title: Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ-opioid receptor.
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 κ2-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 μm) 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 nm 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.
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Reagan L
authors.initials: RL
authors.lastname: Pennock
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA hentgess@colostate.edu.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Hentges
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004399:Dynorphins / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D010879:Piperazines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C071609:GR 89696; D011333:Pro-Opiomelanocortin; D004399:Dynorphins
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