Characterization and visualization of rat and guinea pig brain kappa opioid receptors: evidence for kappa 1 and kappa 2 opioid receptors.

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Abstract
.kappa. opioid receptors (.kappa. receptors) have been characterized in homogenates of guinea pig and rat brain under in vitro binding conditions. .kappa. receptors were labeled by using the tritiated prototypic .kappa. opioid ethylketocyclazocine under conditions in which .mu. and .delta. opioid binding was suppressed. In the case of guinea pig brain membranes, a single population of high-affinity .kappa. opioid receptor sites (.kappa. sites; Kd = 0.66 nM, Bmax = 80 fmol/mg of protein) was observed. In contrast, in the case of rat brain, two populations of .kappa. sites were observed.sbd. high-affinity sites at low density (Kd = 1.0 nM, Bmax = 16 fmol/mg of protein) and low-affinity sites at high density (Kd = 13 nM, Bmax = 111 fmol/mg of protein). To test the hypothesis that the high- and low-affinity .kappa. sites represent two distinct .kappa. receptor subtypes, a series of opioids were tested for their abilities to compete for binding to the two sites. U-69, 593 and Cambridge 20 selectively displaced the high-affinity .kappa. site in both guinea pig and rat tissue, but were inactive at the rat-brain low-affinity site. Other .kappa. opioid drugs, including U-50, 488, ethylketocyclazocine, bremazocine, cyclazocine, and dynorphin (1-17), competed for binding to both sites, but with different rank orders of potency. Quantitative light microscopy in vitro autoradiography was used to visualize the neuroanatomical pattern of .kappa. receptors in rat and guinea pig brain. The distribution patterns of the two .kappa. receptor subtypes of rat brain were clearly different. The pattern of rat high-affinity .kappa. sites paralleled that of guinea pig in the caudate-putamen, midbrain, central gray substance of cerebrum, and substantia nigra; interspecies differences were apparent throughout most of the rest of the brain. Collectively, these data provide direct evidence for the presence of two .kappa. receptor subtypes; the U-69, 593-sensitive, high-affinity .kappa.1 site predominates in guinea pig brain, and the U-69, 593-insensitive, low-affinity .kappa.2 site predominates in rat brain.