Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ‐opioid receptor
| Autor: | Reagan L. Pennock, Shane T. Hentges |
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| Rok vydání: | 2014 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty Patch-Clamp Techniques Pro-Opiomelanocortin Pyrrolidines Physiology medicine.drug_class Voltage clamp Hypothalamus Receptors Opioid mu Neuroscience: Cellular/Molecular Dynorphins Piperazines Mice chemistry.chemical_compound Proopiomelanocortin Opioid receptor Internal medicine medicine Animals Receptor Mice Knockout Neurons biology Receptors Opioid kappa Dynorphin A Enkephalin Ala(2)-MePhe(4)-Gly(5) Analgesics Opioid DAMGO Endocrinology nervous system chemistry biology.protein Endogenous agonist |
| Zdroj: | The Journal of Physiology. 592:4247-4256 |
| ISSN: | 1469-7793 0022-3751 |
| Popis: | 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 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 |
| Databáze: | OpenAIRE |
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