GIRK channel-mediated inhibition of melanin-concentrating hormone neurons by nociceptin/orphanin FQ.

Targeting the melanin-concentrating hormone (MCH) system has been suggested as a potential treatment for obesity, anxiety disorders, as well as addiction. Despite the therapeutic potential of MCH agonists and antagonists, the endogenous factors regulating MCH activity, in particular those implicated in anxiety and reward, are ill-defined. The present study investigated the cellular effects of nociceptin/orphanin FQ (N/OFQ), an endogenous opioid with anxiolytic and antireward properties, on MCH neurons. We found that N/OFQ induced a concentration-dependent reversible outward current in MCH neurons (EC(50) = 50.7 nM), an effect that was blocked by the competitive antagonist of the nociceptin opioid peptide (NOP) receptor UFP-101. N/OFQ-induced outward currents persisted in TTX, reversed near the potassium equilibrium potential, and displayed inward rectification, suggesting direct postsynaptic potassium channel activation. Tertiapin-Q completely abolished the N/OFQ effect, whereas glibenclamide did not, implicating protein G-dependent inwardly rectifying potassium (GIRK) and not ATP-sensitive potassium (K(ATP)) channels as the effector ion channel. The N/OFQ-induced outward current desensitized during repeated applications and occluded the inhibitory effect of dynorphin, suggesting that dynorphin and N/OFQ activate the same pathway. N/OFQ also reversibly inhibited voltage-gated calcium currents in MCH neurons. In conclusion, our study indicates N/OFQ as a robust endogenous regulator of MCH neurons, which may play a role in anxiety and drug addiction.