Beneficial effects of the κ opioid receptor agonist U-50488H in experimental acute brain and spinal cord injury

Abstract

The effects of the selective κ opioid receptor agonist U-50488H (trans-3,4-dichloro- N-methyl- N[2(pyrrolidinyl)-cyclohexyl]-benzeneacetamide) were examined in acute head and spinal injury models. First, in a blinded protocol, male CF-1 mice were treated intravenously with either saline or U-50488H (1, 3 or 10 mg/kg) within 3–5 min following a reproducible and quantifiable moderately severe (900 g/cm) concussive head injury. Using a grip test at 1 h postinjury to evaluate the neurological status of the injured mice, U-50488H produced a dose-related improvement in early recovery compared to the saline-treated mice. The effect was significant ( P < 0.05) after the 3 or 10 mg/kg i.v. doses. A similar concussive injury markedly reduced the % of cardiac output perfusing the forebrain (cerebral blood flow). U-50488H (10 and 20 mg/kg) partially reversed this effect to a significant degree 60 min after a 20 mg/kg dose. Secondly, the effects of U-50488H on the development of progressive post-traumatic spinal cord white matter ischemia after a 500 g/cm contusive injury were studied in pentobarbital-anesthetized cats. In 4 untreated cats, there was a progressive fall in spinal cord and blood flow (SCBF) from a 10-min postinjury level of 10.5 ± 0.7 ml/100 g/min to 6.1 ± 0.3 ( P < 0.03 by paired t at 4 h). In U-50488H-treated cats (3 mg/kg i.v. 30 min before plus 1 mg/kg i.v. at 1.5 h after injury), SCBF only declined from 10.4 ± 1.4 ml/100 g/min at 10 min postinjury to 9.1 ± 0.9 at 4 h ( P < 0.3). The mean SCBF was significantly higher ( P < 0.05 by Student's t-test) at 2 and 4 h postinjury in the U-50488H-treated cats compared to the untreated animals. The results imply that κ receptor activation may be beneficial in the injured nervous system rather than deleterious as other investigators have suggested.