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.
aDepartment of Anesthesiology and Critical Care Medicine, Kochi Medical School
bDepartment of Anesthesiology, Tosa Citizen Hospital, Tosa, Kochi
cDepartment of Anesthesiology, Tokushima University School of Medicine
dDepartment of Dental Anesthesiology, Tokushima University School of Dentistry, Tokushima, Japan
Correspondence to Takashi Kawano, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783 8505, Japan Tel: +81 88 880 2471; fax: +81 88 880 2475; e-mail: firstname.lastname@example.org
Received August 7, 2011
Accepted September 28, 2011