Opiate mixed agonist-antagonist interactions with histamine antagonists vs. morphine.

Anecdotal reports of polydrug abuse in humans using tripelennamine and pentazocine prompted our investigation of drug interactions between tripelennamine, morphine and various synthetic mixed agonist-antagonists in mice. Pentazocine, nalbuphene and butorphanol, at doses of 4.0-8.0 mg/kg, all showed frank or borderline intrinsic antinociceptive activity and potentiated the tripelennamine response, whereas cyclazocine, an experimental compound with very strong mixed agonist-antagonist qualities at 5.0 mg/kg, showed intrinsic antinociceptive activity but was not potentiated by tripelennamine and actually blocked the tripelennamine response. In a comparative study, pentazocine, butorphanol and nalbuphene had no effect on morphine antinociception whereas cyclazocine completely abolished the antinociceptive effects of morphine. Cimetidine blocked the response of cyclazocine, but not nalbuphene, pentazocine or butorphanol. Our findings demonstrate that the mechanism of action of cyclazocine is significantly different from that of the other mixed agonist-antagonists studied. They also suggest possible histaminergic involvement in antinociception, as well as a locus for antinociception separate from the opiate receptor.

Effect of H1 blockers alone and in combination with morphine to produce antinociception in mice.

Antinociception was assessed in male CD-1 mice by a modification of Haffner's tail-clamp procedure. The H1 blockers, including an ethylenediamine (pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine), all produced antinociception when given alone to mice and also caused potentiation when combined with morphine.

The effect of tripelennamine alone and in combination with opiates to produce antinociception in mice.

Antinociception (ANTI) was assessed in male CD-1 mice by a modification of Haffner's tail clamp procedure. Studies revealed that tripelennamine (Tp) alone produced antinociception (ANTI) in mice and also caused potentiation when combined with morphine (M) or nalbuphene (NB). Naloxone (Nx) only partially blocked the effect of Tp, but fully blocked M. Although atropine (At) had no intrinsic ANTI activity, it enhanced that of Tp but not M. Histamine (Hm) had no intrinsic ANTI activity, nor did it interact with either Tp or M. The partial abolition of Tp ANTI, in contrast to complete blockade of M effects with Nx, appears to indicate that Tp can stimulate the opiate receptor as well as another receptor for ANTI at a different locus. The combination of Tp with various opiates may have considerable abuse potential.

Inhibition by d,l-methadone of RNA and protein synthesis in neonatal mice: antagonism by naloxone or naltrexone.

Neonatal mice were injected once daily with d,l-methadone in a dosage of 2 mg/kg. The remaining half of the litter was injected with saline. After one week the incorporation of labeled uridine and labeled leucine was significantly (P less than 0.05) reduced in skeletal muscle. Longer treatment with methadone impaired RNA and protein synthesis in liver, heart, skeletal muscle and brain. The percentage reduction RNA was log-dose related. When methadone was discontinued for 1 week following 4 weeks of treatment, incorporation of precursors into RNA and protein was found to be normal. A specific opioid effect is suggested by the finding that naltrexone or in part, naloxone, given concomitantly with with the methadone prevents development of the biochemical lesion.

Inhibition of growth in young mice treated with d,1-methadone.

Neonatal mice were treated with d,1-methadone, 1-alpha-acetylmethadol (LAAM) or the narcotic antagonists, naloxone, nalorphine or levallorphan. Litter mates were injected with normal saline solution and handled in the same way. Treatment began on the second postpartum day and continued daily or on alternate days for up to 6 weeks. Injection of methadone in dosages of 2 mg/kg to mg/kg inhibited weight gain in a log dose-related fashion. LAAM, 1 mg/kg or 2 mg/kg also retarded weight gain. Mice gained weight normally when naloxone, 10 mg/kg was injected with methadone, 2 mg/kg. Furthermore the daily injection of d-methadone, 4 mg/kg, did not inhibit weight gain nor did any of the narcotic antagonists. There findings indicate that growth inhibition induced by methadone is a stereospecific, opioid effect.