title: The involvement of the neurosteroid allopregnanolone in the antihyperalgesic effect of paroxetine in a rat model of neuropathic pain.
abstract: Paroxetine increases the levels of neurosteroids, such as allopregnanolone (AP), that influence the excitability of the central nervous system by positive allosteric modulation of γ-aminobutyric acid type A receptors. Here, we investigated the role of AP synthesis on the paroxetine-induced antihyperalgesic effect in a rat model of neuropathic pain induced by lumbar spinal nerve ligation (SNL). Subcutaneous administration of paroxetine in SNL rats, dose-dependently decreased the probability of hyperalgesic response and increased AP levels in the spine but not in either brain or serum. Concomitant treatment with an inhibitor of the AP-synthesizing enzyme, finasteride, attenuated the paroxetine-induced antihyperalgesic effect as well as the paroxetine-induced increase in spinal AP levels. Intrathecal injection of exogenous AP mimicked the analgesic effects of paroxetine in vehicle-treated SNL rats, whereas no additional analgesic effects were observed in paroxetine-treated SNL rats. Our findings suggest that the antihyperalgesic effect of paroxetine in a rat neuropathic pain model is AP-mediated. These results also suggest that pharmacological-based therapies targeting AP synthesis might be a promising treatment for neuropathic pain.
authors: Department of Anesthesiology and Critical Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783 8505, Japan. takashika@kochi-u.ac.jp
authors: Takashi
authors: T
authors: Kawano
authors: Tomohiro
authors: T
authors: Soga
authors: Haidong
authors: H
authors: Chi
authors: Satoru
authors: S
authors: Eguchi
authors: Fumimoto
authors: F
authors: Yamazaki
authors: Masataka
authors: M
authors: Yokoyama
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy; D008026:Ligation / Q000009:adverse effects; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D017374:Paroxetine / Q000627:therapeutic use*; D011280:Pregnanolone / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D017374:Paroxetine; D011280:Pregnanolone