Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils.

Abstract

The ability of the K-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-K close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA, neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i. considerable interest has developed concerning the possible role of endogenous opioids in ischemic pathophysiology and neuronal degeneration. Based on the anti-ischemic action of naloxone, an hypothesis has been developed that postischemic neuronal degeneration may in part depend on an excessive activation of endogenous opioid systems, which could be therapeutically antagonized with opiate receptor blocking drugs such as naloxone or naltrexone. However, some investigators have failed to observe a positive effect of naloxone in their particular ischemia models. 67 More recent studies have suggested that pharmacologic stimulation of the K-opiate receptor subtype can actually ameliorate rather than exacerbate postischemic neuronal degeneration and promote neurologic recovery and survival. The initial study in this regard showed that

Arginine vasopressin release inhibitor RU51599 attenuates brian oedema following transient forebrain ischaemia in rats

“…However, some investigators [39] did not find naloxone effective in cerebral ischaemia. Recent experimental studies have demonstrated the existence of at least three receptor subtypes for the endogenous opioid peptides and among them, kappa-opioid receptor binding was increased after ischaemic injury and activation of a kappa-opioid receptor system contributed to exacerbate cerebral ischaemia, while more recent studies [10,21,34] [14] have reported that the kappa agonist served to restore protection. Baskin and his colleagues [2] evaluated the therapeutic efficacy of variable kappa opioid agonists for delayed treatment of experimental focal cerebral ischaemia.…”

Brain Damage Caused by Ischemia: Pathophysiological and Pharmacological Aspects

“…Several other substances, including kappa-agonists such as /-spiradoline and U622066 [87]. thyrotropin releasing hormone analogues [88] and insulin [89] protect against damage to CA 1 cells.…”

Perinatal Cerebral Asphyxia: Pharmacological Intervention

“…Agents that selectively stimulate this system have been shown to reduce post-ischemic delayed neu ronal death in the gerbil [43]. Whether this effect is due to a reduction in acute neuronal swelling by osmotic effects or to a more direct receptor-mediated protection is not known.…”