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The Central Nervous System (Opiate Receptor/Naloxazone/It Receptor/8 Receptor) BENJAMEN L

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The Central Nervous System (Opiate Receptor/Naloxazone/It Receptor/8 Receptor) BENJAMEN L Proc. NatL Acad. Sci. USA Vol. 78, No. 10, pp. 6181-6185, October 1981 Biochemistry Classification of multiple morphine and enkephalin binding sites in the central nervous system (opiate receptor/naloxazone/It receptor/8 receptor) BENJAMEN L. WOLOZIN AND GAVRIL W. PASTERNAK* George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, Departments of Neurology and Pharmacology, Cornell University Medical College, New York, New York 10021 Communicated by Max Tishler, July 17, 1981 ABSTRACT Detailed competitive displacement curves of3H- METHODS labeled [D-Ala2,Met5]enkephalinamide, [D-Ala2,D-Leu5]en- kephalin, and dihydromorphine by a series ofopiates and enkeph- [D-Ala2,D-Leu5]-[3H]Enkephalin, [3H]dihydromorphine, and alins are biphasic, suggesting multiple sites. After treatment of [D-Ala2,D-Met2]-[3H]enkephalinamide were obtained from tissue with naloxazone, the displacement of the three 3H-labeled New England Nuclear, as was Formula 963 scintillation fluor. ligands byall opiates and enkephalins tested becomes monophasic, Brain membranes were prepared from male Sprague-Dawley losing the high-affinity displacement seen with low concentrations rats as described (21) and treated with naloxazone in vitro (16). ofboth opiates and enkephalins. Coupled with Scatchard analysis In brief, naloxazone was dissolved in 1% glacial acetic acid (10 of saturation experiments, these findings suggest a common site mg/ml), and 15 min later the solution was added to tissue to that binds both opiates and enkephalins equally well andwith high- a final concentration of2 rAM. Tissue incubation was carried out est affinity (Kd values, <1 nM). Termed the #1 site, it corresponds at 250C for 30 min, and followed by four washes. Each wash to the previously described high-affinity site and appears to be the consisted of an incubation at 370C for 10 min, followed by cen- site responsible for analgesia under normal circumstances. The trifugation and resuspension in buffer. This wash procedure low-affinity bindingof[3H]dihydromorphine (4d, 3 nM) remaining effectively removes all reversible opiates at this concentration after naloxazone treatment differs dramatically from low-affinity (13, 16). Control tissue in all naloxazone experiments went [D-Ala2,D-Leu5]-[3H]enkephalin binding (Kd, 5 nM). The P2 site, through all incubations and treatments without drug to permit corresponding to the low-affinity [3H]dihydromorphine receptor with naloxazone-treated tissue. sites, binds morphine (1I, 10 nM) and dihydromorphine (Kd, 3 nM) an accurate comparison Binding far better than [D-Ala2,D-Leu5]enkephalin (14, 50 nM). Low-af- assays were performed as described (21), with 20 mg of tissue finity [D-Ala2,D-Leu5]-[3H]enkephalin receptor sites bind [D- per ml. Ala2,D-Leu5]enkephalin (14, 5-8 nM) more potently than mor- phine (14, 71 nM) and correspond to the previously established 8 RESULTS receptor. EffectsofNaloxazone on [D-Ala2,Met5]-flH]Enkephalinamide The binding ofradiolabeled enkephalins directly to brain mem- Binding. Naloxazone effectively and irreversibly blocked the branes was described (1) shortly after their discovery (2-4) and high-affinity component of [D-Ala2,Met5]-[3H]enkephalinamide structural determination (5, 6). Although similar in many re- binding in tissue treated in vitro (Fig. 1). Analysis of the satu- spects to opiate binding, significant differences do exist. Ra- ration data of control tissue by nonlinear, least-squares, diolabeled enkephalin binding is displaced more easily by en- weighted fit (unpublished data) showed two components. The kephalins than by opiates and vice versa (7, 8). On the basis of Sigh-affinity component (kd, 0.2 nM) present in control tissue these findings, it was proposed that enkephalins bind to an en- was eliminated in the tissue pretreated with naloxazone. By kephalin-selective (8) site in the central nervous system, contrast, there was only a mild decrease (15%) in low-affinity whereas opiates such as morphine bind to a morphine-selective binding between the control (Kd, 4.1 nM) and the naloxazone (,) site. This proposal confirms the concept ofdiscrete enkepha- tissue (Kd, 6.9 nM), with no significant change in affinity. lin and opiate mechanisms suggested by the marked differences Effects of Naloxazone on Displacement Studies by Opiates in potency between opiates and enkephalins in the mouse vas and Enkephalins.Displacement studies by a variety of drugs deferens and the guinea pig ileum bioassays (1). were then performed on [D-Ala2,Met5]-[3H]enkephalinamide Multiple populations ofopiate receptors also have been sug- binding to compare their competitive interactions. Morphine