Am. Gray et al., THE INVOLVEMENT OF THE OPIOIDERGIC SYSTEM IN THE ANTINOCICEPTIVE MECHANISM OF ACTION OF ANTIDEPRESSANT COMPOUNDS, British Journal of Pharmacology, 124(4), 1998, pp. 669-674
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.