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PubMed1984

Kappa opioid receptors modulate cardiorespiratory function in hindbrain nuclei of rat.

The respiratory and cardiovascular effects of selective kappa opioid agonists were compared following microinjection (0.1 microliter) into the nucleus ambiguus (NA) and the nucleus tractus solitarius (NTS) regions of spontaneously breathing and artificially respired pentobarbital-anesthetized rats. In spontaneously breathing animals, the benzomorphan derivative MRZ 2549 (MRZ, 3 X 10(-11) to 16 X 10(-9) mol) elicited dose-related decreases of mean arterial pressure (MAP), heart rate (HR), and tidal volume (TV) following NA injection; bremazocine (BREM) decreased MAP, HR, and respiratory rate (RR). Following NTS injection, MRZ (3 X 10(-10) to 16 X 10(-9) mol) lowered MAP and TV, the highest dose also lowering HR and RR; BREM (3 X 10(-9) to 16 X 10(-9) mol) decreased MAP and HR. Naloxone (200 micrograms/kg, i.v.) reversed the respiratory effects of MRZ without consistently altering cardiovascular activity. In ventilated animals, NA injections of MRZ or BREM (3 X 10(-9) to 16 X 10(-9) mol) elicited a dose-related decrease of MAP without altering HR. These responses were not reversed by naloxone. The stereoisomer of BREM (+ BREM) was without effect at similar doses (3 X 10(-9) to 16 X 10(-9) mol). MRZ (16 X 10(-9) mol) elicited a naloxone-reversible tachycardia following NTS injection in ventilated animals; no other cardiovascular responses were observed following NTS administration of BREM (16 X 10(-9) mol) or lower doses of MRZ. Dynorphin (1-13) (6 X 10(-9) to 60 X 10(-9) mol) significantly lowered MAP without altering HR following NA microinjections in ventilated animals; the lower dose decreased MAP following NTS injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Bremazocine: an opiate that induces sedation and analgesia without respiratory depression.

The benzomorphan analogue bremazocine has been shown to be a potent analgesic with a low dependence liability and with no respiratory depressant effects in preliminary pharmacologic screening. As this compound may prove to be of potential interest to anesthesiologists, it was tested in the conscious dog in increasing doses (1, 5, 10, 20, and 40 micrograms/kg) while blood pressure, heart rate, respiratory rate, arterial blood-gas tensions, electrical cortical activity, and somatosensory-evoked potentials (SS-EVP) were recorded. Bremazocine had no significant cardiovascular or respiratory effects. Power spectral analysis of the EEG showed a dose-related increase of power in the theta to delta band. SS-EVP was characterized by a decrease in amplitude of the P45 and P70 waves and an increase in the latency of the P 100 peak. EEG and peak latency changes could be reversed by the kappa-specific antagonist Mr 2266 (20 micrograms/kg), but not by the classic opiate antagonist naloxone (20 micrograms/kg). It is suggested that kappa receptor sites distinct from those interacting with common opioids (mu) are responsible for the observed changes associated with bremazocine.

Analgesics↗
PubMed1995

Peripheral effects of naloxone in mice with acute diarrhea associated with intestinal inflammation.

The aim of the study was to evaluate the effects of centrally and peripherally acting opioid antagonists such as naloxone (NX), naloxone methiodide, (+)-naloxone [(+)NX], (-)-a-5,9-diethyl-2'-hydroxy-2 (3-furylmethyl)-6,7-benzomorphan and naltrindole on gastrointestinal (GI) transit in mice with diarrhea associated with intestinal inflammation. Our hypothesis was that diarrhea/inflammation could induce a release of endogenous opioid peptides that would play an inhibitory role in the physiological response to intestinal inflammation; the administration of opioid antagonists would uncover the effects of the endogenous opioid peptides on the gut. Diarrhea associated with inflammation was induced in mice by administration of croton oil (CO) although control animals received saline (SS); GI transit was evaluated with a charcoal meal. The i.p. administration of 0.1 mg/kg NX or NXME, induced a significant increase in GI transit in CO but not in SS-treated animals (P < .005). At the same dose, (+)NX had no effect either in CO or SS groups. The kappa antagonist MR-2266 (1 and 3 mg/kg) had no effect on GI transit in SS or CO animals. However, the delta antagonist naltrindole (3 mg/kg), caused a small but significant (P < .01) increase in GI transit in the CO group. These results suggest that endogenous opioid peptides are released in CO-treated animals and exert an inhibitory control of intestinal motility, which is unmasked by opioid antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Opioid thermal antinociception in rhesus monkeys: receptor mechanisms and temperature dependency.

