The effects of serotonin/norepinephrine reuptake inhibitors and serotonin receptor agonist on morphine analgesia and tolerance in rats

J Physiol Sci. 2012 Jul;62(4):317-23. doi: 10.1007/s12576-012-0207-x. Epub 2012 Apr 29.


Several studies have demonstrated that serotonergic and noradrenergic systems have important roles in morphine analgesia and tolerance. However, the exact mechanism underlying the development of morphine tolerance is not fully understood. The aim of this study was to investigate the possible role of serotonin/norepinephrine reuptake inhibitors (amitriptyline, venlafaxine) and serotonin receptor (5-HT(1A) and 5-HT(1B/1D)) agonist (dihydroergotamine) in morphine analgesia and tolerance in rats. To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of amitriptyline (20 mg/kg; i.p.), venlafaxine (20 mg/kg; s.c.), dihydroergotamine (100 μg/kg; i.v.) and morphine (5 mg/kg) were considered at 15- to 30-min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. In this study, the data obtained suggested that amitriptyline and venlafaxine significantly increased the analgesic effect of morphine and attenuated the expression of morphine tolerance. However, dihydroergotamine significantly increased the analgesic effect of morphine but did not reduce the expression of morphine tolerance. In conclusion, we determined that co-administration of morphine with amitriptyline and venlafaxine increased the analgesic effects of morphine and attenuated the morphine analgesic tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / pharmacology*
  • Analgesia / methods
  • Analgesics / pharmacology
  • Animals
  • Cyclohexanols / pharmacology*
  • Dihydroergotamine / pharmacology*
  • Drug Tolerance
  • Male
  • Morphine / pharmacology*
  • Pain Measurement
  • Rats
  • Rats, Wistar
  • Serotonin Receptor Agonists / pharmacology*
  • Serotonin Uptake Inhibitors / pharmacology*
  • Venlafaxine Hydrochloride


  • Analgesics
  • Cyclohexanols
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Amitriptyline
  • Dihydroergotamine
  • Morphine
  • Venlafaxine Hydrochloride