Interactions between the effects of opioid, serotonin and alpha-2-adrenergic receptor agonists on growth hormone release in the male rat: Intravenous administration

This study was performed to identify low-dose drug combinations which have stimulatory effects on short-term growth hormone (GH) release when given intravenously to male rats. Rats were given intravenous combinations of the lowest doses of drugs which had increased GH release when given individually. Combinations of clonidine, 6 and 30 μg/kg, and the serotonin agonist quipazine 160 μg/kg had an additive effect on GH release. Almost all combinations of morphine, 40 and 200 μg/kg, with clonidine and quipazine stimulated GH release, but this release was less than additive, and there were significant negative interactions between morphine and clonidine (p = 0.03), morphine and quipazine (p = 0.005) and the three drugs together (p = 0.03). Agonist-antagonist studies were performed in an attempt to further define these interactions. Naloxone 5 mg/kg i.v. inhibited GH release due to morphine 200 μg/kg, but not quipazine 160 μg/kg or clonidine 6 and 30 ug/kg. The CC2 antagonist idazoxan (2 mg/kg i.v.) prevented release due to intravenous clonidine, morphine and quipazine, but not GH-releasing factor (GRF) 25 μg/kg. The 5-hydroxytryptamine antagonist cyproheptadine (0.5 mg/kg i.v.) blocked release due to quipazine and clonidine 30 μg/kg, but not morphine 40 and 200 μg/kg or GRF. The results of these agonist-antagonist studies do not provide a consistent explanation for the observed interactions. These results indicate that in whole animal studies (I) additive or synergistic drug combinations cannot generally be predicted, (2) less than additive interactions of agonists regularly occur and (3) antagonists are unhelpful in dissecting the nature of the negative interactions.