Treatment of acute intracranial hypertension with RU 51599, a selective kappa opioid agonist

RU 51599, a selective kappa opioid agonist which is a potent aquaretic, was studied for its effect on acute intracranial hypertension. In ketamine anesthetized cats acute intracranial hypertension was induced by progressive inflation of an epidural balloon with physiological saline at a constant rate of 0.5 ml/hr for three hours. In the control group (n = 8), the balloon was maintained inflated for another an hour after which it was deflated. In the post deflation period monitoring was continued for one hour. In the treatment group (n = 8), cats were treated by an intravenous (i.v.) injection of RU 51599, at a dose of 1 mg/kg every hour at the beginning of balloon inflation, during balloon inflation, at the completion of inflation, and after deflation. Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), blood gases, serum electrolytes and osmolality, and brain water content water content were studied in both groups. In the control group, epidural brain compression resulted in significant increases in the mean ICP up to 80.7 +/- 9.8 mmHg at 3 hrs (during balloon inflation), 68.6 +/- 8.3 after complete inflation, and 62.1 +/- 11.4 mmHg after deflation (P < 0.01), and significant decreases in CPP to 55.5 +/- 14.0 mmHg at 3 hrs (during balloon inflation), 43.0 +/- 11.2 mmHg after inflation, and 36.3 +/- 9.9 mmHg after deflation (P < 0.01). In the treatment group there were significant decreases in the mean ICP to 35.2 +/- 6.8 mmHg at 3 hrs (during balloon inflation), 32.3 +/- 7.9 after inflation, and 16.1 +/- 3.6 mmHg after deflation (P < 0.01), and significant increases in CPP to 103.2 +/- 6.1 mmHg at 3 hrs (during balloon inflation), 109.0 +/- 8.8 mmHg after inflation, and 102.7 +/- 8.2 mmHg after deflation (P < 0.01). Brain water content was also significantly reduced (P < 0.05). There were no significant changes in the serum electrolytes and osmolality throughout the experiments. Our results suggest that, the mechanism by which RU 51599 reduces ICP is related to reduction in the brain water content.