The antinociceptive effects of the opioid agonists etonitazene and alfentanil, as well as the agonist/antagonists nalbuphine, [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were studied in the warm water (48 degrees and 55 degrees C) tail-withdrawal assay in rhesus monkeys. Etonitazene and alfentanil produced dose-dependent increases in tail-withdrawal latency up to the maximum possible latency of 20 sec in 48 degrees and 55 degrees C water. Nalbuphine, GPA 1657 and profadol produced the maximum possible effect only at 48 degrees C, and were ineffective at 55 degrees C. The opioid antagonist quadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazocine with alfentanil, etonitazene and nalbuphine were homogeneous (7.3-7.7 mol/kg), suggesting their effects were probably mediated by mu opioid receptors. The apparent pA2 value for GPA 1657 was significantly lower (6.2 mol/kg), suggesting GPA 1657 may have produced antinociception by a non mu receptor-mediated mechanism. The selective delta antagonist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effect of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (nor-BNI, 3.2 mg/kg) caused a small rightward shift in the GPA 1657 dose-effect curve. Nalbuphine, GPA 1657 or profadol produced a rightward shift in the alfentanil dose-effect curve in 55 degrees C water, consistent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinociceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.

Alfentanil↗
PubMed1994

In vivo apparent pA2 analysis for naltrexone antagonism of discriminative stimulus and analgesic effects of opiate agonists in rats.

Six opiate agonists were characterized by in vivo apparent pA2 analysis with respect to their discriminative stimulus, rate-decreasing and analgesic effects, by using the antagonist naltrexone. In drug discrimination experiments, rats were trained to discriminate 3.2 mg/kg of morphine from saline under a fixed-ratio 15 schedule of food reinforcement. In analgesia experiments, rat's tails were immersed into 55 degrees C water and latency for tail withdrawal was measured. Naltrexone (0.01-1.0 mg/kg) antagonized discriminative stimulus effects of all agonists, rate-decreasing effects of etorphine, morphine, fentanyl, buprenorphine and GPA 1657 [(1)-B-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan] and analgesic effects of etorphine, morphine, buprenorphine and GPA 1657. Analgesic effects of fentanyl and nalbuphine were not tested. Naltrexone apparent pA2 values across the three behavioral measures were etorphine (7.2-7.4 mol/kg), fentanyl (7.3-7.4 mol/kg), morphine (7.5-8.4 mol/kg), GPA 1657 (7.0-7.3 mol/kg), buprenorphine (7.5-7.7 mol/kg) and nalbuphine (7.7 mol/kg). Apparent pA2 values averaged 7.5 mol/kg and slopes of the naltrexone Schild regressions were not different from unity, suggesting that the measured behavioral effects of these agonists are mediated by mu opioid receptors. Nalbuphine also was used as an antagonist in the tail-withdrawal assay. The apparent pA2 values for nalbuphine were etorphine (4.9 mol/kg), morphine (5.9 mol/kg), GPA 1657 (5.7 mol/kg) and buprenorphine (5.5 mol/kg). Slopes of the Schild regressions differed, suggesting that nalbuphine's modest analgesic effects may have prevented proper conditions for an accurate Schild analysis.

Analgesia↗
PubMed1994

Effects of U-50 488H, a kappa-agonist, on action potentials of isolated ventricular papillary muscle of guinea pigs.

