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At least 775 records · Page 43Linked to original sources
PubMed2003

Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.

Agonists at delta, mu, and kappa opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.

Analgesics, Opioid↗
PubMed2004

Bremazocine increases C-type natriuretic peptide levels in aqueous humor and enhances outflow facility.

A relatively selective agonist of kappa opioid receptors (KOR), bremazocine (BRE), lowers intraocular pressure in rabbits, in part, by increasing natriuretic peptide levels in aqueous humor and by enhancing total outflow facility (TOF). Natriuretic peptide (NP) levels [atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)] were measured in aqueous humor of rabbits either by radioimmunoassay or enzyme immunoassay. TOF was determined in rabbits by two-level constant pressure perfusion of the anterior chamber. Experimental regimens included topical treatment with BRE in the presence or absence of KOR antagonist (norbinaltorphimine), protein kinase C inhibitor (chelerythrine), and natriuretic peptide receptor antagonist (isatin). The rank order of basal NP levels in aqueous humor of rabbits was BNP CNP > ANP. Topical administration of BRE (1-100 microg) caused dose-related elevations of CNP levels in aqueous humor that were inhibited by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or chelerythrine (10 microg, bilaterally). Topically administered BRE (100 microg) also elevated levels of ANP and BNP in aqueous humor and evoked an 80% increase in TOF. The increase in TOF was antagonized by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or isatin (100 microg, bilaterally). Bremazocine induced an increase in NP (ANP, BNP, and CNP) levels and TOF in rabbits by activating KOR. The increase in CNP levels elicited by BRE was inhibited by norbinaltorphimine and chelerythrine; therefore, this event is most likely mediated by a KOR-linked activation of protein kinase C. These data provide evidence that the increase in TOF elicited by BRE was mediated by a KOR-activated paracrine effect of NPs on tissues within ocular outflow tract(s).

Analgesics↗
PubMed2005

Characterization of opioid-binding sites in zebrafish brain.

The pharmacological profile of opioid-binding sites in zebrafish brain homogenates has been studied using radiolabeled binding techniques. The nonselective antagonist [(3)H]diprenorphine binds with high affinity (K(D) = 0.27 +/- 0.08 nM and a B(max) = 212 +/- 14.3 fmol/mg protein), displaying two different binding sites with affinities of K(D1) = 0.08 +/- 0.02 nM and K(D2) = 17.8 +/- 9.18 nM. The nonselective agonist [(3)H]bremazocine also binds with high affinity to zebrafish brain membranes but only displays one single binding site with a K(D) = 1.1 +/- 0.09 nM and a B(max) = 705 +/- 19.3 fmol/mg protein. Competition binding assays using [(3)H]diprenorphine and several unlabeled ligands were performed. The synthetic selective agonists for mammalian opioid receptors DPDPE ([DPen(2),D-Pen(5)]-enkephalin), DAMGO ([D-Ala(2),NMe-Phe(4),Gly(5)-ol]-enkephalin), and U69,593 [(5alpha,7alpha,8beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide] failed to effectively displace [(3)H]diprenorphine binding, whereas nonselective ligands and the endogenous opioid peptides such as dynorphin A showed good affinities in the nanomolar range, although several of the endogenous peptides only displaced approximately 50% of the specifically bound [(3)H]diprenorphine. Our results provide evidence that, although the selective synthetic compounds for mammalian receptors do not fully recognize the opioid-binding sites in zebrafish brain, the activity of the endogenous zebrafish opioid system might not significantly differ from that displayed by the mammalian opioid system. Hence, the study of zebrafish opioid activity may contribute to an understanding of endogenous opioid systems in higher vertebrates.

Animals↗
PubMed2002

Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis.

