Konkoy C S, Childers S R
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157.
Biochem Pharmacol. 1993 Jan 7;45(1):207-16. doi: 10.1016/0006-2952(93)90394-c.
Previously, we showed that kappa-selective ligands inhibit adenylyl cyclase in guinea pig cerebellar membranes. The present studies explore the relationship between kappa 1 binding sites (as determined with [3H]U-69,593 binding) and kappa 1-inhibition of adenylyl cyclase (using U-50,488H) in guinea pig brain membranes. Various kappa opioids displaced [3H]U-69,593 binding at a single site with subnanomolar affinities. These agonists were several hundred-fold weaker in inhibiting adenylyl cyclase, but for most agonists the rank order of adenylyl cyclase inhibition paralleled the displacement of kappa 1 binding. The correlation of IC50 values for both adenylyl cyclase and binding was significant except for alpha-neo endorphin, which was relatively weak at inhibiting adenylyl cyclase despite a Ki value of 0.08 nM versus kappa 1 binding. Comparison between kappa 1 binding and kappa 1-inhibited adenylyl cyclase across eleven guinea pig brain regions revealed that kappa 1-inhibited adenylyl cyclase was highest in the cerebellum, absent in thalamus and superior colliculus, and moderate in other regions. In most regions, kappa 1 binding correlated with the efficacy of kappa 1-inhibited adenylyl cyclase. However, the hippocampus had high levels of kappa 1-inhibited adenylyl cyclase despite low levels of kappa 1 binding, while cortex exhibited a high density of kappa 1 sites but a relatively low level of kappa 1-inhibited adenylyl cyclase. Reaction of cerebellar kappa receptors with beta-chlornaltrexamine (beta-CNA) blocked both kappa 1 binding and kappa 1-inhibited adenylyl cyclase. The effect of beta-CNA on kappa 1-inhibited adenylyl cyclase was to inhibit efficacy with little decrease in agonist potency, thus suggesting no significant level of kappa receptor reserve for this effector system.
此前，我们发现κ-选择性配体可抑制豚鼠小脑膜中的腺苷酸环化酶。本研究探讨了豚鼠脑膜中κ1结合位点（通过[3H]U-69,593结合测定）与κ1对腺苷酸环化酶的抑制作用（使用U-50,488H）之间的关系。各种κ阿片类药物以亚纳摩尔亲和力在单个位点取代[3H]U-69,593结合。这些激动剂在抑制腺苷酸环化酶方面的效力要弱几百倍，但对于大多数激动剂来说，腺苷酸环化酶抑制的排名顺序与κ1结合的取代情况平行。除了α-新内啡肽外，腺苷酸环化酶和结合的IC50值之间的相关性很显著，尽管其与κ1结合的Ki值为0.08 nM，但它在抑制腺苷酸环化酶方面相对较弱。对11个豚鼠脑区的κ1结合和κ1抑制的腺苷酸环化酶进行比较发现，κ1抑制的腺苷酸环化酶在小脑中最高，在丘脑和上丘中不存在，在其他区域中等。在大多数区域，κ1结合与κ1抑制的腺苷酸环化酶的效力相关。然而，海马体中κ1抑制的腺苷酸环化酶水平较高，尽管κ1结合水平较低，而皮质中κ1位点密度高，但κ1抑制的腺苷酸环化酶水平相对较低。小脑κ受体与β-氯代纳曲酮（β-CNA）反应可阻断κ1结合和κ1抑制的腺苷酸环化酶。β-CNA对κ1抑制的腺苷酸环化酶的作用是抑制效力，而激动剂效力几乎没有降低，因此表明该效应系统的κ受体储备水平不显著。
