Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin

Key points center dot In conjunction with fast amino acid transmitters, neuropeptides such as dynorphin play key roles in regulating energy homeostasis. center dot Dynorphin immunoreactive axons are abundant in the hypothalamic arcuate nucleus and terminate near or on proopiomelanocortin (POMC) neurons. center dot Dynorphin directly inhibits POMC cells by a mechanism based on activation of GIRK channels, mediated by kappa-2 opioid receptors. center dot Dynorphin indirectly modulates the activity of POMC neurons by depressing afferent glutamate and GABA synaptic neurotransmission. center dot These data suggest that dynorphin-containing neurons could modulate food intake and energy homeostasis by directly attenuating the activity of the anorexigenic POMC cell. Abstract Dynorphin, an endogenous ligand of kappa () opioid receptors, has multiple roles in the brain, and plays a positive role in energy balance and food intake. However, the mechanism for this is unclear. With immunocytochemistry, we find that axonal dynorphin immunoreactivity in the arcuate nucleus is strong, and that a large number of dynorphin-immunoreactive boutons terminate on or near anorexigenic proopiomelanocortin (POMC) cells. Here we provide evidence from whole-cell patch-clamp recording that dynorphin-A (Dyn-A) directly and dose-dependently inhibits arcuate nucleus POMC neurons. Dyn-A inhibition was eliminated by the opioid receptor antagonist nor-BNI, but not by the receptor antagonist CTAP. The inhibitory effect was mimicked by the 2 receptor agonist GR89696, but not by the 1 receptor agonist U69593. No presynaptic effect of 2 agonists was found. These results suggest that Dyn-A inhibits POMC neurons through activation of the 2 opioid receptor. In whole-cell voltage clamp, Dyn-A opened G-protein-coupled inwardly rectifying potassium (GIRK)-like channels on POMC neurons. Dynorphin attenuated glutamate and GABA neurotransmission to POMC neurons. In contrast to the strong inhibition of POMC neurons by Dyn-A, we found a weaker direct inhibitory effect of Dyn-A on arcuate nucleus neuropeptide Y (NPY) neurons mediated by both 1 and 2 receptors. Taken together, these results indicate a direct inhibitory effect of Dyn-A on POMC neurons through activation of the 2 opioid receptor and GIRK channels. A number of orexigenic hypothalamic neurons release dynorphin along with other neuropeptides. The inhibition of anorexigenic POMC neurons may be one mechanism underlying the orexigenic actions of dynorphin.