Imipramine inhibits intrathecal substance P-induced behavior and blocks spinal cord substance P receptors in mice.
The mechanism of the antinociceptive effect of the tricyclic antidepressant imipramine was investigated in mice. Intrathecal (i.t.) administration of imipramine produced dose-dependent antinociception in the tail-pinch and tail-flick tests with ED50 values (95% confidence limit) of 27.5 (17.0-43.9) and 20.2 (12.6-32.2) nmol, respectively. In substance P (SP)-induced nociceptive behavior, imipramine (i.t.) also produced dose-dependent antinociception with ED50 value of 20.2 (16.1-25.2) nmol. Tissue concentration of imipramine was between 55.2 and 104.4 nmol/g tissue when these ED50 values of imipramine were i.t. administered. In the SP-induced behavior, the antinociceptive effect of 31.6 nmol of imipramine was not antagonized by the alpha-adrenergic receptor antagonist phentolamine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In vitro study, imipramine dose-dependently inhibited specific [3H]SP binding in the spinal cord homogenate with IC50 value of 2.37 x 10(-4) M and this value corresponds to 8.6 mumol/g tissue concentration. These data indicate that imipramine produces antinociceptive effect at about 100 times lower dose than SP receptor blockade.
Iwashita
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T
Department of Pharmacology, School of Medicine, Kagoshima University, Japan.
Shimizu
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007099:Imipramine / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D012702:Serotonin Antagonists; D013373:Substance P; D007099:Imipramine