The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds

Br J Pharmacol. 1998 Jun;124(4):669-74. doi: 10.1038/sj.bjp.0701882.


1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Publication types

  • Comparative Study

MeSH terms

  • Abdominal Muscles / drug effects
  • Abdominal Muscles / physiology
  • Acetic Acid / toxicity
  • Amitriptyline / pharmacology
  • Analgesics / pharmacology*
  • Animals
  • Antidepressive Agents / pharmacology*
  • Cyclobutanes / pharmacology
  • Dothiepin / pharmacology
  • Male
  • Maprotiline / analogs & derivatives
  • Maprotiline / pharmacology
  • Mice
  • Muscle Contraction / drug effects
  • Naloxone / pharmacology
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Neprilysin / antagonists & inhibitors
  • Neurotransmitter Uptake Inhibitors / pharmacology
  • Opioid Peptides / metabolism*
  • Pain Measurement / drug effects
  • Paroxetine / pharmacology
  • Protease Inhibitors / pharmacology
  • Receptors, Opioid / agonists*
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Thiorphan / analogs & derivatives
  • Thiorphan / pharmacology


  • Analgesics
  • Antidepressive Agents
  • Cyclobutanes
  • Narcotic Antagonists
  • Neurotransmitter Uptake Inhibitors
  • Opioid Peptides
  • Protease Inhibitors
  • Receptors, Opioid
  • Serotonin Uptake Inhibitors
  • Amitriptyline
  • Maprotiline
  • Naloxone
  • hydroxymaprotilin
  • Paroxetine
  • Naltrexone
  • racecadotril
  • Thiorphan
  • Neprilysin
  • naltrindole
  • Acetic Acid
  • Dothiepin
  • sibutramine