Heteromers of μ opioid and dopamine D 1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner

Br J Pharmacol. 2017 Sep;174(17):2842-2861. doi: 10.1111/bph.13908. Epub 2017 Jul 18.

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 μ 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 μ 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 μ 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 μ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D1 or μ receptor KO mice and thus unable to form μ receptor-D1 receptor heterodimers, failed to show locomotor sensitization to morphine.

Conclusion and implications: Our results suggest that μ receptor-D1 receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Benzazepines / pharmacology*
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Dopamine
  • Dopamine Antagonists / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • HEK293 Cells
  • Humans
  • Mice, Knockout
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Opioid, mu / metabolism*

Substances

  • Analgesics, Opioid
  • Benzazepines
  • Dopamine Antagonists
  • Proto-Oncogene Proteins c-fos
  • Receptors, Dopamine D1
  • Receptors, Opioid, mu
  • SCH 23390
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • Dopamine