The kappa opioid agonist niravoline decreases brain edema in the mouse middle cerebral artery occlusion model of stroke.
The effect of niravoline (RU 51599), a kappa opioid receptor agonist with water diuretic properties, was assessed on the resorption of postischemic cerebral edema in the conscious mouse in comparison with U 50488, another kappa opioid receptor agonist, and mannitol. Ischemia was obtained by permanent occlusion of the right middle cerebral artery. Twenty-four hours after occlusion, at a time when brain water content is submaximal, blood samples were collected to measure serum osmolality, and brains were removed to measure the brain water content of two samples of frontoparietal cortical tissue corresponding to the core and the periphery of ischemia. When administered from 3 to 30 mg/kg as a single i.p. injection 20 h after occlusion, niravoline significantly reduced the brain cortical water increase by 27% up to 48% in the periphery of the ischemic tissue. At these same doses, it increased the serum osmolality to the same extent in ischemic as in nonischemic mice: 4 to 10 mOsm/kg. U 50488 generally showed a similar activity. In contrast, mannitol (1 or 2 g/kg i.p. 23 h after occlusion) increased serum osmolality but did not decrease brain water content. In conclusion, kappa opiate agonists could be an alternative to hyperosmotic agents in the treatment of cerebral edema of the focal ischemia type, the use of which is limited to the early phase of cerebral edema.
Guéniau
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Pharmacology of Central Effects, Preclinical Research, Roussel Uclaf, Romainville, France.
Oberlander
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D044482:Benzeneacetamides; D001929:Brain Edema / Q000517:prevention & control*; D002536:Cerebral Arteries; D002561:Cerebrovascular Disorders / Q000150:complications*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D051379:Mice; D009994:Osmolar Concentration; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D008353:Mannitol; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C100946:niravoline