Mouse Delta Opioid Receptors are Located on Presynaptic Afferents to Hippocampal Pyramidal Cells

Abstract

Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role on hippocampal activity. We used fluorescent knock-in mice that express a functional delta opioid receptor fused at its carboxy terminus with the green fluorescent protein in place of the native receptor to investigate the receptor neuroanatomical distribution in this structure. Fine mapping of the pyramidal layer was performed in hippocampal acute brain slices and organotypic cultures using fluorescence confocal imaging, co-localization with pre- and postsynaptic markers and correlative light-electron microscopy. The different approaches concurred to identify delta opioid receptors on presynaptic afferents to glutamatergic principal cells. In the latter, only scarce receptors were detected that were confined within the Golgi or vesicular intracellular compartments with no receptor present at the cell surface. In the mouse hippocampus, expression of functional delta opioid receptors is therefore mostly associated with interneurons emphasizing a presynaptic modulatory effect on the pyramidal cell firing rate.

Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures

“…This clear-cut observation demonstrates that the subset of receptors expressed in forebrain GABAergic neurons indeed mediate convulsing effects SNC80. Furthermore, DORs are strongly expressed on GABAergic neurons [16] and their inhibitory activity on these neurons normally leads to increase local network excitability. The pro-convulsant effect of SNC80, therefore, likely results from enhanced excitation of forebrain networks.…”

“…DORs are broadly expressed in the nervous system [14]. In the forebrain, a main site for the control of epileptic seizures [15], DORs are expressed in cortex and hippocampus with well-characterized expression in GABAergic neurons for hippocampus [16, 17]. …”

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

“…Accordingly, anatomical and pharmacological data show that local delta opioid receptors can modulate hippocampal activity. These receptors are abundantly expressed in the HPC (Le Merrer et al, 2009), primarily in GABAergic interneurons (Rezai et al, 2012;Scherrer et al, 2006;Svoboda et al, 1999), and their pharmacological activation on hippocampal slices was found to disinhibit principal glutamatergic cells via interneuron inhibition (Lupica, 1995). Moreover, enkephalins, among endogenous ligands of delta receptors, are released in the lateral perforant path, where delta receptor activation is required for high frequency-induced LTP (Bramham et al, 1991;Chavkin et al, 1985).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…The distribution of AC2/AC4 expression in the brain parallels that of DOPr-positive cAMP responses, with both ACs being present in the olfactory bulbs, prefrontal cortex, and hippocampus (Matsuoka et al, 1997;Baker et al, 1999;Olianas et al, 2013). However, it is interesting to note that in the hippocampus, AC2 and AC4 are predominantly present in dendrites of granule and pyramidal cells (Baker et al, 1999), whereas DOPrs are highly expressed presynaptically, on GABAergic interneurons (Rezaï et al, 2012). This distribution would imply that the few DOPrs of pyramidal cells very effectively modulate these enzymes or that the modulation is indirect via a mechanism that remains to be elucidated.…”