title: The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms.
abstract: The antinociceptive effects of the noradrenergic and specific serotonergic antidepressant (NaSSA) drug mirtazapine and its interaction with various opioid receptor subtypes were evaluated in mice with a hotplate analgesicmeter. Mirtazapine elicited an antinociceptive effect in a dose-dependent manner following doses from 1 to 7.5mg/kg. As the mirtazapine dose increased beyond 10mg/kg latencies returned to baseline, yielding a biphasic dose-response curve. The effect of opioid, adrenergic, and serotonergic receptor antagonists was examined as to their ability to block mirtazapine antinociception. Mirtazapine (at 10mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by beta-FNA nor by naloxonazine, implying the involvement of kappa(1)- and delta-opioid mechanisms. When adrenergic and serotonergic antagonists were used, both metergoline and yohimbine, decreased antinociception elicited by mirtazapine, implying a combined serotonergic and noradrenergic mechanism of antinociception. When mirtazapine was administered together with various agonists of the opioid receptor subtypes, it significantly potentiated antinociception mediated only by kappa(3)-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the kappa(3)-opioid receptor subtype combined with both serotonergic and noradrenergic receptors. These results suggest a potential use of mirtazapine in the management of some pain syndromes, and raise questions regarding a possible indirect opioid-dependence induced by mirtazapine. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mirtazapine when prescribed for pain.
authors.affiliation: Department of Psychiatry, Tel-Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Tel-Aviv, Israel.
authors.forename: Shaul
authors.initials: S
authors.lastname: Schreiber
authors.forename: Tova
authors.initials: T
authors.lastname: Rigai
authors.forename: Yeshayahu
authors.initials: Y
authors.lastname: Katz
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D000078785:Mirtazapine; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D008803:Mianserin; D000078785:Mirtazapine