antagonist (MK-801) microinjected into the RVM on PAG morphine (2.5 μg) analgesia and their potential interactions as measured by the tail-flick test. Rats were anesthetized with sodium pentobarbital and then special cannulae were stereotaxically inserted into the RVM and PAG. After one week recovery, the effects of noncompetitive NMDA antagonist (MK-801) and nonselective NOS inhibitor (L-NAME) microinjection into the RVM and their interactions with each other to alter PAG morphine (2.5 μg) analgesia elicited from the PAG was measured by the tail-flick test. Mesencephalic morphine analgesia was significantly reduced after pretreatment in the RVM with L-NAME (0.6-1.3 μmol) or MK-801 (0.8 nmol). Reduction in mesencephalic morphine analgesia when MK-801 (0.8 nmol) and L-NAME (1 μmol) was sequentially microinjected into the RVM was not different from the effect of MK-801 (0.8 nmol) or L-NAME (1 μmol) when administered individually. These data implicate that NMDA receptors and nitric oxide (NO) production in the RVM modulate the transmission of opioid pain-inhibitory signals from the PAG.