title: Central and systemic kappa-opioid agonists exacerbate neurobehavioral response to brain injury in rats.
abstract: 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.
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia 19104.
authors.forename: T K
authors.initials: TK
authors.lastname: McIntosh
authors.forename: S
authors.initials: S
authors.lastname: Fernyak
authors.forename: I
authors.initials: I
authors.lastname: Yamakami
authors.forename: A I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D044482:Benzeneacetamides; D001921:Brain / Q000503:physiopathology*; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology*; D002319:Cardiovascular System / Q000503:physiopathology; D004399:Dynorphins / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009069:Movement Disorders / Q000209:etiology; D009420:Nervous System / Q000503:physiopathology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D016019:Survival Analysis
chemical_list: D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; C045444:U 69593