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

A. PFEIFFER, G. FEUERSTEIN, R. L. ZERBE, A. I. FADEN and L J. KOPIN

National Institute of Mental Health, National Institutes of Health Bethesda, Maryland 20205
Laboratory of Clinical Science, Department of Human Services, National Institutes of Health Bethesda, Maryland 20205
Neurobiology Research Unit, Uniformed Services University of the Health Sciences Bethesda, Maryland 20814

Address correspondence and requests for reprints to: Dr. Giora Feuerstein, Neurobiology Research Unit, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814.

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 -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 -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. (Endocrinology 113:929, 1983)

Footnotes

^* This work was supported by the Uniformed Services University of the Health Sciences Protocol RO-9201. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. The experiments reported herein were conducted according to the principles set forth in the "Guide for the Care and Use of Laboratory Animals," Institute of Laboratory Animal Resources, National Research Council DHEW Pub. [NIH] 78-23.

Supported the Deutsche Forschungsgemeinschaft.

Received October 21, 1982.

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