There is increasing evidence that kappa-opioid receptor agonists modulate cocaine-maintained behavior, and limited findings implicate the involvement of kappa-opioid receptors in ethanol-maintained behaviors. The purpose of the present study was to investigate the effects of bremazocine, a kappa-opioid agonist, on the self-administration of smoked cocaine base and oral ethanol in rhesus monkeys (Macaca mulatta). To determine the selectivity of bremazocine, the effects of bremazocine pretreatment on the oral self-administration of phencyclidine (PCP), saccharin, and food were also examined. Adult male rhesus monkeys were trained to self-administer oral ethanol, PCP, saccharin (n = 8), food (n = 6), or smoked cocaine base (n = 6) and water during daily sessions. Bremazocine (0.00032-, 0.001-, and 0.0025-mg/kg i.m.) injections were given 15 min before session. The 4 days of stable behavior before pretreatment served as baseline. Demand curves (consumption x fixed ratio; FR) were obtained for smoked cocaine base, ethanol, and PCP by varying the cost (FR) of drug deliveries and measuring consumption (deliveries). Bremazocine (0.001 mg/kg) was administered at each FR value in nonsystematic order. Results indicate that bremazocine dose dependently reduced cocaine, ethanol, PCP, and saccharin intake. Food intake was affected less by bremazocine than the other substances in five of the six monkeys. Generally, bremazocine treatment reduced the demand for cocaine, ethanol, and PCP as well as other measures of response strength. These results extend the findings that kappa-agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys.

Administration, Oral↗
PubMed2004

Reciprocal regulation of agonist and inverse agonist signaling efficacy upon short-term treatment of the human delta-opioid receptor with an inverse agonist.

Rapid regulation of receptor signaling by agonist ligands is widely accepted, whereas short-term adaptation to inverse agonists has been little documented. In the present study, guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding and cAMP accumulation assays were used to assess the consequences of 30-min exposure to the inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) (1 microM) on delta-opioid receptor signaling efficacy. ICI174864 pretreatment increased maximal effect (E(max)) for the partial agonist Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (TIPP) at the two levels of the signaling cascade, whereas E(max) values for more efficacious agonists like (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) and bremazocine were increased in [(35)S]GTPgammaS binding but not in cAMP accumulation assays. Pre-exposure to ICI174864 also induced a shift to the left in dose-response curves for bremazocine and TIPP. On the other hand, E(max) for the inverse agonist H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH was reduced in both assays, but no changes in potency were observed. For the weaker inverse agonist naloxone, E(max) in [(35)S]GTPgammaS binding was drastically modified because the drug turned from inverse agonist to agonist after ICI174864 pretreatment. Likewise, ICI174864 turned from inverse agonist to agonist when tested in cAMP accumulation assays. In both cases, inversion of efficacy was concomitant with marked increase in potency for agonist effects. Together with functional changes, short-term treatment with ICI174864 reduced basal receptor phosphorylation and increased immunoreactivity for Galpha(i3) in membrane preparations. Functional consequences of ICI174864 pretreatment were simulated in the cubic ternary complex model by increasing receptor/G protein coupling or G protein amount available for interaction with the receptor. Taken together, these data show that inverse agonists may induce rapid regulation in receptor signaling efficacy.

Benzomorphans↗
PubMed2004

Efficacy as a vector: the relative prevalence and paucity of inverse agonism.

This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.

Animals↗
PubMed1986

14-beta-Methyl-8-oxacyclorphan (BC-3016), a morphinan derivative with high affinity for kappa opioid receptor: comparison with dynorphin-A(1-13).

14-beta-Methyl-8-oxacyclorphan (BC-3016) was tested for its ability to depress the electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with the binding of prototype ligands selective for kappa-, mu-, or delta-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum. BC-3016 was a very potent agonist in the GPI and MVD preparations, with ID50 of 0.7 and 31 nM, respectively. The activity of levorphanol, a standard alkaloid related to BC-3016, was much lower in both assays with ID50 values of 44 and 86 nM, respectively. Conversely, the activity of BC-3016 was quite comparable to that of dynorphin-A(1-13) in both preparations. In the GPI assay, a putative kappa-receptor antagonist, MR-2266, was 6.6 and 5.5 times more potent than naloxone in blocking the activity of BC-3016 and dynorphin-A(1-13), respectively. BC-3016 was also very potent in displacing bound [3H]ethylketocyclazocine ([3H]EKC) to membrane preparations of the guinea pig cerebellum, a brain component containing predominantly kappa-opioid receptors (Ki of 0.58 nM). Its potency in the displacement of the bound mu-ligand, 3H-labelled (D-Ala2,MePhe4,Gly-OH5)-enkephalin ([3H]DAGO), to rat brain homogenates was somewhat lower (Ki of 0.8 nM) but still high when compared with its ability to displace the delta-ligand, 3H-labelled (D-Ser2, Thr6)-Leu-enkephalin ([3H]DSLET) to rat brain homogenates (Ki of 4.45 nM). The affinity of BC-3016 for the opioid receptor was 2.1-fold higher than that of U-50488H, a selective kappa-opioid ligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Enhancement of [3H]DAGO1 binding to rat brain by low concentrations of monovalent cations.

The effects of mono- and di-valent cations and the nonhydrolyzable guanyl nucleotide derivative 5'-guanylimidodiphosphate (Gpp(NH)p) on the binding of the selective, high affinity mu-opiate receptor agonist, [3H]DAGO ([3H]Tyr-D-Ala-Gly-Mephe-Gly-ol), to rat brain membranes were studied in a low ionic strength 5 mM Tris-HCl buffer. Na+ and Li+ (50 mM) maximally increased [3H]DAGO binding (EC50 values for Na+, 2.9 mM and Li+, 6.2 mM) by revealing a population of low affinity binding sites. The density of high affinity [3H]DAGO binding sites was unaffected by Na+ and Li+, but was maximally increased by 50 mM K+ and Rb+ (EC50 values for K+, 8.5 mM and Rb+, 12.9 mM). Divalent cations (Ca2+, Mg2+; 50 mM) inhibited [3H]DAGO binding. Gpp(NH)p decreased the affinity of [3H]DAGO binding, an effect that was enhanced by Na+ but not by K+. The binding of the mu-agonist [3H]dihydromorphine was unaffected by 50 mM Na+ in 5 mM Tris-HCl. In 50 mM Tris-HCl, Na+ (50 mM) inhibited [3H]DAGO binding by decreasing the density of high affinity binding sites and promoting low affinity binding. The effects of Na+ in 5 mM and 50 mM Tris-HCl were also investigated on the binding of other opiate receptor agonists and antagonists. [3H]D-Ala-D-Leu-enkephalin binding was increased and inhibited. [3H]etorphine binding increased and was unchanged, and both [3H]bremazocine and [3H]naloxone binding increased by 50 mM Na+ in 5 mM and 50 mM Tris-HCl, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Vascular effects of some opioid receptor agonists.

Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2 alpha, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2 alpha-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone. MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Inhibition of cardiac sarcolemmal Na+/H+ antiporter by opioids.

In our routine screening of chemicals that would inhibit cardiac sarcolemmal Na+/H+ antiporter, we discovered that some of the opioids produced inhibition of cardiac sarcolemmal Na+/H+ antiporter in micromolar concentrations. Using U-50,488H, a selective kappa-opioid agonist, we characterized the nature of interaction between opioids and the Na+/H+ antiporter. The inhibitory effect of U-50,488H on Na+/H+ antiporter was immediate and reversible, and was not mediated through the interaction with the opioid receptors but due to the direct interaction of U-50,488H with the Na+/H+ antiporter. The kinetic data show that in the presence of U-50,488H the Km for Na+ was increased from 2.5 +/- 0.2 to 5.0 +/- 0.3 mM, while the Vmax (52.0 +/- 5.0 nmol.mg-1.min-1) remained the same. These results suggest that U-50,488H and Na+ compete for the same site on the antiporter. When testing the effect of U-50,488H on other transport systems of cardiac sarcolemma, we found that U-50,488H also inhibited Na+/Ca2+ antiporter and Na+/K+ pump but at much higher concentrations suggesting that U-50,488H shows some degree of selectivity for cardiac sarcolemmal Na+/H+ antiporter. When we compared the inhibitory potency of U-50,488H with amiloride and its analog, namely 5-(N,N-hexamethylene)amiloride, we found that U-50,488H (IC50 = 100 +/- 15 microM) was threefold more potent than amiloride (IC50 = 300 +/- 20 microM) but it was three-fold less potent than the amiloride analog (IC50 = 30 +/- 10 microM) in inhibiting cardiac sarcolemmal Na+/H+ antiporter. These results show that although U-50,488H is more potent than amiloride, the inhibitory characteristics of U-50,488H on cardiac sarcolemmal Na+/H+ antiporter are similar to amiloride.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Atrial natriuretic polypeptide secretion via selective activation of kappa-opioid receptor: role of dynorphin.

