Responses to [d-Ala², MePhe⁴, Gly-ol⁵]enkephalin, a selective agonist for μ-receptors, were recorded intracellularly from 26 neurons in slices of guinea-pig hypothalamus. Of eight cells tested in the supraoptic nucleus, all of which had electrical properties characteristic of magnocellular neuroendocrine cells, four were sensitive to the agonist applied in the perfusion bath or with microdrops. The main effect was a decrease or suppression of spontaneous firing. In the paraventricular nucleus, seven of 18 cells tested also had electrophysiological characteristics similar to magnocellular neurons: two of them were sensitive to the μ-agonist and the effect was similar to that observed in the supraoptic nucleus. The remaining paraventricular neurons displayed low-threshold Ca²⁺ spikes, and thus had electrophysiological characteristics different from putative magnocellular neurons. Ten of 11 cells with low-threshold Ca²⁺ spikes were hyperpolarized by more than 10 mV by the μ-agonist, and showed a 33 ± 1.9% (S.E.M.) decrease in input resistance. In both types of cells, when synaptic transmission was blocked with tetrodotoxin, the μ-agonist could still induce a hyperpolarization, suggesting that the effect was in part direct. Hyperpolarization was also obtained when the Cl⁻ reversal potential was shifted to more positive values by using KCl electrodes, thus excluding a Cl⁻ conductance mechanism.

These results provide evidence that opioid peptides can directly inhibit hypothalamic neurons, that the mechanism is an increase in K⁺ conductance, and that two types of hypothalamic neurons appear to have different sensitivities to a μ-agonist.