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Opioids Regulate Cgmp Formationin Cloned Neuroblastoma Cells

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Opioids Regulate Cgmp Formationin Cloned Neuroblastoma Cells Proc. NatL. Acad. Sci. USA Vol. 79, pp. 690-694, January 1982 Neurobiology Opioids regulate cGMP formation in cloned neuroblastoma cells (cyclic nucleotides/opiate receptor/desensitization) GERMAINE J. GWYNN AND ERMINIO COSTA* Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032 Communicated by Floyd E. Bloom, October 8, 1981 ABSTRACT Opioid agonists caused a rapid dose-related el- cumulation in rat striatal slices with characteristics that fulfill evation of the cGMP content of N4TG1 murine neuroblastoma the criteria for a specific narcotic action (6). In contrast, the cells. An excellent correlation was found between the rank order decrements in the cGMP content ofcerebellar tissue observed of potency of agonists in stimulating cGMP accumulation and in after morphine administration are probably indirect effects of displacing [3H]etorphine ([H]ETP) bound to intact cells. The nar- opioid receptor stimulation mediated by the modulation of y- cotic antagonists naloxone and diprenorphine failed to increase aminobutyric acid or acetylcholine collateral neuronal loops (7, cGMP content; moreover, in the presence of 5 ,IM naloxone, the 8). A functional role for cGMP in opioid action is further sug- EC50 of ETP increased from w9 nM to >1 ,uM. N4TG1 cells that had been incubated for 20 min with 0.32 ItM ETP and thoroughly gested by the pivotal role that calcium ions play both in regu- washed displayed a marked loss in sensitivity to subsequent ETP lating cGMP formation (for review, see refs. 9, 10) and in me- challenge. This desensitization was characterized by a 40-50% diating the acute and chronic effects ofopioids (for review, see decrease in maximal response and an increase in the apparent Ka refs. 11, 12). Changes in intracellular cGMP content modulate of ETP from 4 to 50 nM. Desensitization was complete after a 7- the activity of cGMP-dependent protein kinases (13). Opioids min incubation with 0.32 jIM ETP (t112 1 min) and was only clearly control the phosphorylation of synaptic membrane pro- slowly reversible (t4/2 > 60 min). Naloxone (5 ,AM) and dipren- teins, some of which may be specific substrates for cGMP-de- orphine (0.1 ujM) failed to elicit desensitization, but they blocked pendent kinases (14, 15). ETP-induced desensitization. Dextrophan and (+)-ethylketazo- Clonal cell lines derived from mouse neuroblastoma C1300 cine were <1% as effective as levorphanol and (-)-ethylketazo- exhibit many properties characteristic of neurons (for review, cine, respectively, in both stimulating cGMP accumulation and see refs. 16, 17). The use of such clonal lines as model systems inducing desensitization. When the binding of [3H]ETP (0.2-20 to study the operation ofopioid receptors obviates many of the nM) was examined under identical experimental conditions, cells interpretative complications inherent to studies with intact tis- that were completely desensitized by incubation with ETP (7 min sues. Opioid binding sites are negatively coupled to adenylate with 0.32 ,IM or 20 min with 15 nM) showed no loss ofhigh-affinity cyclase in the neuroblastoma x glioma hybrid line 108CC15 recognition sites. After longer incubation with ETP (0.32 ,AM for (18-20) and in the N4TG1 neuroblastoma clone (21). Studies 20-60 min), the maximal binding of [3H]ETP was reduced purported to show that opioids modify cGMP levels in the hy- 17-41%. The specific short-term desensitization of cGMP accu- brid 108CC15 line (22, 23) have proven to be unreliable (24, 25). mulation is not mediated or accompanied by a decrement in the We report that opioid receptor agonists elicit a rapid dose-re- number of agonist binding sites. lated elevation ofcGMP content in the N4TG1 clone and pres- ent evidence that both this acute response and its subsequent Despite the intensive characterization of high-affinity cellular desensitization exhibit some of the properties ofa specific nar- recognition sites for opioids, our knowledge of the molecular cotic effect. mechanisms by which stimuli are amplified and internalized by these sites remains remarkably meager. In fact, we are still MATERIALS AND METHODS seeking appropriate ways to classify the multiple types of rec- Materials. Drugs were from the following sources: [D- ognition, coupling, and amplifying systems associated with the Ala2,D-Leu5]enkephalin, human f3-endorphin, and dynorphin various types of opioid receptors. Undoubtedly, the endoge- 1-13 (Peninsula Laboratories, San Carlos, CA); naloxone hy- nous population of opioid ligands is heterogeneous and these drochloride (Endo Laboratories, New York); morphine sulfate different molecular forms may well subserve different receptor (Mallinckrodt); levorphanol and dextrophan tartrates (Hoff- mechanisms. mann-LaRoche); etorphine (ETP) and diprenorphine hydro- Several lines of evidence suggest that the stimuli reaching chlorides (National Institute of Drug Abuse, Rockville, MD); opioid recognition sites are often amplified by changes in the and the ethylketazocine compounds (W. Michne, Sterling- formation of cyclic nucleotides and, therefore, by cyclic nu- Winthrop, Rensselaer, NY). 