Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype.

Kappa receptor multiplicity is a complex area. We now present evidence from binding studies suggesting the existence of four kappa receptor subtypes. The guinea pig cerebellum contains high levels of U50,488-sensitive, or kappa 1, receptors. Kappa opiates (U50,488, tifluadom, Mr2034, Mr2266 and Win44,441) compete [3H]ethylketocyclazocine binding to kappa 1 receptors with kappa, values under 10 nM and Hill coefficients of approximately one, as does dynorphin A (kappa 1, 0.27 +/- 0.05 nM; Hill coefficient, 0.83 +/- 0.20, n = 4). However, competition studies with dynorphin B yield a Hill coefficient of 0.46 +/- 0.03 (n = 5) and nonlinear regression analysis of the competition curve is best fit by two sites. alpha-Neoendorphin Neoendorphin competition curves (Hill coefficient, 0.46 +/- 0.07; n = 3) also were best fit with two components. Competition studies with both alpha-neoendorphin and dynorphin B together suggest that both compounds label the same site with high affinity. Similar results were obtained using [3H]U69,593. Dynorphin B and alpha-neoendorphin competed binding with Hill coefficients of 0.45 +/- 0.04 (n = 3) and 0.59 +/- 0.09 (n = 3), respectively. These data suggest two subtypes of kappa 1 receptors in the guinea pig cerebellum: kappa 1a and kappa 1b. Classical kappa opiates and dynorphin A have high affinity for both subtypes whereas dynorphin B and alpha-neoendorphin label kappa 1b over 50-fold more potently than kappa 1a sites. [3H]Naloxone benzoylhydrazone [( 3H]NalBzoH) labels a novel, U50,488-insensitive kappa receptor subtype, kappa 3, in membranes from calf striatum, rat and mouse brain. We now have developed a relatively selective assay in calf striatum.(ABSTRACT TRUNCATED AT 250 WORDS)