Central inhibition of opioid receptor subtypes and its effect on haemorrhagic hypotension in conscious sheep R. Frithiof, S. Eriksson and M. Rundgren Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Received 31 January 2007, revision requested 12 March 2007, revision received 22 March 2007, accepted 18 April 2007 Correspondence: Dr R. Frithiof, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm S-17177, Sweden. E-mail: robert.frithiof@ki.se Abstract Aim: To investigate the contribution of cerebral l-, j- and d-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 (CTOPl-receptor antagonist), ICI 174,864 (d-receptor antagonist) or nor-binaltorphimine dihydrochloride (nor-BNI, j-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 ¼ 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 l-opioid receptor blockade had no effect on baseline circulation or the response to haemorrhage. Conclusion: Activation of j- and d-opioid receptors adjacent to the ven- tricular 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. Keywords angiotensin, bradycardia, haemorrhage, hypotension, opioid, renal blood flow, shock, vasopressin. The cardiovascular response to blood loss has two consecutive phases. Initially, tachycardia and periph- eral vasoconstriction counteracts the diminishing blood volume and maintains blood pressure at near normal level. At a certain amount of blood loss, heart rate (HR) and total vascular resistance are suddenly and considerably reduced. This causes the arterial blood pressure to fall and vital organ blood flow becomes critically impaired. The two phases are often referred to as the compensatory (first) and decompensatory (second) phase (Schadt & Ludbrook 1991). The trigger mechanism for the decompensatory phase remains unknown although c-fibre afferents from cardiac mechanoreceptors have been suggested to convey the key stimulus to the brain (Thoren 1979). The cerebral part has mainly been studied in rabbits and rodents but many experiments involved anaesthetics that potentially can affect the circulation and interact with autonomic mechanisms. In conscious animals subjected to haemorrhage or simulated hypovolaemia the opioi- Acta Physiol 2007, 191, 25–34 Ó 2007 The Authors Journal compilation Ó 2007 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2007.01720.x 25