Differential Time-Course Decreases in Nonselective, μ-, δ-, and κ-Opioid Receptors After Focal Cerebral Ischemia in Mice

Abstract

Background and Purpose —Neuroprotection studies have demonstrated the involvement of opioids in ischemia, and we have previously demonstrated alterations in B max of opioidergic receptors after 2 post-MCAO time points in mice. Methods —In the present study, we have investigated in a detailed manner the postischemic time course of variations in [ 3 H]diprenorphine (nonselective), [ 3 H]DAMGO (μ), [ 3 H]DADLE (δ), and [ 3 H]U69593 (κ) relative binding densities after focal cerebral ischemia (0 to 48 hours) in mice. Results —In frontoparietal cortices, our results demonstrate decreases in (1) δ receptor densities at 1 to 3 hours after MCAO, (2) μ and nonselective binding sites at 6 to 12 hours after MCAO, and (3) κ receptor densities between 6 and 24 hours after MCAO. In the rostral part of the infarct border zone, a decrease in δ-receptors was found concomitant with the extension of the infarct core; conversely, the decrease in δ-receptors appeared before (6 to 12 hours) macroscopic histological damage, which occurred between 12 hours and 24 hours after MCAO in the caudal part of this area. In this frontier, μ- and especially κ-binding sites were decreased later (12 to 48 hours after MCAO). Conclusions —These differential alterations in opioidergic receptors could be due to the selective sublocalization of receptors, postsynaptically on cortical interneurons for μ- and δ-receptors versus presynaptically on cortical afferent pathways for the κ subtype. Further, our results suggest that δ- and μ-opioidergic receptors could be markers of infarct extension and neuronal death; the study of [ 3 H]diprenorphine and selective binding sites argues in favor of the use of receptor-specific ligands. Finally, the relative preservation of κ-receptors might be correlated with the neuroprotective role of κ-agonists, as previously reported.