The present study was designed to investigate the direct effect of dynorphin on atrial natriuretic polypeptide (ANP) secretion in cultured rat atrial cardiocytes via a kappa-opioid receptor activation as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) system in the secretion of ANP from cardiocytes. Dynorphin stimulated ANP secretion dose and time dependently from 2-day cultured atrial cardiocytes. The dynorphin-induced ANP secretion was partially antagonized by MR2266, a selective kappa-opioid receptor antagonist. U-62066E, a selective kappa-opioid receptor agonist, stimulated ANP secretion. This stimulation was also antagonized by MR2266. However, no stimulation of ANP secretion was seen with [D-Ala2,D-Leu5]enkephalin, methionine (Met)-enkephalin, or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. Dynorphin at 10(-6) M significantly decreased the production of cAMP in the cultured cardiocytes. However, 10(-6) M Met-enkephalin had no effect on cAMP at all. The decrease in cAMP production by the addition of dynorphin was partially antagonized with a simultaneous addition of MR2266. The dynorphin-induced ANP secretion, as well as the basal secretion, were significantly decreased by the addition of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, as compared with the respective controls. Dibutyryl cAMP at 10(-3) M significantly decreased the basal secretion of ANP as compared with the control. Therefore, the present studies show that dynorphin selectively stimulates ANP secretion, at least in part, via the activation of a specific kappa-opioid receptor.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Kappa-opioid peptide receptor stimulation increases cytosolic pH and myofilament responsiveness to Ca2+ in cardiac myocytes.

Although kappa- and delta-opioid receptors on mammalian cardiac myocytes have been discovered recently, the intracellular effects that result from stimulation of these receptors remain unknown. We examine the effects of a rapid and brief exposure to a kappa-opioid receptor agonist on intracellular Ca2+, pH, and cell length in individual isolated rat ventricular cells. The specific kappa-agonist trans-dl-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzene-acetamide (U-50488H) (methane sulfonate salt) caused a transient increase in cytosolic pH (pHi) measured from the change in SNARF-1 fluorescence and an increase in cytosolic [Ca2+] (Cai), indexed by a change in indo-1 fluorescence. The initial Cai increase often was followed by Cai oscillations. Both pHi and Cai effects were blocked by the specific antagonist kappa-opioid receptor l-(N-furylmethyl)-alpha-normetazocine methane-sulfonate (Mr 1452). The amplitude of contraction that accompanied the Cai increase elicited by U-50488H was greater than that associated with a similar increase in Cai elicited by electrical stimulation or by the rapid exposure of cells to caffeine. Thus an acute and brief kappa-opioid receptor stimulation of cardiac cells leads to an increase in Cai and pHi. The pHi increase was abolished by 1) blockade of the Na(+)-H+ exchanger by ethyl isopropyl amiloride and 2) inhibition of protein kinase C (PKC) activity via pretreatment with staurosporine or prolonged incubation with 4 beta-phorbol 12-myristate 13-acetate. These maneuvers did not abolish the U-50488H-induced increase in Ca.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Opioid receptor-mediated inhibition of omega-conotoxin GVIA-sensitive calcium channel currents in rat intracardiac neurons.

