Do alpha(2)-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. alpha-Adrenoceptors play an i mportant role in pain processing and alpha(2)-adrenoceptor agonists have be en used in clinical pain management so we have investigated whether alpha-a drenoceptor sub-types mediate the antinociceptive activity of antidepressan ts. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following a lpha(1) or alpha(2) adrenoceptor antagonism. The antidepressants or monoami ne reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin-noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (-)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these co mpounds have been previously shown to be antinociceptive in this paradigm. The respective alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not pro duce antinociception though at 1.0 mg kg(-1); s.c., RX821002 but not prazos in blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (-)-oxaprotiline were all blocked by RX821002 but not by prazosin . Additionally, both morphine and aspirin antinociception was resistant to alpha(1)- and alpha(2)-adrenoceptor antagonism. Thus, alpha(2)-rather than alpha(1)-adrenoceptors may play an integral role in antidepressant antinoci ception irrespective of the propensity for inhibiting reupcake of not only noradrenaline but also serotonin. It is probable, however, that other diffe ring pharmacological properties of some antidepressants, such as opioid-lik e activity, may complicate any empirical correlation between monoamine upta ke and analgesia. (C) 1999 Elsevier Science B.V. All rights reserved.