Alpha 2-adrenergic, kappa-opiate, and P1-purinergic autoreceptors have mutually antagonistic effects: a new regulatory mechanism?
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.
Adamson
P
P
Department of Biochemistry, Institute of Psychiatry, London, England.
Mantzouridis
T
T
Xiang
J Z
JZ
Hajimohammadreza
I
I
Brammer
M J
MJ
Campbell
I C
IC
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000241:Adenosine / Q000031:analogs & derivatives*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D006706:Homeostasis; D019329:Idazoxan; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D011983:Receptors, Purinergic / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D001572:Benzofurans; D004146:Dioxanes; D005456:Fluorescent Dyes; D011759:Pyrrolidines; D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; D009270:Naloxone; D002110:Caffeine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000241:Adenosine; D003000:Clonidine; D002118:Calcium; D016257:Fura-2; D019329:Idazoxan