Prolonged Morphine Treatment Selectively Increases Membrane Recruitment of δ-Opioid Receptors in Mouse Basal Ganglia

Abstract

In recent years, we demonstrated that prolonged (48-h) treatment of rats or mice with selective m-opioid receptor ((mu)OR) agonists induced a translocation of delta-opioid receptors ((delta)ORs) from intracellular compartments to neuronal plasma membranes in the dorsal horn of the spinal cord. It remained to be determined whether this phenomenon also occurred in the brain. To resolve this issue, we analyzed by immunogold histochemistry the subcellular distribution of (delta)ORs in the nucleus accumbens, dorsal neostriatum, and frontal cortex in mice treated or not with morphine (48 h). We observed that prolonged treatment with morphine induced a translocation of (delta)ORs from intracellular to subplasmalemmal and membrane compartments in dendrites from both the nucleus accumbens and the dorsal neostriatum but not from the frontal cortex. We propose that this (mu)OR-(delta)OR interaction might prolong and modulate the sensitivity of neurons to opiates in specific target regions.

Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum

“…It is more likely that some property unique to CINs accounts for this difference. This would be consistent with the fact that Lucido and colleagues did not distinguish cell types in their study [10], and were likely sampling mostly from cells other than CINs, which represent only 2-3% of striatal cells [17].…”

“…These differences presumably arise from the effects of ovarian steroid hormones. Moreover, this response has also been noted in the rostral striatum itself, in both its ventral and dorsal divisions [10]. Hence it is unlikely that the present lack of accumulation is related to a regional process specific to the rostral striatum.…”

“…Lucido and colleagues [10] also reported no change in DOPr expression in frontal cortex , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 consistent with the interpretation that whether or not DOPr expression is increased after chronic morphine depends on the cell type.…”

“…It is unclear which property of CINs (or frontal cortex cells [10] NAc-S versus NAc-C CINs is unknown. Moreover, it is not known if MOPr expression is required in the same neuron to alter expression of DOPr after chronic morphine exposure [1,12].…”

“…It was later demonstrated that this trafficking response is not specific to morphine challenge, and other opioids including methadone, etorphine and fentanyl likewise induce membrane DOPr accumulation following chronic treatment, an effect that appears to depend upon MOPr function [7]. Numerous in vivo rodent studies have since provided further histochemical and physiological evidence for this trafficking response to opioids in neurons in a number of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 regions, including studies of dorsal root ganglion (DRG) and dorsal horn of the spinal cord [6 -8], periaqueductal grey (PAG) [9], nucleus accumbens (NAc) and dorsal striatum [10], nucleus raphe magnus [11], and amygdala central nucleus [12], indicating that this phenomenon is common and not limited to a single region within the nervous system. This upregulation of cell membrane DOPr levels, and consequently DOPr function, carries important clinical implications.…”