Dexamethasone modulates hypotension induced by opioids in anaesthetised rats

Abstract

The effect of dexamethasone on hypotension induced by μ-, κ- and δ-opioid receptor agonists was investigated in pentobarbital-anaesthetised rats. Morphine (nonselective opioid receptor agonist), DAGO ( d-Ala 2- N-methyl-[Phe 4-Gly 5-ol]enkephalin; μ-opioid receptor-selective agonist), U50-488H ( trans(±)-3,4-dichloro- N-methyl- N-(2[1pyrrolidynyl]cyclohexyl)-benzeneacetamide; κ-opioid receptor-selective agonist) and deltorphin II (δ-opioid receptor-selective agonist), given intravenously, 5 μmol/kg, induced hypotension in rats. This hypotension was characterised by a fall in mean arterial blood pressure in 1–2 min that recovered in 30 min for morphine and U50-488H and in 5 or 20 min for DAGO and deltorphin II, respectively. Dexamethasone per se at a dose of 7.5 μmol/kg, i.v. did not significantly modify the mean arterial blood pressure of animals. Dexamethasone administration 90 min, but not 30 or 60 min, before the opioid agonists injection, prevented the hypotension induced by morphine or U50-488H, but not that induced by DAGO or deltorphin II. Pretreatment with RU-38486 (mifepristone; 7.5 μmol/kg, i.v.), a glucocorticoid receptor antagonist, 15 min before the steroid, prevented dexamethasone inhibition of hypotension induced by morphine and U50-488H. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor (3.5 μmol/kg, i.v.), was also able to abolish the effects of dexamethasone on morphine- and U50-488H-induced hypotension. Results of the present study indicate that dexamethasone inhibited κ-opioid receptor-mediated hypotension in rats, indicating a further important functional interaction between corticosteroids and the opioid system at κ receptors. The ability of cycloheximide and RU-38486 to block dexamethasone effects indicates that steroid interference with κ-opioid receptor-mediated hypotension involves a protein synthesis-dependent mechanism via glucocorticoid receptors.