?2-Adrenergic, k-Opiaie, and PrPurinergic Autoreceptors Have Mutually Antagonistic Effects: A New Regulatory Mechanism?

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Abstract
Rat cortical synaptosomes prepared on four-step discontinuous Percoll density gradients were loaded with the fluorescent Ca2+-indicator fura-2 to allow measurement of the intrasynaptosomal free calcium concentration ([Ca2+]i). When P1-purinergic, .alpha.2-adrenergic, or .kappa.-opiate agonists were incubated with these synaptosomes for 1 min, there was a highly significant, dose-dependent reduction in [Ca2+]i. The effects of these agonists were blocked by inclusion of appropriate specific antagonists. When .alpha.2-adrenergic and P1-purinergic agonists were coincubated, a mutual antagonism of their effects was observed, and, in fact, an increase rather than a decrease in [Ca2+]i was apparent. This mutual antagonism was reversed by addition of either a P1-purinergic or a .alpha.2-adrenergic antagonist. Parallel studies in which .kappa.-opiate and P1-purinergic agonists were coincubated also demonstrated a mutual antagonism between the individual effects that was reversed by prior inclusion of either a .kappa.-opiate or P1-purinergic antagonist. As these mutually antagonistic effects have been observed between .alpha.2-adrenergic, .kappa.-opiate, and P1-purinergic receptor-mediated events, we suggest that this may be a general phenomenon and may be a regulatory mechanism at nerve endings.