Modulation of depolarization-activated ionic conductances by opioid receptor agonists was investigated in isolated parasympathetic neurons from neonatal rat intracardiac ganglia by using the whole cell perforated patch clamp technique. Met-enkephalin (10 muM) altered the action potential waveform, reducing the maximum amplitude and slowing the rate of rise and repolarization but the afterhyperpolarization was not appreciably altered. Under voltage clamp, 10 muM Met-enkephalin selectively and reversibly inhibited the peak amplitude of high-voltage-activated Ca2+ channel currents elicited at 0 mV by approximately 52% and increased three- to fourfold the time to peak. Met-enkephalin had no effect on the voltage dependence of steady-state inactivation but shifted the voltage dependence of activation to more positive membrane potentials whereby stronger depolarization was required to open Ca2+ channels. Half-maximal inhibition of Ba2+ current (IBa) amplitude was obtained with 270 nM Met-enkephalin or Leu-enkephalin. The opioid receptor subtype selective agonists, DAMGO and DADLE, but not DPDPE, inhibited IBa and were antagonized by the opioid receptor antagonists, naloxone and naltrindole with IC50s of 84 nM and 1 muM, respectively. The kappa-opioid receptor agonists, bremazocine and dynorphin A, did not affect Ca2+ channel current amplitude or kinetics. Taken together, these data suggest that enkephalin-induced inhibition of Ca2+ channels in rat intracardiac neurons is mediated primarily by the mu-opioid receptor type. Addition of Met-enkephalin after exposure to 300 nM omega-conotoxin GVIA, which blocked approximately 75% of the total Ca2+ channel current, failed to cause a further decrease of the residual current. Met-enkephalin inhibited the omega-conotoxin GVIA-sensitive but not the omega-conotoxin-insensitive IBa in rat intracardiac neurons. Dialysis of the cell with a GTP-free intracellular solution or preincubation of the neurons in Pertussis toxin (PTX) abolished the attenuation of IBa by Met-enkephalin, suggesting the involvement of a PTX-sensitive Gprotein in the signal transduction pathway. The activation of mu-opioid receptors and subsequent inhibition of N-type Ca2+ channels in the soma and terminals of postganglionic intracardiac neurons is likely to inhibit the release of ACh and thereby regulate vagal transmission to the mammalian heart.

Acetylcholine↗
PubMed1999

Site-specific effects of the nonsteroidal anti-inflammatory drug lysine clonixinate on rat brain opioid receptors.

In addition to effects in the periphery through inhibition of prostaglandin synthesis, several lines of evidence suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) act in the central nervous system. The possibility that the central action of NSAIDs involves regulation of opioid receptors was investigated by quantitative autoradiography of mu, delta, and kappa sites in rat brain slices. Increased (p < 0.05) labeling of mu receptors was observed in thalamic nuclei, gyrus dentate, and layers of the parietal cortex of rats treated for 10 days with lysine clonixinate. Labeling of delta receptors was lower in the lateral septum, and kappa sites decreased in thalamic nuclei. These effects were not mediated through direct interaction with opioid-binding sites, since receptor-binding assays using rat brain membranes confirmed that clonixinate up to 1 x 10(-4) mol/l does not inhibit mu, delta, and kappa receptor specific binding. Central effects of NSAIDs might, therefore, involve interaction with the opioid receptor system through indirect mechanisms.

Analgesics↗
PubMed2002

Effect of bremazocine, a kappa-opioid receptor agonist, on inositol phosphate formation in isolated iris-ciliary bodies.

The goal of the current study was to examine the effect of the kappa-opioid agonist, bremazocine (BRE), on inositol phosphate (IP) formation in the rabbit iris-ciliary body (ICB). Concentrations of BRE (10(-7) to 10(-5) M) augmented levels of IP. Incubation of ICBs with BRE (10(-6) M) produced a time-dependent increase in IP levels that peaked at 60 s and declined to basal levels by 5 min. The increase in IP levels produced by BRE (10(-6) M) was inhibited by the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI, 10(-7) to 10(-5) M) and by activation of PKC with PDBu (10(-7) M). These results demonstrate that kappa-opioid receptor activation by BRE in the rabbit ICB is linked to IP production. Thus, opioid agonist-induced increases in IP activity could play a role in BRE-induced increases in atrial natriuretic peptide release and alterations in aqueous humor dynamics.

