Antinociceptive activity and toxicity of meperidine and normeperidine in mice.

The antinociceptive (radiant heat tail-flick), convulsant and lethal activities of meperidine (MEP) and normeperidine (NMEP) were studied after s.c. and i.c.v. administration to mice. Both compounds s.c. exhibited naloxone-reversible antinociceptive activity. MEP (ED50 = 23 mg/kg) was 2.5 to 5 times more potent, on a molar basis, than NMEP (ED50 = 72 mg/kg). NMEP was a convulsant [ED50 = 105 mg/kg (s.c.) and 64 micrograms/mouse (i.c.v.)], with a small therapeutic index relative to analgesia whose activity was potentiated by naloxone and antagonized by pentobarbital or morphine, s.c. Death due to s.c. MEP was preceded by convulsions, whereas i.c.v. MEP provoked a primarily depressant lethality. Naloxone antagonized death due to i.c.v. MEP while unmasking its convulsant activity. It is concluded that NMEP is the principal mediator of MEPs central nervous system excitation, that convulsions are mediated by a different population of receptors than either analgesia or respiratory depression and that naloxone exacerbates the convulsant activity of MEP and NMEP.