Beneficial effects of the kappa opioid receptor agonist U-50488H in experimental acute brain and spinal cord injury.
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)
Hall
E D
ED
CNS Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
Wolf
D L
DL
Althaus
J S
JS
Von Voigtlander
P F
PF
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000517:prevention & control*; D002415:Cats; D002560:Cerebrovascular Circulation / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply; D013119:Spinal Cord Injuries / Q000517:prevention & control*
D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer