STUDY OF THE ANTINOCICEPTIVE EFFECT OF TETRAHYDROPAPAVEROLINE DERIVATIVES - INTERACTION WITH OPIOIDS

The antinociceptive effect of racemic tetrahydropapaveroline (THP), of its two R(+)- and S(-) enantiomers, of 1-2-dehydro-THP and of 1-carbo xy-THP was assessed using different pain tests in mice. None of these drugs possessed a significant activity in the hot-plate and tail-flick tests. However, after i.p. injection, they reduced the number of abdo minal writhes induced by phenylbenzoquinone, with ED(50) values of 51 +/- 7, 73 +/- 9 and 79 +/- 7 mg/kg for the most potent compounds : 1,2 -dehydro-THP, +/-THP and -THP, respectively. This activity was not ant agonized by naloxone (1 mg/kg, s.c.). However combination of inactive doses of these three compounds (32 mg/kg, i.p.) and of morphine (0.5 m g/kg, s.c.) led to a significant antinociceptive effect (83 to 85% of reduction of the number of writhes). This synergistic potentiation con firmed with the combination of +/-THP (16 mg/kg, i.p.) and morphine (0 .5 mg/kg, s.c.) was totally inhibited by naloxone (1 mg/kg, s.c.). The se results, although excluding a direct agonistic effect of THP deriva tives on opiate receptors, suggest an indirect interaction of these dr ugs with the endogenous opioid system.