Differential Expression and Sensitivity of Presynaptic and Postsynaptic Opioid Receptors Regulating Hypothalamic Proopiomelanocortin Neurons

Abstract

Hypothalamic proopiomelanocortin (POMC) neurons release the endogenous opioid beta-endorphin and POMC neuron activity is inhibited by opioids, leading to the proposal that beta-endorphin acts to provide feedback inhibition. However, both intrinsic properties and synaptic inputs contribute to the regulation of POMC neurons such that attributing an autoregulatory role to opioids must include consideration of opioid receptor localization and sensitivity at both presynaptic and postsynaptic sites. In the present study, whole-cell recordings were made in POMC cells in mouse brain slices and the presynaptic and postsynaptic regulation of POMC neurons was examined using selective agonists for mu, kappa, and delta opioid receptors. Activation of mu, but not kappa or delta, receptors induced a direct postsynaptic outward current. Agonists for each of the receptors inhibited the frequency of spontaneous IPSCs. Mu and kappa, but not delta, agonists reduced the amplitude of evoked IPSCs and appeared to colocalize in a significant portion of GABAergic terminals onto POMC neurons. The presynaptic inhibition caused by the mu agonist DAMGO had an EC 50 of 80 nM, whereas the EC 50 was 350 nM when measuring the postsynaptic outward current. This differential sensitivity adds an unexpected component of opioid-dependent feedback regulation, where low levels of opioid receptor activation would likely disinhibit POMC neuron activity and higher concentrations would result in an overall inhibition. The results may help explain why it has been difficult to clearly discern the role that opioids play in the regulation of food intake and other processes involving POMC neurons.

G-protein-gated inwardly rectifying K+ channel 4 (GIRK4) immunoreactivity in chemically defined neurons of the hypothalamic arcuate nucleus that control body weight

“…MOR agonists hyperpolarize POMC neurons and inhibit action-potential firing (Slugg et al, 2000;Cowley et al, 2001;Ibrahim et al, 2003;Roseberry et al, 2004;Hentges et al, 2009). There is a differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating POMC neurons (Pennock and Hentges, 2011). Our results showing prominent labeling of GIRK4 immunoreactivity in POMC neurons add further evidence for involvement of GIRK channels in POMC neurons and suggest that at least the GIRK4 subunit is involved in the propagation of this inhibitory action.…”

Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

“…An alternative explanation for oxycodone’s effect is that oxycodone treatment may lead to long-lasting MOPr desensitization. Arguing against this explanation, however, presynaptic opioid receptors, such as those thought to contribute to striatal OP-LTD, are more resistant to desensitization than their post-synaptic counterparts 45,46 . Opioid receptor downregulation or alterations in receptor-effector coupling may also be involved in the effects of oxycodone on mOP-LTD.…”

Neuroanatomical distribution of μ-opioid receptor mRNA and binding in monogamous prairie voles (Microtus ochrogaster) and non-monogamous meadow voles (Microtus pennsylvanicus)

“…For example, in cerebellar cortex, MOR mRNA is localized in the granular layer and the ligand binding in the molecular layer. MOR protein in some brain regions is synthesized in the cell body, transported and incorporated to the membrane of the axon terminals (Aicher et al, 2000a, Aicher et al, 2000b, Jaferi and Pickel, 2009, Pennock and Hentges, 2011). These data are consistent with the hypothesis that MOR mRNA is transcribed in granule cells and the protein is localized in axon terminals in the molecular layer.…”