Dataset Information

Heteromers of ? opioid and dopamine D₁ receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

ABSTRACT:

Background and purpose

Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear.

Experimental approach

Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization.

Key results

The dopamine D₁ receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of ? opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D₁ receptor knockout (KO) mice, suggesting that SCH23390 modified ? receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of ? receptor-D₁ receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited ? receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D₁ or ? receptor KO mice and thus unable to form ? receptor-D₁ receptor heterodimers, failed to show locomotor sensitization to morphine.

Conclusion and implications

Our results suggest that ? receptor-D₁ receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.

SUBMITTER: Tao YM

PROVIDER: S-EPMC5554314 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Heteromers of μ opioid and dopamine D<sub>1</sub> receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Tao Yi-Min YM Yu Chuan C Wang Wei-Sheng WS Hou Yuan-Yuan YY Xu Xue-Jun XJ Chi Zhi-Qiang ZQ Ding Yu-Qiang YQ Wang Yu-Jun YJ Liu Jing-Gen JG

British journal of pharmacology 20170718 17

<h4>Background and purpose</h4>Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear.<h4>Experimental approach</h4>Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Funct ...[more]

PMID: 28608532

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Project description:The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders.The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.

Dataset Information

Heteromers of ? opioid and dopamine D₁ receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Heteromers of μ opioid and dopamine D<sub>1</sub> receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Heteromers of ? opioid and dopamine D1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Heteromers of μ opioid and dopamine D<sub>1</sub> receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Heteromers of ? opioid and dopamine D₁ receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.