The antinociceptive effects of
trazodone (a triazolopyridine derivative with
antidepressant activity) and its interaction with various
opioid,
noradrenaline and
serotonin receptor subtypes were evaluated. Mice were tested with a hotplate
analgesia meter.
Trazodone induced a dose-dependent antinociceptive effect following i.p. administration. The ED(50) for mice in the hotplate assay for
trazodone was 24.8 mg/kg (9.8; 67.4; 95% CL). The effect of
opioid,
adrenergic and serotonergic receptor antagonists was examined as to their ability to block
trazodone antinociception.
Trazodone-induced antinociception was significantly inhibited by
naloxone,
beta-FNA and
naloxonazine, but not by
nor-BNI or
naltrindole, implying involvement of mu1- and mu2-opioid mechanisms. When
adrenergic and serotonergic antagonists were used,
metergoline (p<0.05) but not
phentolamine or
yohimbine, decreased antinociception elicited by
trazodone, implying a clear
5-HT mechanism of antinociception. When
trazodone was administered together with various agonists of the
opioid receptor subtypes, it significantly potentiated antinociception mediated by mu1- and mu2-
opioid receptor subtypes. Summing up these results, we conclude that the antinociceptive effect of
trazodone is mainly influenced by the mu1- +mu2-
opioid receptor subtype combined with the serotonergic receptor. These results explain the diffuse clinical use of
trazodone in the management of some
pain syndromes, and in
opioid- and alcohol-detoxification programs, but raise questions regarding a possible 'indirect'
opioid-dependence induced by
trazodone itself.