Trans(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzeneacetamide-methanesulfonate-hydrate (U-50 488H), a specific kappa-agonist, at 1-10 mumol.L-1 caused concentration-dependent reductions in the action potential duration at 50% and 90% of repolarization (APD50 and APD90) without modifying the resting potential (RP), the action potential amplitude (APA) and the maximal upstroke velocity (Vmax). The effects were attenuated by (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2L-hydroxy-6,7-benzomorphan (M(r) 2266 BS, 1 mumol.L-1), a specific kappa-antagonist which itself had no effect on the action potentials of the ventricular papillary muscle of guinea pigs, indicating that U-50 488H at 1-10 mumol.L-1 acts via specific cardiac kappa-receptors. At 100 mumol.L-1, U-50 488H not only shortened APD50 and APD90, but also reduced RP, APA, and Vmax, which were not attenuated by Mr 2266 BS (1 mumol.L-1) suggesting that the effects of U-50 488H at 100 mumol.L-1 were probably nonspecific.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Apparent pA2 analysis on the respiratory depressant effects of alfentanil, etonitazene, ethylketocyclazocine (EKC) and Mr2033 in rhesus monkeys.

Respiratory depression is a limiting factor in the therapeutic use of opioid analgesics. It has been suggested that respiratory depression is mediated by mu rather than kappa receptors and may involve a decrease in central nervous system sensitivity to hypercapnia. This study investigated opioid receptor mechanisms underlying respiratory depression in unanesthetized rhesus monkeys (n = 3) breathing air or 5% CO2 in air into a pressure displacement head plethysmograph. Apparent pA2 analyses of s.c. quadazocine (a mu-selective antagonist) were carried out on the effects of cumulative doses of s.c. bremazocine, ethylketocyclazocine (EKC) and (+/-)-(1-R/S,5-R/S,2 = R/S)-5,9-dimethyl-2'-hydroxy-2- tetrahydrofurfuryl-6,7-benzomorphan (Mr2033) (compounds with kappa agonist effects in other in vivo assays), alfentanil and etonitazene (compounds with mu agonist effects in other in vivo assays). Alfentanil, bremazocine, EKC and Mr2033 were approximately equipotent in causing dose-dependent depression of respiratory minute volume of CO2-stimulated and air respiration, whereas etonitazene was approximately 10-fold more potent than the above compounds. Dose-effect curves for respiratory frequency, tidal volume and respiratory minute volume for all of the agonists except bremazocine were shifted to the right by increasing quadazocine doses. Together with data previously obtained in drug discrimination and analgesia assays, results of the present study demonstrating homogeneous pA2 values for quadazocine with alfentanil, etonitazene, EKC and Mr2033 strongly suggest that the latter two compounds decrease respiratory function in rhesus monkeys by acting on mu receptors.

Alfentanil↗
PubMed1993

Increase in extracellular acetylcholine level by sigma ligands in rat frontal cortex.

The effects of sigma ligands on the central acetylcholine (ACh) systems in the rat frontal cortex were examined. By using brain microdialysis techniques, we showed that nonbenzomorphan sigma ligands, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and 1,3-di(2-tolyl)guanidine (DTG) dose-dependently increased the extracellular ACh level in this area. Similarly, benzomorphan sigma ligands, (+/-)-pentazocine and (+)-N-allylnormetazocine [(+)-SKF-10,047] also increased the extracellular ACh level. The increase in extracellular ACh level elicited by (+)-SKF-10,047 was greater than that by (-)-SKF-10,047. Moreover, the (+)-SKF-10,047- and DTG-induced increase in the extracellular ACh level were reduced significantly by simultaneous administration of haloperidol, a putative sigma receptor antagonist, whereas the (+)-SKF-10,047-induced increase was unaffected by (+/-)-3-(2- carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a competitive N-methyl-D-aspartate receptor channel antagonist. On the other hand, none of the sigma ligands tested in this study had any effects on acetylcholinesterase or choline acetyltransferase activity and sodium-dependent high affinity choline uptake site in the rat frontal cortex. Ranking of potency for increasing extracellular ACh level was in the following order: (+/-)-pentazocine > (+)-SKF-10,047 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine > DTG. This order was positively correlated with the order of binding potency for the (+)-[3H]SKF-10,047 binding site in the rat frontal cortex, but was not correlated with binding to the [3H]DTG, [3H]quinuclidinyl benzylate and [3H]AF-DX116 ([3H]11-[(2-[(dimethylamino)methyl]-1-piperidinyl)acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex.

