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PubMed1985

Central and peripheral involvement of mu receptors in gastric secretory effects of opioids in the dog.

The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions dermorphin and morphine, infused systemically at graded doses, produced a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphin. Under these conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output 'per se' from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that mu receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.

Animals↗
PubMed1987

Peripheral opioid receptors mediate gastrointestinal secretory and motor effects of dermorphin N-terminal tetrapeptide (NTT) in the dog.

Dermorphin N-terminal-tetrapeptide-amide (NTT) increased both basal and pentagastrin- or histamine-induced secretion in conscious dogs chronically implanted with both gastric fistulae and Heidenhain pouches. These excitatory effects were significantly prevented by the opioid receptor antagonists naloxone and N-methyl-levallorphan-methanesulphonate. In conscious dogs fitted with electrodes and strain-gauges in different parts of gastrointestinal tract, a premature phase III of the migrating myoelectric complex (MMC) in the duodeno-jejunum was triggered by NTT, while the activity of the antrum was not significantly modified. Further, the peptide enhanced the contractile activity of both proximal and distal portions of the colon, including a long-lasting period of increased muscle tone on the distal colon. Either naloxone or N-methyl-levallorphan-methanesulphonate completely prevented motor effects of NTT on gastrointestinal tract. It is concluded that NTT displays significant opiate-like activity on gastric acid secretion and intestinal motility of the dog by activating peripheral mu opioid receptors.

Animals↗
PubMed1995

Modulation by mu-opioid agonists of guanosine-5'-O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells.

The ability of mu-opioid agonists to activate G proteins has been demonstrated by studying the binding of the GTP analogue guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) to membranes from the human neuroblastoma SH-SY5Y cell line. The potent opioid agonist fentanyl caused an approximate doubling of basal [35S]GTP gamma S binding in a naloxone-sensitive manner, confirming this to be an opioid receptor-mediated process. The presence of GDP was necessary to observe this effect. Pretreatment of the cells with pertussis toxin (100 ng/ml, for 24 hr) completely prevented the fentanyl-stimulated increase in [35S]GTP gamma S binding and lowered the basal binding of [35S]GTP gamma S. These latter data suggest an involvement of Gi and/or Go proteins and their activation by added membrane-bound receptors even in the absence of agonist. The order of potency of a series of opioid agonists in stimulating the binding of [35S]GTP gamma S was buprenorphine > cyclazocine = levallorphan > nalorphine > [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) > fentanyl > morphine > pentazocine. DAMGO, fentanyl, and morphine were full agonists but the remaining compounds showed decreasing levels of intrinsic activity in the order buprenorphine > pentazocine > cyclazocine = nalorphine > levallorphan. The opioid antagonist naloxone was without effect. Under the conditions of the [35S]GTP gamma S assay, binding of agonists was to a high affinity site, indicating that a high agonist affinity state of the mu-opioid receptor is responsible for the observed stimulation of [35S]GTP gamma S binding. The level of [35S]GTP gamma S binding (597 fmol/mg of protein) stimulated by DAMGO was 2-fold greater than the maximal number of mu-opioid agonist binding sites (Bmax) determined using [3H]DAMGO (254 fmol/mg of protein). The opioid agonist-mediated stimulation of [35S]GTP gamma S binding in SH-SY5Y cell membranes thus provides a "functional" measure of agonist occupation of mu-opioid receptors and offers a simple method for the determination of efficacy and intrinsic activity of mu-opioid agonists.

Diprenorphine↗
PubMed1999

Liquid chromatography-fast atom bombardment mass spectrometry for detection and determination of pentazocine in human tissues.

