Effects of μ‐opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits

Abstract

1 Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood Po2 and Pco2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min. 2 The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were; 4th ventricular (-)-naloxone HCl (10-100 nmol), 4th ventricular H-Tyr-D-Ala-Gly-MePhe-NH(CH2)20H (DAMGO; 30-300pmol), and i.v. morphine sulphate (0.5-5.Opmolkg1'). The interactions of graded 4th ventricular doses of naloxone (3-100nmol) with the actions of DAMGO (100-300pmol) on these responses were also assessed. 3 After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to <40mmHg. 4 Low 4th ventricular doses of naloxone (10-30nmol) and DAMGO (30-l00pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol) and DAMGO (100-300pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables.5 Low doses of i.v. morphine (0.5-1.Spumolkg-1) also had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of morphine (1.5-5.Opmol kg 1) abolished the decompensatory phase. These high doses caused respiratory depression without affecting the resting haemodynamic variables. 6 The prevention of circulatory decompensation by high doses of DAMGO was reversed by 3-10nmol of naloxone in 3 out of 4 rabbits and by 10-30 nmol of naloxone in all 4 rabbits. The decompensatory phase was, however, prevented by the combined high doses of DAMGO (100-300pmol) and naloxone (30-100 nmol). 7 These findings provide strong evidence that activation of u-opioid receptors in the central nervous system abolishes circulatory decompensation during acute reduction of central blood volume in conscious rabbits. This effect does not appear to be due to activation of arterial chemoreceptors or to a non-specific increase in sympathetic vasoconstrictor drive, since respiratory depression and hypertension were not observed after 4th ventricular doses of DAMGO which abolished circulatory decompensation. Our results also provide indirect confirmation of our previous finding that naloxone acts to prevent circulatory decompensation by an antagonist action at central 6-receptors.

Activation of lateral parabrachial nucleus neurons restores blood pressure and sympathetic vasomotor drive after hypotensive hemorrhage

“…The sympathoinhibition and bradycardia associated with hypotensive blood loss appear to be mediated by CNS serotonergic and opioid receptors (11,12,16,31,40,(43)(44)(45) that may be located in the rostral ventrolateral medulla (10,43) and periaqueductal grey (3,9,42), respectively. However, there is little known about the neuroanatomical pathways and CNS neurotransmitter systems that reverse sympathoinhibition and restore blood pressure back to normotensive levels after hemorrhagic hypotension has developed.…”

Effects of Halothane, Ketamine, Propofol and Alfentanil Anaesthesia on Circulatory Control in Rabbits

“…It is likely that this effect of alfentanil is a consequence of its p-agonist property (Leysen et a/. 1983), since we have shown in the conscious rabbit that injection of morphine intravenously, or the specific p-agonist DAMGO (HTyr-~-Ala-Gly-MePhe-NH(CH2)20H) into the fourth ventricle, have similar actions (Evans, Ludbrook & Van Leeuwen 1989;Evans & Ludbrook 1990). Our supplementary experiment suggests that alfentanil also acts in the hindbrain, since small fourth ventricular doses (1.5-7.5 pg) were as potent as much greater intravenous doses (-240 pg) in preventing circulatory decompensation during simulated haemorrhage.…”

Chemosensitive cardiopulmonary afferents and the haemodynamic response to simulated haemorrhage in conscious rabbits

“…Vertical bars indicate 1 ,.. ....... sbols:Vertil ( s inodatmen I rabbits the sympathoinhibitory phase of simulated haemorsymbols)(E) no treatment rhage depends on a 5-opioid receptor mechanism within the 2222 (1.0mg kg-l), 4th yen-central nervous system, and its expression can also be preventventricular H-Tyr-D-Ala-Gly-ed by activating central p-opioid receptors (Figures 2, 4 and 6) 300pmol). P values attribut- (Evans et al, 1989b;Evans & Ludbrook, 1990). We have now iin ANOVA.…”

“…Data were analysed as described previously (Evans et al, 1989a,b;1990a;Evans & Ludbrook, 1990). MHR, 234+13 beats min1.…”

“…This sympathoinhibition is initiated by a signal from the heart (Burke & Dorward, 1988;Evans et al, 1989a) and depends on activation of a 6-opioid receptor mechanism within the central nervous system (Evans et al, 1989b). The sympathoinhibition of Phase 2 can also be prevented by injecting a specific p-opioid receptor agonist into the 4th ventricle (Evans & Ludbrook, 1990).…”