Effect of N-omega-nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, on stress- and morphine-induced prolactin release in male rats

1 The effect of the nitric oxide synthesis inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) was investigated on stress- and morphine-induced prolactin (PRL) secretion in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2 Three doses of L-NAME were tested (1, 10 and 30 mg kg(-1)) and were given intraperitoneally one hour before blood sampling; control rats received saline. After the first blood sample, rats received an initial intravenous injection of morphine (3, 6 or 12 mg kg(-1)) or were subjected to immobilization stress. In the case of a morphine administration, rats received a second dose of morphine (3, 6 or 6 mg kg(-1), respectively) 90 min later, when tolerance had developed, while rats subjected to immobilization stress received 6 mg kg(-1) morphine 90 min after onset of stress. 3 L-NAME had no effect on basal plasma PRL concentration. However, it potentiated acute morphine-induced PRL secretion and attenuated the subsequent tolerance in a dose-dependent way. Immobilization stress-induced PRL secretion was inhibited dose-dependently by L-NAME, as was its subsequent tolerance to morphine; however, in this case, in a reversed dose-dependent way. 4 When the highest dose of morphine (12 mg kg(-1)) was combined with the highest dose of L-NAME pretreatment (30 mg kg(-1)), all rats showed a dramatic potentiation of the morphine-induced PRL rise compared to controls. Moreover, all of these rats died within 90 min after the administration of morphine. 5 These results show that NO plays a role in the acute opioid action on PRL release during stress as well as in the development of tolerance to the opioid effect, and some possible mechanisms are discussed.