Study of the antinociceptive effect of tetrahydro-papaveroline 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-carboxy-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 abdominal writhes induced by phenylbenzoquinone, with ED50 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 antagonized 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 mg/kg, s.c.) led to a significant antinociceptive effect (83 to 85% of reduction of the number of writhes). This synergistic potentiation confirmed 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.). These results, although excluding a direct agonistic effect of THP derivatives on opiate receptors, suggest an indirect interaction of these drugs with the endogenous opioid system.
Fialip
J
J
Laboratoire de Pharmacologie, Faculté de Pharmacie, Clermont-Ferrand, France.
Eschalier
A
A
Bétoin
F
F
Durif
F
F
Dostert
P
P
Dordain
G
G
D000698:Analgesia; D000700:Analgesics; D000818:Animals; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology; D013237:Stereoisomerism; D013765:Tetrahydropapaveroline / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry
D000700:Analgesics; D009270:Naloxone; D013765:Tetrahydropapaveroline; D009020:Morphine