α-Receptors Mediate Opioid Cardiovascular Effects at Anterior Hypothalamic Sites through Sympatho- Adrenomedullary and Parasympathetic Pathways*

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Abstract
Intracerebroventricular injections of selective opioid agonists were used to investigate the role of opiate receptor subtypes in cardiovascular function in awake rats. The μ-agonist (D-Ala2,MePhe4,Gly5-ol)enkephalin (1 nmol) caused a prolonged increase in blood pressure and an initial decrease followed by a delayed increase in heart rate. These effects were antagonized by the selective μ-antagonist β-funaltrexamine. A selective 5-agonist (dimeric tetrapeptide enkephalin) was devoid of cardiovascular effects at 10 nmol, whereas a benzomorphan κ-agonist MRZ caused a pressor response which was not antagonized by β-funaltrexamine. The mechanisms by which opioids elicit cardiovascular effects were analyzed in detail by using microinjections into the anterior hypothalamic area. Low doses of enkephalin produced increases in heart rate and blood pressure. Associated elevations of plasma norepinephrine and epinephrine, but not vasopressin, suggested a stimulation of sympatho-adrenomedullary pathways. Higher doses caused increases in blood pressure but decreases in heart rate. Peripheral vagal blockade with atropine methyl nitrate caused a large sudden rise in heart rate, indicating that an increased vagal outflow counteracted the sympathetic activation. Adrenal demedullated rats displayed no tachycardia after anterior hypothalamic injection of low doses of enkephalin, whereas high dose caused pronounced bradycardia. Additional treatment of demedullated rats with the sympathetic blocker bretylium led to severe hypotension in addition to bradycardia. These data provide evidence that α-opiate receptors primarily mediate cardiovascular effects of opiates in awake rats. At low doses, a sympathetic adrenomedullary activation occurs, whereas higher doses additionally activate parasympathetic efferents, both possibly from anterior hypothalamic sites. (Endocrinology113:929, 1983)