We determined the ability of a new benzomorphan derivative [2R-[2 alpha, 3(R*),6 alpha]]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)- 6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride (BIII 277 CL) to inhibit the N-methyl-D-aspartic acid (NMDA) receptor-channel complex in vitro and in vivo. BIII 277 CL potently displaced [3H]MK-801 binding from the NMDA receptor-channel complex in synaptosomal membrane preparations from rat brain cortex (Ki = 4.49 nmol/l). It was much less effective at displacing [3H]dihydromorphine, [3H]naloxone and [3H]ditolyguanidine binding in similar membrane preparations: the Ki values were 3323, 8031 and 1017 nmol/l, respectively. BIII 277 CL did not exhibit any marked affinities for a variety of other central neurotransmitter receptors. BIII 277 CL antagonized NMDA-induced [3H]noradrenaline release (EC50 = 1.7 mumol/l) and NMDA-induced inhibition of protein synthesis in rat hippocampal slices (EC50 = 3.0 mumol/l). In mice, BIII 277 CL prevented NMDA-induced lethality (ID50 = 0.54 mg/kg s.c.) and, as expected, also caused disturbances in motor coordination in the same dose range (ED50 = 0.47 mg/kg s.c.). The duration of BIII 277 CL was much shorter than than of (+)MK-801 in both tests. Finally, BIII 277 CL (0.3 mg/kg s.c. 5 times over 24 h) reduced the cortical infarct area in mice that had been subjected previously to focal cerebral ischemia by unilateral occlusion of the middle cerebral artery. In summary, these results indicate that BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex which could be used for the treatment of acute thromboembolic stroke in humans.

Animals↗
PubMedDate not supplied

[Search for an endogenous ligand for sigma receptors].

Whether there is an endogenous ligand for sigma receptors remains unknown. A total lipid fraction was isolated from the porcine liver, which was then subjected to chromatographic separation, yielding nine chromatographic fractions eluated at various chloroform/methanol ratios: each fraction was tested for its capacity of inhibiting the binding of (+)-[3H]SKF 10047 to hepatic sigma-receptors. The chromatographic fraction 7 + 7A (eluated at chloroform/methanol ratios of 60:40-10:90) which consisted mainly of phospholipids was found to have the highest activity. However, a complex analysis of this fraction revealed no relationship of its sigma-inhibiting activity to phospholipids. It is suggested that the non-competitive inhibition of (+)-[3H]SKF 10047 binding by the isolated active fraction is due to its presence of an endogenous ligand which, interacting with sigma-2 receptor, allosterically inhibits the binding of the labelled (+)-benzomorphan.

Allosteric Regulation↗
PubMed1996

The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro.

There is increasing evidence that opiates not only have analgesic properties, but also regulate mechanisms activated during the stress response, such as the hypothalamic-pituitary-adrenal (HPA) axis. Indeed, opioid-containing neurons innervate the paraventricular nucleus and the median eminence, thus modulating inputs to ACTH-controlling neurons. In addition, dynorphin (the endogenous ligand of the kappa-opioid receptor)-like peptides have been found co-localized with corticotrophin-releasing hormone (CRH) and are believed to be co-secreted with it in the hypophyseal portal circulation to modulate ACTH release. In this study, we evaluated the effects of the selective kappa-opioid receptor agonist MR-2034 [(-)-N-(2-tetrahydrofurfuryl)-normetazocine] on the HPA axis in vivo and in vitro. MR-2034 was given intravenously to catheterized, freely moving, male Sprague-Dawley rats and serial blood samples were collected for ACTH and corticosterone (B) measurements. We evaluated also the site of MR-2034 action on the HPA axis in vivo, after the administration of alpha-helical CRH9-41, a CRH receptor antagonist, on hypothalamic CRH, pituitary ACTH, and B release in vitro. MR-2034 increased plasma ACTH and B levels in a dose-related fashion and this effect was antagonized by the selective kappa-opioid receptor antagonist MR-1452. In the presence of alpha-helical CRH9-41, the responses of plasma ACTH and B to MR-2034 were blunted significantly, suggesting that this compound activates the HPA axis through a CRH-dependent mechanism. Accordingly, MR-2034 stimulated hypothalamic CRH release in vitro in a concentration-dependent fashion and this effect was antagonized dose-dependently by MR-1452. However, the stimulatory effect of MR-2034 on plasma ACTH and B in vivo was not completely abolished by alpha-helical CRH9-41, suggesting that an additional, CRH-independent, mechanism was involved. Indeed, MR-2034 was able to stimulate basal ACTH output in a dose-dependent manner and this effect was antagonized by MR-1452 in vitro. On the other hand, MR-2034 did not have any effect on B release from adrenocortical cells or adrenal quarters in vitro. These results show that the benzomorphan MR-2034 stimulates the HPA axis in the rat by acting at the hypothalamic and the pituitary level. We hypothesize that endogenous kappa-opioid peptides not only act at the pituitary level to increase ACTH output, but may also act at the hypothalamic level to increase CRH release through an autocrine and/or ultrashort positive feedback mechanism.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Antagonistic effect of MR2266 and MR2267 on morphine or nalbuphine analgesia at the spinal levels in rats.

