Approximately one-half million new strokes occur each year in the United States; mean survival time is less than 4 years, and the residual neurologic deficit exacts devastating clinical, sociologic, and economic tolls. A significant effect of opiate antagonists, notably naloxone, in the reversal of neurologic deficits associated with focal cerebral ischemia has been demonstrated in humans and in gerbils, baboons, and cats. The precise mechanism for this action has not been defined. These studies are proposed to examine physiologic and pharmacologic effects of opiate antagonists on animals with profound cerebral ischemia; to provide information on the mechanism of endogenous opioid that may lead to new forms of therapy for these previously untreatable conditions; and to validate the effectiveness of NMR imaging for evaluating ischemic cerebral lesions and their response to new forms of treatment. I. The effects of conventional opiate antagonists to the mu, delta, and kappa opiate receptor subpopulation on ischemic neurologic deficits will be tested in a cat model of focal cerebral ischemia. If prior work suggesting that the mu-type antagonists reverse such deficits most effectively is confirmed, cats that have undergone middle cerebral artery (MCA) occlusion will be treated with different mu-type antagonists, naloxone, naltrexone, and diprenorphine, given continuously through a subcutaneously placed osmotic minipump, in order to test the extent to which these agents will reduce morbidity and mortality from the ischemic insult. II. Naloxone decreases local blood flow to the ischemic cortex in anesthetized cats after MCA occlusion. This study will further evaluate effects of naloxone and other opioid compounds on local cortical blood flow in awake, unanesthetized cats and on regional flow in deep brain regions. III. The effect of opiate agonists and antagonists on local cerebral glucose metabolism will be studied to find if the behavioral effects of these agents are mediated by direct changes in neuronal metabolism, and thus neuronal activity. Unilateral carotid artery ligation in the gerbil will provide the model of acute cerebral ischemia. A double-label autoradiographic technique will be used to evaluate local glucose metabolism before and after the administration of naloxone or other opioid compounds to determine the specific effect of these agents on postischemic glucose metabolism. IV. NMR, a highly sensitive tool for detecting and evaluating acute cerebral ischemia and infarction, will be evaluated using unilateral carotid artery ligation in the gerbil as a model of focal cerebral ischemia to determine if naloxone or other opioid compounds reverses changes in signal intensity of the NMR image observed previously.
| Baskin, D S; Hosobuchi, Y (1986) Treatment of experimental stroke with the opiate antagonist win 44,441-3 effects on neurologic function, infarct size, and survival. NIDA Res Monogr 75:531-4 |
| Kuroda, H; Baskin, D S; Matsui, T et al. (1986) Effects of dynorphin1-13 on opiate binding and dopamine and GABA uptake in stroked cat brain. Brain Res 379:68-74 |
| Baskin, D S; Hosobuchi, Y; Grevel, J C (1986) Treatment of experimental stroke with opiate antagonists. Effects on neurological function, infarct size, and survival. J Neurosurg 64:99-103 |
| Baskin, D S; Kuroda, H; Hosobuchi, Y et al. (1985) Treatment of stroke with opiate antagonists--effects of exogenous antagonists and dynorphin 1-13. Neuropeptides 5:307-10 |