A reliable and sensitive method was developed for the detection and determination of pentazocine in human solid tissues using liquid chromatography-dynamic fast atom bombardment (FAB) mass spectrometry, combined with a three-step liquid-liquid extraction procedure. Levallorphan tartrate served as an internal standard. The extract was evaporated to dryness and dissolved in the mobile phase, acetonitrile-10 mM ammonium acetate solution (20:80, pH 4.0) containing 0.5% glycerol as FAB matrix. The eluent was pumped at a flow rate of 25 microl/min and split before introduction to FAB mass spectrometer. Quantitative analysis was carried out by means of monitoring quasi-molecular ions with m/z 286 for pentazocine and m/z 284 for levallorphan. The lower limit of detection of pentazocine in each tissue tested was 1 ng/g with scan mode and 0.1 ng/g with SIM mode. Using this method, the concentrations of pentazocine were determined in the tissues of an autopsied individual to perform toxicological evaluation.

Aged↗
PubMed1983

Enkephalins and opiate antagonists control calmodulin distribution in neuroblastoma-glioma cells.

The calcium binding protein calmodulin and the opiate receptor binding sites are unevenly distributed in various subcellular fractions of neuroblastoma-glioma NG108-15 cells. The crude mitochondrial-membrane fraction of these cells contains two membrane fractions that are separable by sucrose gradient centrifugation. These two differ in the content of both calmodulin and opiate receptors. Leucine enkephalin and D-Ala2-methionine enkephalinamide decrease the amount of membrane-bound calmodulin in the NC108-15 cells in a time- and dose-dependent manner, whereas the opiate antagonists naloxone and levallorphan have an opposite effect. Naloxone blocks the effect of leucine enkephalin and dextrallorphan has no significant effect. The opiate alkaloids entorphine and phenazocine induce changes similar to that of the enkephalins whereas morphine is inactive even at high concentrations. The alteration in the amount of membrane-bound calmodulin after a short incubation (15 min) with the enkephalins or with naloxone is reflected as an opposite change in the amount of calmodulin in the cell cytosol. Naloxone and levallorphan also increase the number of opiate receptors in NG108-15 cells but dextrallorphan has no such effect. Modulation of the intracellular distribution of calmodulin by opioid peptides and alkaloids may control the activity of various membrane-bound and cytosolic systems that are calmodulin- and/or calcium-dependent.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Enhancement of a nociceptive reaction by opioid antagonists in mice.

1. The opioid antagonists, naloxone, GPA 2163, levallorphan and Mr-2266 reduced the latency of the jumping reaction of mice in the hot plate test. The (+)-isomers of levallorphan and Mr-2266 which are devoid of antagonistic activity did not increase this latency. 2. In the same nociceptive reaction test, the enhancing effect of naloxone progressed in a dose-range similar to that required for the antagonism by naloxone of the depressive action of morphine. 3. The facilitatory effect of naloxone was not blocked by the previous administration of morphine or etorphine but it was prevented by pretreatment with a high dose of buprenorphine. 4. The antagonism by naloxone of morphine and of buprenorphine did not follow the same pattern. 5. The factors which are or may be involved in the efficacy of naloxone in enhancing nociceptive reactions are discussed. 6. The enhancing effect of naloxone may be due to an antagonism of endogenous ligands for the opiate receptor. If so, these ligands would be involved in reaction to but not in perception of nociceptive stimuli which need not be harmful ones.

Animals↗
PubMed1989

Swim-stress-induced antinociception in young rats.

