In previous studies we found that in the extremely polydipsic special strain of mice, STR/N, spontaneous drinking was greatly attenuated by injection of the opioid antagonists given intracerebroventricularly as well as subcutaneously. Therefore, we investigated, using hypothalamic slice preparations, responses of neurons in the anteroventral third ventricle region (AV3V) of the STR/N and its control, Swiss/Webster (S/W) mice to morphine and opiate peptides. An application of morphine at 10(-6) M to the circulating medium inhibited activities of 44% of AV3V neurons (45 of 102) in the STR/N, and 59% (76/129) in the S/W, demonstrating that morphine affected a smaller proportion of neurons of the polydipsic mice than that of controls. Opioid agonists for 3 receptor types, mu, delta and kappa, at 10(-6) to 10(-5) M inhibited AV3V neurons in both the STR/N and S/W mice, but to a different degree. No cell of either strain was excited by morphine or any of the opioids. The mu-receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO), was the most potent inhibitor of AV3V neurons; in the STR/N 53% (25/47), and in the S/W 77% (34/44) were inhibited. The kappa-agonist, dynorphin A-(1-13) (DYN), inhibited fewer cells in the STR/N (9%, 4/47), compared with the S/W (36%, 16/44). Only a few cells responded to the delta-agonist, [D-Pen2,5]enkephalin (DPDPE), in both strains. The inhibitory actions of the opiates were reversibly blocked by naloxone, and persisted under synaptic blockade. The threshold concentration of morphine or DAGO for inhibition of AV3V neurons was higher in the STR/N (approximately 10(-8) M for both morphine and DAGO) than in S/W mice (approximately 10(-9) M for morphine and less than 10(-9) M for DAGO). Although the AV3V also contains angiotensin II-sensitive neurons, they were not affected by morphine (10(-6) M). Similarly neurons inhibited by morphine were not excited by angiotensin II (10(-7) M); some neurons were unresponsive to both chemicals. We conclude that morphine and opiate peptides directly inhibit the AV3V neurons of both the STR/N and S/W strains of mice and the sensitivity of these neurons to the opiates is lower in the polydipsic inbred mice compared to their controls. The results, together with our behavioral studies, suggest involvement of the central opioid system in the polydipsia of the STR/N mice.