The effect of forced swim stress on morphine sensitization: Involvement of D1/D2-like dopamine receptors within the nucleus accumbens

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Oct 3;70:92-9. doi: 10.1016/j.pnpbp.2016.05.006. Epub 2016 May 26.


Nucleus accumbens (NAc) plays an essential role in morphine sensitization and suppression of pain. Repeated exposure to stress and morphine increases dopamine release in the NAc and may lead to morphine sensitization. This study was carried out in order to investigate the effect of forced swim stress (FSS), as a predominantly physical stressor and morphine on the development of morphine sensitization; focusing on the function of D1/D2-like dopamine receptors in the NAc in morphine sensitization. Eighty-five adult male Wistar rats were bilaterally implanted with cannulae in the NAc and various doses of SCH-23390 (0.125, 0.25, 1 and 4μg/0.5μl/NAc) as a D1 receptor antagonist and sulpiride (0.25, 1 and 4μg/0.5μl/NAc) as a D2 receptor antagonist were microinjected into the NAc, during a sensitization period of 3days, 5min before the induction of FSS. After 10min, animals received subcutaneous morphine injection (1mg/kg). The procedure was followed by 5days free of antagonist, morphine and stress; thereafter on the 9th day, the nociceptive response was evaluated by tail-flick test. The results revealed that the microinjection of sulpiride (at 1 and 4μg/0.5μl/NAc) or SCH-23390 (at 0.25, 1 and 4μg/0.5μl/NAc) prior to FSS and morphine disrupts the antinociceptive effects of morphine and morphine sensitization. Our findings suggest that FSS can potentiate the effect of morphine and causes morphine sensitization which induces antinociception.

Keywords: D1-like dopamine receptor; D2-like dopamine receptor; Forced swim stress; Morphine sensitization; Nucleus accumbens.

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Disease Models, Animal
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Male
  • Morphine / pharmacology*
  • Morphine Dependence / metabolism
  • Narcotics / pharmacology*
  • Nociception / drug effects
  • Nociception / physiology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Rats, Wistar
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Stress, Psychological / metabolism*
  • Sulpiride / pharmacology
  • Swimming


  • Benzazepines
  • Dopamine D2 Receptor Antagonists
  • Narcotics
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • SCH 23390
  • Morphine
  • Sulpiride