Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Submitted 26 January 2006 ; accepted in final form 13 April 2006 After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phas...

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Published in:American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2006-10, Vol.291 (4), p.R987-R996
Main Authors: Frithiof, R, Rundgren, M
Format: Article
Language:English
Subjects:
Acute Disease
Analgesics, Opioid - pharmacology
Animals
Arginine Vasopressin - blood
Blood Pressure - drug effects
Blood Pressure - physiology
Central Venous Pressure - drug effects
Central Venous Pressure - physiology
Consciousness
Dose-Response Relationship, Drug
Female
Heart Rate - drug effects
Heart Rate - physiology
Hemorrhage - physiopathology
Hypotension - physiopathology
Hypovolemia - physiopathology
Injections, Intraventricular
Medicin och hälsovetenskap
Morphine - pharmacology
Naloxone - pharmacology
Narcotic Antagonists - pharmacology
Receptors, Opioid - physiology
Recovery of Function
Renin - blood
Sheep
Species Specificity
Vascular Resistance - drug effects
Vascular Resistance - physiology
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Summary:Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Submitted 26 January 2006 ; accepted in final form 13 April 2006 After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml·kg –1 ·min –1 ) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 µg/min but not 20 or 2.0 µg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 ± 3.2 vs. 13.9 ± 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 µg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 ± 1.5 vs. 13.9 ± 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 µg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated µ-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1 ) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2 ) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase. naloxone; morphine; intracerebroventricular; vasopressin; renin Address for reprint requests and other correspondence: R. Frithiof, Karolinska Institutet, Dept. of Physiology & Pharmacology, S-17177, Stockholm, Sweden (e-mail: robert.frithiof{at}ki.se )
ISSN:0363-6119
1522-1490
DOI:10.1152/ajpregu.00070.2006