gested on the basis of biochemical evidence (9, 10). By using inhibited radiolabeled enkephalin analogs in a biphasic manner differences in binding affinities, this method classified recep- (Fig. 2A), confirming previous reports (7, 8, 15). The initial tors as "high-" and "low-" affinity sites, the terms being in a displacement was quite sensitive to morphine, occurring at relative sense because even the lower-affinity site binds opiates <1 nM morphine. The remaining binding, which comprises quite potently (Kd, <10 nM). Our understanding ofthese high- morphine's second displacement, required far larger doses. and low-affinity sites has been greatly expanded by the use of Treatment of this tissue with naloxazone eliminated the dis- naloxazone (11-20), an irreversible ligand selective for the high- placement of [D-Ala2,Met5]-[3H]enkephalinamide binding by affinity site and active both in vivo and in vitro. In this study, low morphine concentrations. Thus, naloxazone selectively in- we investigated the pharmacological properties ofboth enkeph- hibited the high-affinity binding site for both [3H]morphine (15) alins and a variety of opiates in an effort to correlate the high- and [D-Ala2,Met5]-[3H]enkephalinamide (Fig. 1) measured di- and low-affinity sites with ,u and 8 receptors. rectly by Scatchard analysis in addition to blocking morphine's The publication costs ofthis article were defrayed in part by page charge Abbreviation: IC50, concentration causing 50% maximal inhibition. payment. This article must therefore be hereby marked "advertise- * To whom reprint requests should be addressed at: Memorial Sloan- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. % Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. 6181 Downloaded by guest on September 29, 2021 6182 Biochemistry: Wolozin and Pasternak Proc. Nad Acad. Sci. USA 78 (1981) - 0 8 b bi .4 42w C> to 0 100 x .0 14. 75 mo p- 50 1 25 0 B E la-4 0 le I I fl 4)04 ¢) 100 75 [D-Ala2,Met5]-[3HlEnkephalinamide bound, 50 fmol/mg of tissue 25 FIG. 1. Scatchard analysis of [D-Ala2,Met5]-[3H]enkephalinamide 0 binding in naloxazone-treated and control tissue. Rat brain mem- 100 0 branes were prepared and treated with no drug (e) or naloxazone (o) Drugs, nM and assayed with [D.Ala2,Mete]-[PHlenkephalinamide (0.1-4.7 nM). Saturation data were analyzed by a nonlinear, weighted, least squares FIG. 2. Displacementof [D-Ala2,Met5]-[3Hlenkephalinamidebind- fit (unpublished data). Control binding was into two compo- broken ing by opiates. Rat brain membranes were and treated with nents with different affinities (Kds, 0.2 and 4.1 nM), whereas only a prepared no drug (o) or naloxazone (a). [-Ala2,Met ]-[Hhlenkephalinamide (1 single component was demonstrated in naloxazone-treated tissue (Kd, nM)binding was determined inthe presence ofthefollowingunlabeled 6.9 nM). TheKd value of the lower-affinity control tissue (4.1 nM), was drugs: morphine (A), ketocyclazocine (B), SKF 10,047 (C), naloxone not significantly different from that of naloxazone-treated tissue (6.9 (D), naltrexone (E), and levallorphan (o, e) and dextrallorphan (A, nM). Naloxazone treatment eliminated the high-affinity site, causing A) (F). Points are from one experiment and represent the mean ± SEM only a small decrease (around 15%) in the lower-affinity site. The ex- of triplicate determinations. Similar results have been replicated in periment has been replicated three times. B/f, bound/free. three different experiments. The percentage oftotal binding that com- prises the initial displacement can vary up to 10% from experiment to experiment. For this reason, a single preparation of brain membranes high-affinity competitive displacement of [D-Ala2,Met5]- was divided into two fractions, treated with no drugor naloxazone, and [3H]enkephalinamide binding. Together, these results suggest assayed together with a single unlabeled ligand. Because the different that both drugs bind with highest affinity to the same site. unlabeled ligands were assayed in different experiments, variations Scatchard analysis of saturation experiments shows that nal- in the initial displacement are probably not significant. oxazone also abolishes the high-affinity binding component for a number of other opiates, including the K drug [3H]ethyl- tion, agreeing with previous findings utilizing I"2-labeled [D- ketocyclazocine (14), the o- drug [3H]SKF 10,047 (17), and the AlaO,D-Leu5]enkephalin (18). antagonists [3H]naloxone (12, 13) and [3H]naltrexone (15). Because naloxazone treatment of membranes also abolished Therefore, we investigated naloxazone's actions on the displace- the high-affinity binding component of [3H]dihydromorphine, ment of [D-Ala2,Met ]-[3H]enkephalinamide binding by a va- we examined the inhibition of this ,u agonist by [D-AWa2,D- riety of unlabeled ligands (Fig. 2B-F). [D-Ala2,Met5]- Leu5]enkephalin
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