Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ‐opioid receptor

Key points Dynorphin A inhibits anorexigenic hypothalamic proopiomelanocortin neurons by activating a potassium conductance. Although dynorphin A is considered selective for κ‐opioid receptors, the present data show that the dynorphin A‐induced potassium conductance is reversed by a μ‐opioid receptor‐selective antagonist and is absent in mice lacking functional μ‐opioid receptors. Thus, μ‐opioid receptors mediate the inhibition of proopiomelanocortin neurons caused by dynorphin A, consistent with other studies showing that κ‐opioid receptor‐selective agonists and antagonists can act at the μ‐opioid receptor when used at sufficiently high concentrations. The results indicate that if dynorphin A inhibits proopiomelanocortin neurons to increase food intake, it does so either by activating μ‐opioid receptors on these neurons or by inhibiting κ‐opioid receptors located in the presynaptic compartment of proopiomelanocortin neurons.Abstract It has recently been shown that dynorphin A (Dyn A), an endogenous agonist of the κ‐opioid receptor (KOR), directly inhibits proopiomelanocortin (POMC) neurons in the hypothalamus through activation of G‐protein‐coupled inwardly rectifying K + channels (GIRKs). This effect has been proposed to be mediated by the putative κ 2 ‐opioid receptor (KOR‐2), and has been suggested as a possible mechanism for the orexigenic actions of KOR agonists. Using whole‐cell voltage clamp recordings in brain slice preparations, the present study demonstrates that Dyn A (1 or 5 μ m ) induces an outward current in POMC neurons that is reversed by the highly selective μ‐opioid receptor (MOR) antagonist CTAP and is absent in mice lacking MORs. Additionally, the KOR‐2‐selective agonist GR89696 binds MORs on POMC neurons but fails to induce an outward current. Similar to Dyn A, the KOR‐selective antagonist nor ‐binaltorphimine (nor‐BNI) lacked specificity when used at sufficiently high concentrations. Maximal concentrations of the MOR‐selective agonist DAMGO induced outward currents in POMC neurons that were completely reversed by a relatively high concentration of nor‐BNI. Experiments using a half‐maximal concentration of DAMGO demonstrate that nor‐BNI must be used at concentrations <100 n m to avoid non‐specific actions of the antagonist at MORs located on POMC neurons. These data suggest that direct inhibition of POMC neurons by Dyn A is mediated through the MOR, not the KOR‐2, which is consistent with previous studies demonstrating that Dyn A can act at the μ‐opioid receptor (MOR) when present in high concentrations.