Animals↗
PubMedDate not supplied

kappa-Opioid receptor functions: possible relevance to experimental allergic encephalomyelitis.

The present study deals with the influence of preferential kappa-opioid agonist MR 2034 on experimental allergic encephalomyelitis (EAE). For this purpose, 9-week-old male Dark August rats were treated intraperitoneally with 0.2 mg/kg of MR 2034 as follows: (a) from the day of EAE induction until sacrifice; (b) from the day of EAE induction until the appearance of neurological signs, and (c) from the appearance of neurological signs until sacrifice. Repeated injections of MR 2034 given during the whole period of observation produced the most pronounced suppression of EAE clinical signs, histological lesions in the brain and spinal cord, and anti-myelin basic protein antibody production. These results suggest that kappa-opioid receptors may be involved in the development of EAE.

Animals↗
PubMed1985

Effects of opioid agonists and antagonists on oxytocin and vasopressin release in vitro.

The rat neurohypophysis contains both opioid receptors and substantial amounts of endogenous opioid peptides. Inhibitory influences of opioids on the secretion of both oxytocin and vasopressin have been described. We have examined the effects of a range of opioid agonists and antagonists with differing relative selectivities towards opioid receptor subclasses on the secretion of oxytocin and vasopressin from the isolated neurohypophysis. Oxytocin and vasopressin release evoked by brief periods of electrical stimulation in control experiments was compared to evoked release in the presence of test compounds. Oxytocin release was depressed approximately 25% by the delta-agonist (D-Ala2, D-Leu5)-enkephalin but not affected by putative kappa-agonists or by beta-endorphin. The use of opioid antagonists revealed a strong inhibition of oxytocin secretion by endogenous opioids released during electrical stimulation. Naloxone, relatively mu-selective, enhanced oxytocin secretion by up to 90% with a half-maximal effect at approximately 10(-6) M. MR2266, a relatively kappa-selective antagonist also enhanced oxytocin secretion but displayed agonist-like activity at high concentrations. ICI 154129, a delta-selective antagonist, was without effect on oxytocin secretion. Vasopressin release was unaffected by any of the agonists tested and not potentiated by antagonists at a range of stimulation frequencies. The data do not support the suggestion of an inhibitory endogenous opioid influence over vasopressin secretion within the neurohypophysis but indicate that an endogenous opioid peptide, possibly acting via mu- or kappa rather than delta-receptors, strongly suppresses the secretion of oxytocin.

Animals↗
PubMed1986

Opioid kappa receptors and the secretion of prolactin (PRL) and growth hormone (GH) in the rat. I. Effects of opioid kappa receptor agonists bremazocine and U-50,488 on secretion of PRL and GH: comparison with morphine.

The effects of bremazocine and U-50,488, two selective opioid kappa receptor agonists, and the preferential mu receptor agonist morphine on the secretion of PRL and GH were compared in conscious male rats bearing permanent right atrial cannulae for serial blood sampling and drug delivery. All three opioids stimulated PRL secretion in a dose-related manner, but the kappa agonists differed from morphine in several respects. They were considerably more potent than morphine in triggering a PRL response, but were unable to elevate PRL levels to more than 100 ng/ml, whereas morphine, at the highest dose (4.5 mg/kg), induced an almost twice larger response. Also their PRL-releasing effect was inhibited more strongly by the preferential kappa receptor antagonist Mr-2266 than by naloxone, whereas Mr-2266 and naloxone, which are equipotent as antagonists of the mu receptors, were equipotent in suppressing the PRL-stimulating effect of morphine, a mu agonist. In a complete contrast to morphine, which effectively stimulated GH secretion, the kappa agonists had no effect on GH release at lower doses and suppressed it at higher doses. It is concluded that the PRL-releasing effect of the kappa agonists is mediated by the kappa receptors which may participate with the mu receptors in regulation of PRL secretion by opioids. The GH-inhibiting effect of the kappa agonists requires further clarification.

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