1. Opioid and non-opioid mechanisms have been implicated in the phenomenon of stress-induced antinociception in adult rodents. We have studied stress-induced antinociception in developing rats and characterized differences in the neurochemical basis of this effect in pre- and post-weanling animals. 2. Twenty and 25 day old rats were stressed using warm water (20 degrees C) swimming for 3 or 10 min periods and antinociception was assessed by the tail immersion test (50 degrees C). 3. A 3 min swim in 20 and 25 day old rats produced marked antinociception which was blocked by naloxone, Mr 1452, 16-methyl cyprenorphine and levallorphan but not Mr 1453 or N-methyl levallorphan. The delta-opioid receptor antagonist ICI 174,864 attenuated stress-induced antinociception in 25 day old rats but was without effect in 20 day old animals. 4. A 10 min swim in 25 day old rats produced antinociception which was non-opioid in nature. In contrast, antinociception was not observed in 20 day old rats after a 10 min swim-stress. 5. Pretreatment of animals with dexamethasone blocked 3 min swim-stress antinociception in 20 and 25 day old animals but had no effect on antinociception induced by a 10 min swim. 6. Swim-stress-induced antinociception can be observed in young rats and dissociated into opioid and non-opioid types dependent on the duration of swimming stress. The non-opioid type appears to develop more slowly and cannot be observed in preweanling rats. The opioid type is a predominantly mu-receptor phenomenon in preweanling animals but delta-receptor components are observable in postweanling rats.

Aging↗
PubMed1996

Reversible inhibition of cholinesterases by opioids: possible pharmacological consequences.

The inhibitory potency of opioids belonging to different structural categories on electric eel and rat brain acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was investigated. The phenylazepine meptazinol, the pyrrolo-[2,3-b]-indole derivative eseroline and the benzomorphan normetazocine were the most potent inhibitors of AChE among the compounds tested. These were followed by (-)-metazocine, N-allylnorcyclazocine, 3-(1,3-dimethyl-3-pyrrodinyl)-phenol, levallorphan, levorphanol and pentazocine. The opioids which inhibited horse serum BuChE were in order of potency: meptazinol, methadone, profadol, levallorphan and 1,2,3-trimethyl-3-(3-hydroxyphenyl)-piperidine. The results of this work appear consistent with the fact that the anticholinesterase activity of the opioids is not confined to specific structural categories, although conformationally constrained molecules, like those of morphinans, benzomorphans or pyrrolo-[2,3-b]-indoles, appear to favour affinity for AChE, whereas highly flexible molecules, like those of acyclic opioids, inhibit BuChE in a rather selective way. In all cases, the inhibitory action of opioids markedly differed from that of carbamates or organophosphorous compounds, in that it was time-independent and immediately reversible on dilution. In general the anticholinesterase action of opioids does not seem to influence appreciably the pharmacological properties of the drugs since it is evidenced at drug doses higher than those which are analgesic. However, in the case of mixed agonist/antagonist opioids with rather weak analgesic activity, the enzyme inhibition caused by the levels of circulating drugs can be so marked as to exert also a cholinergic component of action.

Acetylcholinesterase↗
PubMed1978

Morphine-induced changes in cyclic AMP metabolism and protein kinase activity in the brain.

The effects of consecutive oral administration of morphine on the cyclic AMP synthesizing system and cyclic AMP dependent protein kinase activity in the cerebral cortex of mice were examined. The administration of morphine (2--4 weeks) induced an increase of the cyclic AMP formation by activating adenylate cyclase, whereas responses of the cyclic AMP synthesizing system to biogenic amines (norepinephrine, dopamine and histamine) added in vitro was found to be significantly attenuated in these animals. Cyclic AMP dependent protein kinase activity in the cerebral cortex was also increased following a consecutive oral administration of morphine. These changes in the activities of adenylate cyclase and protein kinase were found mainly in crude mitochondrial and/or synaptosomal fractions. Morphine induced decrease in the response of the cyclic AMP synthesizing system to biogenic amines was rapidly reversed, and a significant increase of the cyclic AMP formation in the presence of added norepinephrine compared with that found in morphinized animals was observed following the administration of levallorphan, a narcotic antagonist. On the other hand, the changes in adenylate cyclase and cyclic AMP dependent protein kinase activities were not affected significantly by levallorphan administration. These results suggest that alterations in activities of cyclic AMP synthesizing system and of cyclic AMP dependent protein kinase may be involved in processes of the formation of morphine dependence. Possible involvement of abrupt increments in the sensitivity of "norepinephrine receptor-adenylate cyclase" system and a subsequent increase in cerebral cyclic AMP is also suggested as a cause of morphine withdrawal syndrome.

