u-50488 and Brain-Injuries

The endogenous opioid peptide dynorphin has been implicated in the pathophysiology of secondary tissue injury after central nervous system (CNS) trauma. The detrimental effects of dynorphin appear to be mediated through both opioid receptors (probably kappa-receptors) and nonopioid mechanisms. However, both kappa-opioid agonists and antagonists have been reported to improve outcome in models of CNS trauma. To attempt to clarify this controversy, we examined the effects of centrally or systemically administered kappa-opioid agonists on neurological recovery after experimental fluid-percussion brain injury in the rat. Agonists included dynorphin A-(1-17) [Dyn A-(1-17)], which has actions at both kappa 1- and kappa 2-sites, and the selective kappa 1-agonists U-50,488H and U-69,593. des-Tyr-dynorphin A-(2-17) [Dyn A-(2-17)], which is inactive at opioid receptors, was also used. Microinjection of Dyn A-(1-17), but not Dyn A-(2-17) or U-50,488H, into the lateral ventricle 15 min before brain injury significantly worsened motor deficits over a 2-wk period. However, systemic administration of high doses of the kappa-agonists U-50,488H and U-69,593 also significantly worsened neurological outcome. These results fail to demonstrate any protective actions of kappa 1-agonists in this model of experimental traumatic brain injury and suggest that the opioid-related pathophysiological actions of dynorphin may be mediated by kappa 2-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Benzeneacetamides; Brain; Brain Injuries; Cardiovascular System; Dynorphins; Injections, Intravenous; Injections, Intraventricular; Male; Movement Disorders; Nervous System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Survival Analysis

The effects of the selective kappa 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 less than 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 less than 0.03 by paired t at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Blood Pressure; Brain Injuries; Cats; Cerebrovascular Circulation; Female; Male; Mice; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries