Neuroprotective actions of GR89696, a highly potent and selective κ‐opioid receptor agonist

1 The effect of a novel, highly potent and selective κ‐opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2 In the Mongolian gerbil model, administration of GR89696 (3 to 30 μg kg −1 , s.c.), immediately before and at 4h after insult, produced a dose‐dependent reduction in the hippocampal CA 1 neuronal cell loss resulting from a 7‐min bilateral carotid occlusion. Similar effects were obtained with two other κ‐agonists, GR86014 (1 mg kg −1 , s.c.) and GR91272 (1 mg kg −1 , s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mg kg −1 , s.c. Repeated post‐treatment with GR89696 (100 μg kg −1 , s.c.) or GR44821 (10 mg kg −1 , s.c.) was also effective in protecting completely the hippocampal CA 1 neurones from ischaemia‐induced neurodegeneration. 3 In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 μg kg −1 , s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 μg kg −1 ) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4 The results indicate that the potent κ‐opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.