The aim of this paper was to study the effect of two benzomorphan derivatives MR2266 and MR2267 with predominant antagonism to kappa-opioid receptors administered intrathecally on the analgesic action of morphine and nalbuphine. Both compounds attenuated the analgesia elicited by examined opioid agonists. Our results support the hypothesis that the spinal opioid receptors take part in analgesic effect of morphine and nalbuphine. It was for the first time described that MR2267, considered as inactive enantiomer of MR2266, is an active opioid antagonist when administered intrathecally.

Analgesics, Opioid↗
PubMed1997

Naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: an opioid/sigma receptor?

A naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein was partially purified from rat liver and rat brain membranes in an affinity chromatography originally designed to purify sigma receptors. Detergent-solubilized extracts from membranes were adsorbed to Sephadex G-25 resin containing an affinity ligand for sigma receptors: N-(2- 3,4-dichlorophenyl]ethyl)-N-(6-aminohexyl)-(2-[1-pyrrolidinyl]) ethylamine (DAPE). After eluting the resin with haloperidol, a protein that bound [3H](+)SKF-10047 was detected in the eluates. However, the protein was not the sigma receptor. [3H](+)SKF-10047 binding to the protein was inhibited by the following compounds in the order of decreasing potency: (+)pentazocine > (-) pentazocine > (+/-)cyclazocine > (-)morphine > (-)naloxone > haloperidol > (+)SKF-10047 > DADLE > (-)SKF-10047. Further, the prototypic sigma receptor ligands, such as 1,3-di-o-tolylguanidine (DTG), (+)3-PPP, and progesterone, bound poorly to the protein. Tryptic digestion and heat treatment of the affinity-purified protein abolished radioligand binding. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of the partially-purified protein from the liver revealed a major diffuse band with a molecular mass of 31 kDa, a polypeptide of 65 kDa, and another polypeptide of > 97 kDa. This study demonstrates the existence of a novel protein in the rat liver and rat brain which binds opioids, benzomorphans, and haloperidol with namomolar affinity. The protein resembles the opioid/sigma receptor originally proposed by Martin et al. [(1976): J. Pharmacol. Exp. Ther., 197:517-532.]. A high degree of purification of this protein has been achieved in the present study.

Animals↗
PubMed1990

Steroid binding at sigma receptors: CNS and immunological implications.

The sigma receptor has been suggested to be the mediator of the psychomimetic effects induced by certain benzomorphan opioids and phencyclidine. Potent sigma receptor ligands include haloperidol and other 'atypical' potential antipsychotic drugs. The sigma receptor is found in the central nervous system and also in the immune and endocrine systems. Gonadal and adrenal steroids such as progesterone, testosterone, deoxycorticosterone and corticosterone were found to be competitive inhibitors of binding of the sigma receptor ligand [3H] d-SKF-10,047. The sigma receptor is not the traditionally recognized cytosolic progesterone receptor and is found in crude membrane fractions. Results from molecular modelling using geometric fitting and electrostatic potential calculations suggested that the molecular skeleton of steroid hormones shares common features with prototypic sigma ligands such as d-SKF-10,047 and that the oxygen of the C-20 carbonyl group on these steroids may represent a critical 'pharmacophore' for their interactions with sigma receptors. Comparison of the affinities of steroids at sigma receptors with their efficacies is an anti-inflammatory test yielded a striking qualitative correlation. Taken Taken together these results suggest that sigma receptors may mediate certain aspects of steroid-induced mental disturbances and alterations in immune function.

