Vol. 295, Issue 1, 162-167, October 2000

Antinociceptive Effect of Pregabalin in Septic Shock-Induced Rectal Hypersensitivity in Rats

Helene Eutamene, Anne-Marie Coelho, Vassilia Theodorou, Magali Toulouse, Maria Chovet, Annette Doherty, Jean Fioramonti and Lionel Bueno

Department of Neurogastroenterology and Nutrition, Institut National de la Recherche Agronomique, Toulouse (H.E., M.C., A.D.); Research Institut of Jouveinal/Parke Davis, Fresnes (V.T.); and Ecole Superieure d'Agriculture de Purpan, Toulouse, France (A.M.C., M.T., J.F., L.B.)

Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interaction with the ₂-subunit of voltage-dependent Ca²⁺ channels. In this study, we investigate the antinociceptive activity of pregabalin in a rat model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharide (LPS) administration. LPS (Escherichia coli, serotype O111:B4) leads to a delayed lowering threshold (9-12 h) of abdominal contractions in response to rectal distension (RD) in awake rats surgically prepared for electromyography of abdominal muscles. This allodynic effect of LPS was blocked by morphine (0.3 mg/kg s.c.), and the action of morphine was antagonized by naloxone (2.5 mg/kg s.c.). A single i.p. (10, 30 mg/kg) and oral (1, 3, 10 and 30 mg/kg) treatment of pregabalin dose dependently suppressed LPS-induced rectal hypersensitivity. When administered 2 h before RD (but preceded 12 h by LPS injection), the oral dose of 10 mg/kg was effective both in the allodynic response induced by LPS and in the intensity of the nociceptive response related to RD. Pretreatment by either naloxone or bicuculline (a GABA_A antagonist, 0.5 mg/kg i.p.) did not affect the antiallodynic effect of pregabalin. We conclude that pregabalin is a therapeutic candidate in the treatment of gut hypersensitivity not acting through GABA_A and opiate receptors.