Antinociceptive effect of pregabalin in septic shock-induced rectal hypersensitivity in rats

Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interact ion with the alpha(2)delta-subunit of voltage-dependent Ca2+ channels. In t his study, we investigate the antinociceptive activity of pregabalin in a r at model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharid e (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 electromyog raphy of abdominal muscles. This allodynic effect of LPS was blocked by mor phine (0.3 mg/kg s.c.), and the action of morphine was antagonized by nalox one (2.5 mg/kg s.c.). A single i.p. (10, 30 mg/kg) and oral (1, 3, 10 and 3 0 mg/kg) treatment of pregabalin dose dependently suppressed LPS-induced re ctal hypersensitivity. When administered 2 h before RD (but preceded 12 h b y LPS injection), the oral dose of 10 mg/kg was effective both in the allod ynic response induced by LPS and in the intensity of the nociceptive respon se 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 pre gabalin. We conclude that pregabalin is a therapeutic candidate in the trea tment of gut hypersensitivity not acting through GABA(A) and opiate recepto rs.