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

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