RT Journal Article
SR Electronic
T1 Differential desensitization observed at multiple effectors of somatic mu opioid receptors underlies sustained agonist-mediated inhibition of proopiomelanocortin neuron activity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1030-17
DO 10.1523/JNEUROSCI.1030-17.2017
A1 Philip D. Fox
A1 Shane T. Hentges
YR 2017
UL http://www.jneurosci.org/content/early/2017/08/07/JNEUROSCI.1030-17.2017.abstract
AB Activation of somatic mu opioid receptors (MORs) in hypothalamic proopiomelanocortin (POMC) neurons leads to the activation of G-protein-coupled inward rectifier potassium (GIRK) channels and hyperpolarization, but in response to continued signaling, MORs undergo acute desensitization resulting in robust reduction in the peak GIRK current after minutes of agonist exposure. We hypothesized that the attenuation of the GIRK current would lead to a recovery of neuronal excitability whereby desensitization of the receptor would lead to a new steady-state of POMC neuron activity reflecting the sustained GIRK current observed after the initial decline from peak with continued agonist exposure. However, electrophysiologic recordings and GCaMP6f Ca2+ imaging in POMC neurons in mouse brain slice indicate that maximal inhibition of cellular activity by these measures can be maintained after the GIRK current declines. Blockade of the GIRK current by Ba2+ or Tertiapin-Q did not disrupt the sustained inhibition of Ca2+ transients in the continued presence of agonist, indicating the activation of an effector other than GIRK channels. Use of an irreversible MOR antagonist and Furchgott analysis revealed a low receptor reserve for the activation of GIRK channels, but a >90% receptor reserve for the inhibition of Ca2+ events. Altogether, the data show that somato-dendritic MORs in POMC neurons inhibit neuronal activity through at least two effectors with distinct levels of receptor reserve and that differentially reflect receptor desensitization. Thus, in POMC cells, the decline in the GIRK current during prolonged MOR agonist exposure does not reflect an increase in cellular activity as expected.SIGNIFICANCE STATEMENTDesensitization of the mu opioid receptor (MOR) is thought to underlie the development of cellular tolerance to opiate therapy. The present studies focused on MOR desensitization in hypothalamic POMC neurons as these neurons produce the endogenous opioid beta-endorphin and are heavily regulated by opioids. Prolonged activation of somatic MORs in POMC neurons robustly inhibited action potential firing and Ca2+ activity despite desensitization of the MOR and reduced activation of a potassium current over the same time course. The data show that somatic MORs in POMC neurons couple to multiple effectors that have differential sensitivity to desensitization of the receptor. Thus, in these cells, the cellular consequence of MOR desensitization cannot be defined by the activity of a single effector system.