| First Author | Pennock RL | Year | 2014 |
| Journal | J Physiol | Volume | 592 |
| Issue | 19 | Pages | 4247-56 |
| PubMed ID | 25085890 | Mgi Jnum | J:225555 |
| Mgi Id | MGI:5693498 | Doi | 10.1113/jphysiol.2014.275339 |
| Citation | Pennock RL, et al. (2014) Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the mu-opioid receptor. J Physiol 592(Pt 19):4247-56 |
| abstractText | It has recently been shown that dynorphin A (Dyn A), an endogenous agonist of the kappa-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 kappa2-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 mum) induces an outward current in POMC neurons that is reversed by the highly selective mu-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 mu-opioid receptor (MOR) when present in high concentrations. |
