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 [3H]diprenorphine (nonselective), [3H]DAMGO (μ), [3H]DADLE (δ), and [3H]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 [3H]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.