PARACETAMOL EXERTS A SPINAL ANTINOCICEPTIVE EFFECT INVOLVING AN INDIRECT INTERACTION WITH 5-HYDROXYTRYPTAMINE(3) RECEPTORS - IN-VIVO AND IN-VITRO EVIDENCE

Rats (Sprague-Dawley), submitted ta a mechanical noxious stimulus (paw pressure), were tested to determine 1) the antinociceptive effects of p.o. (200, 400 and 800 mg/kg), i.v. (50, 100, 200 and 300 mg/kg) and intrathecal (i.t.) (100 and 200 mu g/rat) administrations of paracetam ol; 2) the influence of i.t. administered tropisetron, a 5-hydroxytryp tamine(3) (5-HT3) receptor antagonist (0.5, 1 or 10 mu g/rat) on parac etamol-induced antinociception; 3) the influence of indomethacin (25 m g/kg s.c.), naloxone (10 mu g/rat i.t.) and yohimbine (1 mg/kg i.v.) o n the effect of paracetamol (200 mg/kg i.v.) to determine the involvem ent of prostaglandins, opioids and alpha-2 adrenoceptors. The displace ment by paracetamol of radioligand binding to various receptors was al so investigated. Paracetamol induced a significant antinociceptive eff ect after p.o., i.v, and i.t. administration. A total inhibition of th e effect of paracetamol, administered p.o. or i.t., occurred at the do se of 0.5 mu g/rat of tropisetron, whereas 10 mu g/rat of this antagon ist was needed to totally inhibit the action of i.v. administered para cetamol. Indomethacin, naloxone and yohimbine failed to modify paracet amol antinociceptive action. In vitro studies failed to show any bindi ng of paracetamol to 5-HT3 and several other receptors and to 5-HT upt ake sites. It is concluded that paracetamol has a central antinocicept ive effect, based on an indirect involvement of spinal 5-HT3 receptors .