Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Nat Neurosci. 2014 Feb;17(2):254-61. doi: 10.1038/nn.3622. Epub 2014 Jan 12.


μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Corpus Striatum / cytology*
  • Disease Models, Animal
  • Dopamine / metabolism
  • Enkephalins / genetics
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Flow Cytometry
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microdialysis
  • Morphine / pharmacology
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Narcotics / pharmacology
  • Neural Pathways / physiology*
  • Neurons / classification
  • Neurons / drug effects
  • Neurons / physiology*
  • Pain / drug therapy
  • Pain / genetics
  • Pain Measurement / drug effects
  • Protein Precursors / genetics
  • Receptors, Opioid, mu / deficiency
  • Receptors, Opioid, mu / metabolism*
  • Reward*
  • Substance Withdrawal Syndrome / drug therapy


  • Enkephalins
  • Narcotic Antagonists
  • Narcotics
  • Protein Precursors
  • Receptors, Opioid, mu
  • Green Fluorescent Proteins
  • Naloxone
  • Morphine
  • preproenkephalin
  • Dopamine