THE INVOLVEMENT OF THE OPIOIDERGIC SYSTEM IN THE ANTINOCICEPTIVE MECHANISM OF ACTION OF ANTIDEPRESSANT COMPOUNDS

1 Debate exists as to the nature of antidepressant-induced antinocicep tion. It is unclear whether antidepressants are inherently antinocicep tive, are able to potentiate opioid antinociception or both. We have u sed the acetic acid induced abdominal constriction assay in mice to in vestigate antidepressant-induced antinociception. 2 All the antidepres sants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin w ere 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, sibu tramine, (+)-oxaprotiline and paroxetine). In this context the naloxon e dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole d ose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respect ively. Naloxone also shifted the morphine dose-response relationship t o the right, by a factor of 2.62, whilst naltrindole had no effect upo n morphine antinociception. Aspirin antinociception remained unaffecte d by both opioid antagonists. 4 The enkephalin catabolism inhibitor ac etorphan, 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 lin ear dose-response relationship against acetic acid-induced abdominal c onstriction. 5 When acetorphan was administered before either the anti depressants or morphine, there was a clear potentiation of the antidep ressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception.6 Since neither of the opioid ant agonists were able to attenuate, nor was acetorphan able to potentiate , aspirin antinociception, we concluded that the mechanism of antidepr essant-induced antinociception is different from that of the non-stero idal anti-inflammatory drugs. 7 These data are consistent with the vie w that antidepressants may induce endogenous opioid peptide release, a s shown by the acetorphan study. In this context, the ability of naltr indole to displace the antidepressant dose-response relationship to th e right without affecting morphine antinociception, implicates the del ta-opioid receptor and endogenous opioid peptides in antidepressant-in duced antinociception.