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 whe n given intravenously to male rats. Rats were given intravenous combin ations of the lowest doses of drugs which had increased GH release whe n given individually. Combinations of clonidine, 6 and 30 mug/kg, and the serotonin agonist quipazine 160 mug/kg had an additive effect on G H release. Almost all combinations of morphine, 40 and 200 mug/kg, wit h clonidine and quipazine stimulated GH release, but this release was less than additive, and there were significant negative interactions b etween morphine and clonidine (p = 0.03), morphine and quipazine (p = 0.005) and the three drugs together (p = 0.03). Agonist-antagonist stu dies were performed in an attempt to further define these interactions . Naloxone 5 mg/kg i.v. inhibited GH release due to morphine 200 mug/k g, but not quipazine 160 mug/kg or clonidine 6 and 30 mug/kg. The a2 a ntagonist idazoxan (2 mg/kg i.v.) prevented release due to intravenous clonidine, morphine and quipazine, but not GH-releasing factor (GRF) 25 mug/kg. The 5-hydroxytryptamine antagonist cyproheptadine (0.5 mg/k g i.v.) blocked release due to quipazine and clonidine 30 mug/kg, but not morphine 40 and 200 mug/kg or GRF. The results of these agonist-an tagonist studies do not provide a consistent explanation for the obser ved interactions. These results indicate that in whole animal studies (1) additive or synergistic drug combinations cannot generally be pred icted, (2) less than additive interactions of agonists regularly occur and (3) antagonists are unhelpful in dissecting the nature of the neg ative interactions.