Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Abstract

Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, in mice, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, aside from largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs in a way that impacts somato-dendritic potassium currents or synaptic transmission. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

Endocytic trafficking determines cellular tolerance of presynaptic opioid signaling

“…MOR is not the only receptor mediating presynaptic neuromodulation by opioids. DOR is another well-known example that mediates Gi-coupled inhibition of neurotransmitter release in response to opioids ( Bardoni et al, 2014 ; He et al, 2021 ; Piskorowski and Chevaleyre, 2013 ). Physiological tolerance to DOR-mediated effects is well established ( DiCello et al, 2019 ; Pradhan et al, 2010 ), and agonist-induced internalization of DOR has been clearly demonstrated in the soma and dendrites of neurons ( Pradhan et al, 2009 ; Scherrer et al, 2006 ).…”

“…Physiological tolerance to DOR-mediated effects is well established ( DiCello et al, 2019 ; Pradhan et al, 2010 ), and agonist-induced internalization of DOR has been clearly demonstrated in the soma and dendrites of neurons ( Pradhan et al, 2009 ; Scherrer et al, 2006 ). Recent evidence indicates that DOR does not rapidly desensitize at the presynapse ( He et al, 2021 ). However, DOR trafficking in axons has not been studied previously, and it is not known if longer-term tolerance develops to DOR-mediated presynaptic inhibition.…”

“…DOR is co-expressed with MOR in some neurons, and it has been proposed that such co-expression can underlie functional cross-talk and cross-regulation between these distinct opioid receptor types ( He et al, 2021 ; Wang et al, 2018 ). This motivated us to ask if presynaptic tolerance elicited by chronic agonist exposure is receptor-specific or if chronic activation of one receptor type promotes the development of tolerance at the other.…”

Endocytic trafficking determines cellular tolerance of presynaptic opioid signaling

“…DOR exhibits a higher degree of tolerance than MOR and indicates that tolerance is an homologous process MOR is not the only receptor mediating presynaptic neuromodulation by opioids. DOR is another well-known example that mediates Gi-coupled inhibition of neurotransmitter release in response to opioids (Bardoni et al, 2014;He et al, 2021;Piskorowski and Chevaleyre, 2013). Physiological tolerance to DOR-mediated effects is well established (DiCello et al, 2019;Pradhan et al, 2010), and agonist-induced internalization of DOR has been clearly demonstrated in the soma and dendrites of neurons (Pradhan et al, 2009;Scherrer et al, 2006).…”

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

“…In support of this, one study showed that MORs inhibit FSI GABA, but not regular spiking GABA basket cell input to CA1 pyramidal neurons ( Glickfeld et al, 2008 ; Shao et al, 2020 ). However, a very recent study showed that both MORs and DORs independently activate GIRK in PV neurons as well as inhibit GABA release on to pyramidal neurons ( He et al, 2021 ). MORs hyperpolarize FSI basket cell neurons, but not regular spiking basket cell neurons.…”