Role of central opiate receptor subtypes in the circulatory responses of awake rabbits to graded caval occlusions.

Abstract

SUMMARY1. In unanaesthetized rabbits, haemorrhage was simulated by inflating a cuff placed round the inferior vena cava so that cardiac output fell at a constant rate of 8 % of its resting value per minute. The circulatory responses were measured after injections into the fourth ventricle of saline vehicle, selective opioid antagonists, selective opioid agonists, and agonist-antagonist mixtures. Three sets of experiments were done to determine if a specific subtype of opiate receptor within the central nervous system is responsible for the circulatory decompensation that occurs during simulated haemorrhage.2. In six rabbits the effects of ascending doses of the antagonists naloxone (,uZselective), Mr 2266 (K-and ,t-selective), ICI 174864 (6-selective) and nor-binaltorphimine (K-selective) were tested. In three rabbits the effects of the antagonist naloxone, the agonists HTyr-D-Ala-Gly-MePhe-NH(CHi)2OH (DAGO, ,u-selective), U 50488H (K-selective), and [D-Pen2, D-Pen5]-enkephalin (DPDPE, 6-selective), and combinations of these agonists with naloxone were tested. In four rabbits the doserelated effects of DAGO on respiratory, as well as circulatory, functions were examined.3. After injecting saline vehicle, the circulatory response to simulated haemorrhage had two phases. During the first phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only -10 mmHg. A second, decompensatory, phase began when cardiac output had fallen to -50 % of its resting level. At this point, there was an abrupt rise in systemic vascular conductance and a fall in mean arterial pressure to < 40 mmHg.4. The lower range of doses of naloxone (3-30 nmol), Mr 2266 (10-100 nmol), ICI 174864 (10-30 nmol), and all doses of nor-binaltorphimine (1-100 nmol), were without effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol), Mr 2266 (100-300 nmol) and ICI 174864 (30-100 nmol) abolished the decompensatory phase. The relative order of antagonist potency was ICI 174864 > naloxone > Mr 2266 > nor-binaltorphimine.5. In the second set of experiments, the critical dose of naloxone necessary to prevent circulatory decompensation during simulated haemorrhage was 30-150 1.S 74: 16 R. G. EVANS, J. LUDBROOK AND A. F. VANLEEUWEN nmol. The d-agonist DPDPE (50 nmol) did not affect the haemodynamic response to simulated haemorrhage, but it did block the effect of naloxone on the response. The u-agonist DAGO (30 nmol) and the K-agonist U 50488H (300 nmol) prevented circulatory decompensation during simulated haemorrhage, whether given alone or in combination with the critical dose of naloxone, but DAGO (30 mmol) also raised arterial pressure, lowered systemic vascular conductance and slowed respiration.6. In the third set of experiments we found that lower doses of DAGO (100-300 pmol) would also prevent circulatory decompensation during simulated haemorrhage. These doses did not affect resting arterial pressure or systemic vascular conductance, and had insignificant effects on res...

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

“…We have previously provided evidence that this effect of naloxone is mediated by an antagonist action at central 6-receptors (Evans et al, 1989b). We have also extended our finding that circulatory decompensation is abolished after 4th ventricular administration of 30 nmol of the u-agonist DAMGO (Evans et al, 1989b), by demonstrating that the threshold dose for this effect is as low as 100-300pmol.…”

“…We have also found, unexpectedly, that 4th ventricular administration of the selective u-opioid receptor agonist H-Tyr-D-Ala-Gly-MePhe-NH(CH2)20H (DAMGO) (Handa et al, 1981) in a dose of 30nmol prevents circulatory decompensation during simulated haemorrhage (Evans et al, 1989b). We have argued that it is unlikely that this effect is mediated by blockade of 6-opioid receptors, since DAMGO is at least 500 times less potent than naloxone as a 6-antagonist (Sheehan et al, 1986).…”

“…There is strong evidence that its subsequent failure is triggered by a signal from the heart (Burke & Dorward, 1988;Evans et al, 1989a). There is also evidence, based on the relative abilities of selective antagonists injected into the 4th ventricle to prevent its occurrence, that it is mediated by an endogenous opioid mechanism within the central nervous system which involves 6-receptors (Evans et al, 1989b).…”

The effects of naloxone on the cardiovascular and respiratory effects of centrally administered corticotrophin releasing factor in conscious rabbits

“…The doses of naloxone used in these studies would be expected to block central 3-opioid receptors as they were similar to those which caused a pressor effect when given to rabbits after haemorrhage (Rutter et al, 1986), an effect which is mediated by central 5-opioid receptors (Evans et al, 1989). The doses of naloxone were also higher than those which reversed the effects of centrally administered u-and S-opioid agonists in conscious rabbits (May et al, 1989a).…”

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

“…When about 30% of blood volume has been withdrawn (Schadt et al, 1984;Burke & Dorward, 1988;Ludbrook & Rutter, 1988), or when cardiac output has fallen by about 50% (Evans et al, 1989a, b), a second phase begins in which there is an abrupt decrease in sympathetic activity, peripheral resistance and mean arterial pressure. 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).…”