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

Gray, A. M., Pache, D. M. and Sewell, Robert David Edmund 1999. Do alpha(2)-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds? European Journal of Pharmacology 378 (2) , pp. 161-168. 10.1016/S0014-2999(99)00464-1

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Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. α-Adrenoceptors play an important role in pain processing and α2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether α-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following α1- or α2-adrenoceptor antagonism. The antidepressants or monoamine 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 compounds have been previously shown to be antinociceptive in this paradigm. The respective α1- and α2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg−1; s.c., RX821002 but not prazosin 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 α1- and α2-adrenoceptor antagonism. Thus, α2- rather than α1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Publisher: Elsevier
ISSN: 0014-2999
Last Modified: 04 Jun 2017 07:57

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