TY - JOUR
T1 - The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms
AU - Schreiber, Shaul
AU - Rigai, Tova
AU - Katz, Yeshayahu
AU - Pick, Chaim G.
PY - 2002/9/30
Y1 - 2002/9/30
N2 - 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 7.5 mg/kg. As the mirtazapine dose increased beyond 10 mg/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 10 mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by β-FNA nor by naloxonazine, implying the involvement of κ1- and δ-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 κ3-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the κ3-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.
AB - 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 7.5 mg/kg. As the mirtazapine dose increased beyond 10 mg/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 10 mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by β-FNA nor by naloxonazine, implying the involvement of κ1- and δ-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 κ3-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the κ3-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.
KW - Antidepressants
KW - Antinociception
KW - Hotplate
KW - Mirtazapine
KW - Noradrenaline
KW - Opioid receptor subtypes
KW - Pain
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=0037201092&partnerID=8YFLogxK
U2 - 10.1016/S0361-9230(02)00825-0
DO - 10.1016/S0361-9230(02)00825-0
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AN - SCOPUS:0037201092
SN - 0361-9230
VL - 58
SP - 601
EP - 605
JO - Brain Research Bulletin
JF - Brain Research Bulletin
IS - 6
ER -