Animals↗
PubMed1995

Tricyclic CNS active agents by intramolecular Oxa-Pictet-Spengler reaction.

Mitsunobu inversion of the (S)-configurated lactate (S)-7, which is prepared in four steps starting from (S)-tyrosine, leads to the (R)-configurated lactate (R)-7. The key step in the transformation of the enantiomeric lactates (S)-7 and (R)-7 into the benzomorphan analogous tricycles (R,S)-16a,b, (S,R)-16a,b, (S,S)-22, and (R,R)-22 is an intramolecular Oxa-Pictet-Spengler reaction: The amides (S)-13, (R)-13, (S)-19 and (R)-19, in which the carbonyl moiety-masked as an acetal-is linked to the 2-phenylethanol moiety, are cyclized to give the tricyclic amides (R,S)-15, (S,R)-15, (S,S)-21, and (R,R)-21, respectively. In a concentration of 100 microM both enantiomers of 16a, 16b, and 22 are not able to compete with 3H-(+)-MK 801 for the phencyclidine binding sites of NMDA receptors. In vivo, only (R,S)-16b and (S,S)-22 exhibit weak sedative and analgesic activity.

Analgesics, Non-Narcotic↗
PubMed1989

Stereochemical influences upon the opioid ligand activities of 4-alkyl-4-arylpiperidine derivatives.

The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative.

Animals↗
PubMed1992

Characterization of specific binding sites for [3H]-1,3-di-o-tolyl-guanidine (DTG) in the rat glioma cell line C6-BU-1.

The aim of the present study was to find out if a cell line of glial origin possesses sigma and/or phencyclidine (PCP) binding sites. Binding of [3H]1,3-di-o-tolyl-guanidine (DTG), a highly selective ligand for sigma binding sites, and of [3H]N-[1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP), a radioligand specific for PCP receptors, to C6-BU-1 glioma cells was investigated. Binding of [3H]DTG to C6-BU-1 cell membranes was reversible, saturable (Bmax = 10.5 pmol/mg protein), and of high affinity (KD = 26 nM). C6-BU-1 cells do not possess PCP receptors as indicated by negligible specific binding of [3H]TCP to C6-BU-1 cell membranes. Specific binding of [3H]DTG was reduced in the presence of Ca2+ and to a lesser extent by Mg2+. The rank order of potency of various PCP and sigma ligands was DTG > (+)3-[(3-hydroxy-phenyl)-N-n-propyl-piperidine] [(+)3-PPP] > haloperidol > pentazocine > (-)3-PPP > PCP > metaphit > dextromethorphan > (-)butaclamol > (+)butaclamol > (-)N-allylnormetazocine [(-)SKF 10,047] > MK801 > (+)SKF 10,047 > ketamine. The drug specificity, confirmed by a reversed stereoselectivity for the benzomorphan opiate SKF 10,047, indicated that these sites correspond to a subtype of sigma binding sites, the so-called sigma 2 binding site. Thus, the C6-BU-1 cell line is the first glial cell line demonstrated to have sigma 2 binding sites.

Animals↗
PubMed1983

Interaction of cyclazocine and the sympathetic nervous system.

Cyclazocine, a benzomorphan derivative narcotic agonist-antagonist, reduced the uptake of tritiated norepinephrine and reduced the recovery of [3H]3,4-dihydroxymandelic acid, but did not significantly alter the recovery of [3H]normetanephrine in the rat heart in vivo. Cyclazocine also reduced endogenous levels of norepinephrine in the rat heart. Comparatively, desipramine reduced the uptake of [3H]norepinephrine, the recovery of [3H]3,4-dihydroxymandelic acid, and the recovery of [3H]normetanephrine in the rat heart in vivo. Further, cyclazocine added to the perfusion medium or administered systemically reduced the uptake of radiolabeled norepinephrine by the isolated rat heart. The cyclazocine-induced decrease in the accumulation of [3H]norepinephrine in the rat heart in vivo and in vitro presumably is due to an alteration of sympathetic function through the inhibition of neuronal uptake. It is further suggested that cyclazocine has other actions on the sympathetic nervous system, such as promoting neurotransmitter release.

Animals↗