3-Isobutyl-l-methylxanthine (IBMX) cleotide-regulated processes. Numerous studies have shown was from Aldrich. [3H]ETP (specific activity, 32-60 Ci/mmol; that the adenylate cyclase system of the central and peripheral 1 Ci = 3.7 X 1010 becquerels) and 125I-labeled cGMP (2'-O- nervous systems is modified by opioid administration in vivo succinyliodotyrosinemethyl ester) were from Amersham. All and in vitro (for review, see refs. 1-4). The relationship between drug doses were calculated as base content. opioid effects and the guanylate cyclase system has, however, Methods. Stock cultures ofmouse neuroblastoma cells ofthe not been fully explored. Analgesic doses of morphine cause a N4TG1 clone (a gift from K.-J. Chang, Burroughs Wellcome, dose-related increase in rat striatal cGMP content that is ster- Research Triangle Park, NC) were grown in 250-ml plastic flasks eoselective and blocked by naltrexone (5). In addition, mor- (Falcon) in Dulbecco's modified Eagle's medium (GIBCO)/ phine and the enkephalin pentapeptides increase cGMP ac- 5% fetal calf serum (GIBCO or M. A. Bioproducts, Bethesda, MD) supplemented with penicillin G at 25 units/ml and strep- The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise- Abbreviations: IBMX, 3-isobutyl-1-methylxanthine; ETP, etorphine. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. * To whom reprint requests should be addressed. 690 Downloaded by guest on September 26, 2021 Neurobiology: Gwynn and Costa Proc. Natl. Acad. Sci. USA 79 (1982) 691 tomycin at 25 /.g/ml (GIBCO) at 370C in humidified 95% air/ 5% CO2. Cells were subcultured using 1 mM EDTA and grown 80 to confluency (4-6 days) in 60 x 15 mm plastic Petri dishes for use in the cGMP and monolayer culture [3H]ETP binding as- says. In these studies, stationary phase cultures of passages o ~.60 16-29 were used 16 hr after their last feeding. cGMP are Details of methodology for the determinations 40 given in the legend to Fig. 1. For the [3H]ETP binding assays, monolayer cultures were incubated at 370C for various times (1-60 min) in the presence (desensitized cells) or absence (con- trol cells) ofunlabeled ETP (10-320 nM) and washed according 2 20 to the protocol B used for the cGMP determinations. After a 10-min equilibration in 2 ml of medium II (total binding) or medium 11/50 AM levoThanol (nonspecific binding), the cul- 0 1 2 3 4 5 10 15 20 tures were treated with [ H]ETP (0.2-20 nM) for 1 min (unless Time, min otherwise noted). The reaction was terminated by four rapid washes with ice-cold medium II (requiring '10 sec). Subse- FIG. 1. Time course of increase in cGMP content of N4TG1 cells caused by ETP. Monolayer cultures (passage were incubated for 20 quently, 1 ml of 1.0 M NaOH was added to each dish and ali- 19) min at 37°C in medium II and then treated with 0.32 ,M ETP (A) or quots were processed for protein and tritium determinations. 0.9% NaCl (.) (protocol A). Data represent mean ± SEM for 3-5 cul- Specific binding constituted 60-90% of total binding under tures, each assayed in duplicate. This study was repeated twice (pas- these conditions. The SAM 27 program (available from the Na- sages 20 and 21) with similar results. cGMP determinations were car- tional Institutes of Health) was used to calculate the apparent ried out at 37°C. The growth medium was removed and each dish Kj and the maximum number of binding sites. was washed twice with 4 ml of medium I (137 mM NaCl/7.8 mM Na2HPO4/2.7 mM KC1/1.5 mM KH2PO4/0.9 mM CaCl2/0.5 mM RESULTS MgCl2/5.6 mM glucose, pH 7.2). After a 10-min equilibration period, medium I was replaced with 2 ml of medium II (medium 1/0.5 mM Characteristics of the Elevation of cGMP Content Caused IBMX). From this point, protocol B was followed when desensitization by Opiate Receptor Agonists. In N4TG1 cells treated with 0.5 was being measured and protocol A was followed when it was not. In mM IBMX, the addition of 0.32 AM ETP caused a rapid tran- protocol A, cultures were incubated in medium II for 20 min and then sient elevation of intracellular cGMP content (Fig. 1). The treated with the test drug for 1 min. In protocol B, cultures were first in II in presence or cGMP content 70% increase 20 sec, incubated medium the (desensitizing condition) attained ofthe maximal by absence (desensitization control) of various drugs for 20 min, washed peaked at 1 min, and decreased to control values by 5 min. This four times with 4 ml of medium II, and, after a 10-min equilibration rapid decrease is due to a combination offactors, including re- in 2 ml of medium II, treated with the test drug for 1 min.
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