Evaluation of delayed treatment of focal cerebral ischemia with three selective kappa-opioid agonists in cats.
OBJECTIVE
The purpose of this study was to determine the therapeutic efficacy of three kappa-opioid agonists used for delayed treatment of experimental focal cerebral ischemia.


METHODS
Forty halothane-anesthetized cats underwent permanent occlusion of the right intracranial internal carotid, middle cerebral, and anterior cerebral arteries via a transorbital, microsurgical approach. Six hours after occlusion, animals received a blinded bolus injection, and a subcutaneous osmotic pump was implanted to provide continuous release for 7 days. The injection and pump contained either saline or one of three kappa-agonists: dynorphin (1-13), U-50,488, or DuP E3800. Survival, neurological function, tissue damage, and brain weight were assessed.


RESULTS
As a group, kappa-agonist-treated animals had higher survival (P < .02), less tissue damage (P < .02), and lower brain weight (P < .05) than saline controls. U-50,488 more effectively improved survival (P < .03) than dynorphin (P < .07) or E3800 (P < .07). Each of the three kappa compounds improved tissue damage (dynorphin, P < .02; U-50,488, P < .05; E3800, P < .05). Greater improvement in neurological function was seen after treatment with dynorphin (P < .05) than with U-50,488 (P < .6) or E3800 (P < .7). The only significant reduction in brain weight was seen after dynorphin treatment (P < .01).


CONCLUSIONS
Compounds that act at the kappa subclass of opiate receptors are effective in increasing survival, improving neurological function, and decreasing tissue damage and edema in a cat model of focal cerebral ischemia. The current study provides support for the benefits of treatment of acute cerebrovascular ischemia with kappa-opioid agonists. The agents may prove to be of superior clinical utility because of efficacy even when administered 6 hours after the onset of stroke.
Baskin
D S
DS
Department of Surgery, Veterans Affairs Medical Center, Houston, Tex.
Widmayer
M A
MA
Browning
J L
JL
Heizer
M L
ML
Schmidt
W K
WK
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D044482:Benzeneacetamides; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002415:Cats; D004399:Dynorphins / Q000008:administration & dosage / Q000627:therapeutic use*; D007260:Infusion Pumps; D007275:Injections, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009897:Optic Chiasm / Q000187:drug effects / Q000473:pathology; D009929:Organ Size; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012677:Sensation / Q000187:drug effects / Q000502:physiology; D016037:Single-Blind Method; D015996:Survival Rate; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016138:Walking / Q000502:physiology
D000700:Analgesics; D044482:Benzeneacetamides; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; C083309:E 3800; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins