Central inhibition of opioid receptor subtypes and its effect on haemorrhagic hypotension in conscious sheep.
OBJECTIVE
To investigate the contribution of cerebral mu-, kappa- and delta-opioid receptors in causing the hypotension, bradycardia and renal hypoperfusion evoked by haemorrhage.


METHODS
Adult conscious ewes were bled continuously from a jugular vein until mean arterial blood pressure (MAP) was reduced to below 50 mmHg. Starting 30 min before and continuing until 60 min after haemorrhage either artificial cerebrospinal fluid (control), d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP micro-receptor antagonist), ICI 174,864 (delta-receptor antagonist) or nor-binaltorphimine dihydrochloride (nor-BNI, kappa-receptor antagonist) were infused intracerebroventricularly. In a randomized crossover fashion the effect of antagonizing one central opioid receptor subtype was compared to control experiments in the same animal (n = 6 in all groups).


RESULTS
Compared to corresponding controls, nor-BNI and ICI 174,864 significantly increased the haemorrhage volume needed to reduce MAP to below 50 mmHg (+4.7 mL kg(-1), SD 1.8 and +3.1 mL kg(-1), SD 3.0 respectively). In the nor-BNI group this was accompanied by a significantly augmented tachycardia before MAP fell. Both nor-BNI and ICI 174,864 also postponed haemorrhagic bradycardia and prolonged adequate blood flow to the kidney. The infusions did not affect the circulation per se or the recovery after haemorrhage. The micro-opioid receptor blockade had no effect on baseline circulation or the response to haemorrhage.


CONCLUSIONS
Activation of kappa- and delta-opioid receptors adjacent to the ventricular compartment contributes to initiating haemorrhagic hypotension and bradycardia in conscious sheep. However, other parts of the brain and different receptors are likely to play a role as well.
Frithiof
R
R
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. robert.frithiof@ki.se
Eriksson
S
S
Rundgren
M
M
D000818:Animals; D001919:Bradycardia / Q000517:prevention & control; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D006470:Hemorrhage / Q000150:complications / Q000378:metabolism*; D007022:Hypotension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007276:Injections, Intraventricular; D023421:Models, Animal; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists; D011897:Random Allocation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation; D012756:Sheep
D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D004743:Enkephalin, Leucine; D009271:Naltrexone; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine