Cues predicting drug or food reward restore morphine-induced place conditioning in mice lacking delta opioid receptors

Psychopharmacology (Berl). 2012 Sep;223(1):99-106. doi: 10.1007/s00213-012-2693-1. Epub 2012 Apr 18.


Rationale: The exact role of delta opioid receptors in drug-induced conditioned place preference (CPP) remains debated. Under classical experimental conditions, morphine-induced CPP is decreased in mice lacking delta opioid receptors (Oprd1 (-/-)). Morphine self-administration, however, is maintained, suggesting that drug-context association rather than drug reward is deficient in these animals.

Objectives: This study further examined the role of delta opioid receptors in mediating drug-cue associations, which are necessary for the expression of morphine-induced CPP.

Methods: We first identified experimental conditions under which Oprd1 (-/-) mice are able to express CPP to morphine (5, 10 or 20 mg/kg) in a drug-free state and observed that, in this paradigm, CPP was dependent on circadian time conditions. We then took advantage of this particularity to assess the ability of various cues (internal or discrete), predicting either drug or food reward, to restore CPP induced by morphine (10 mg/kg) in Oprd1 (-/-) mice in conditions under which they normally fail to express CPP.

Results: We found that presentation of circadian, drug or auditory cues, predicting morphine or food reward, restored morphine CPP in Oprd1 (-/-) mice, which then performed as well as control mice.

Conclusions: This study reveals that, in contrast to spatial cues, internal or discrete morphine-predicting stimuli permit full expression of morphine CPP in Oprd1 (-/-) mice. Delta receptors, therefore, appear to play a crucial role in modulating spatial contextual cue-related responses. This activity may be critical when context gains control over behavior, as is the case for context-induced relapse in drug abuse.

Publication types

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

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Circadian Rhythm
  • Conditioning, Classical / drug effects*
  • Cues
  • Dose-Response Relationship, Drug
  • Feeding Behavior
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Receptors, Opioid, delta / genetics*
  • Reward*


  • Analgesics, Opioid
  • DOR-1 protein, mouse
  • Receptors, Opioid, delta
  • Morphine