Adrenalectomy↗
PubMed1976

Effects of opiate agonists and antagonists on central neurons of the cat.

Morphine, naloxone, nalorphine, levorphanol, dextrorphan and levallorphan were ejected electrophoretically from micropipettes near cholinoceptive and noncholinoceptive cells of the spinal cord, ventrobasal thalamus and cerebral cortex of decerebrate and barbiturate-anesthetized cats. Morphine excited those cells having nicotinic receptors for acetylcholine. Naloxone and nalorphine reduced the action of morphine and acetylcholine on these cells but not the effects of excitant amino acids. Levorphanol excited spinal neurons also excited by acetylcholine, an effect antagonized by naloxone, but also showed atropine-like activity when ejected for prolonged periods. Dextrorphan depressed the firing of both cholinoceptive and noncholinoceptive spinal neurons. Levallorphan reduced the effects of both acetylcholine and excitant amino acids on spinal neurons. The depressant effects of morphine and levorphanol on noncholinoceptive spinal neurons were not antagonized by naloxone.

Acetylcholine↗
PubMed1989

Discriminative stimulus effects of mu and kappa opioids in the pigeon: analysis of the effects of full and partial mu and kappa agonists.

Pigeons were trained to discriminate a dose of either 0.01 mg/kg of bremazocine or 0.05 mg/kg of fentanyl from water using a two-key drug discrimination procedure. During tests of substitution, the selective kappa-opioid agonists bremazocine, U50, 488 and tifluadom substituted for the bremazocine stimulus, whereas the less selective kappa-opioid agonists ethylketocyclazocine, levallorphan, proxorphan and nalorphine substituted for the fentanyl stimulus. The full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol, as well as the partial agonists nalbuphine, butorphanol and buprenorphine, substituted for the fentanyl stimulus. Compounds with partial-opioid agonist effects, namely nalbuphine, butorphanol, buprenorphine, proxorphan, levallorphan and nalorphine, produced 50% fentanyl-appropriate responding at doses 25 to 369.2 times smaller than the doses required to decrease response rates to 50% of control values. In contrast, the full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol produced 50% fentanyl-appropriate responding at doses only 1.3 to 10.9 times smaller than those required to decrease response rates by 50%. During tests of antagonism, both naloxone and Mr2266 produced a dose-dependent attenuation of the stimulus effects of bremazocine and fentanyl, whereas beta-funaltrexamine antagonized the stimulus effects of fentanyl but not bremazocine. Although bremazocine has been reported to have mu-opioid antagonist effects, it failed to antagonize the stimulus effects of the training dose of fentanyl. The present investigation establishes further that pigeons can discriminate selective kappa-opioid agonists from mu-opioid agonists and that in pigeons the classification of numerous opioid compounds on the basis of their kappa-like or mu-like stimulus effects differ from those in rat and monkey. In addition, under the drug discrimination procedure the actions of compounds classified as partial-opioid agonists can be differentiated from those of full mu-opioid agonists on the basis of the ratio of the dose required to engender fentanyl-like stimulus effects to the dose required to reduce response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1978

Discriminative effects of cyclazocine in the squirrel monkey.

In order to characterize the discriminative stimulus properties of cyclazocine squirrel monkeys were trained to discriminate between intramuscular injections of 0.1 mg/kg of cyclazocine and drug vehicle in a discrete-trial avoidance paradigm in which a response on one of two levers would prevent or terminate the delivery of a mild electric shock to the tail. Behavior was considered to be under stimulus control when the monkeys completed at least 22 trials of a 25-trial session on the appropriate choice lever after they received cyclazocine or vehicle. Stimulus generalization (i.e., dose-response) curves were then determined for a variety of drugs over a broad range of doses. The following analgesics with narcotic antagonist properties produced stimulus control of behavior comparable to that produced by 0.1 mg/kg of cyclazocine: ketocyclazocine (0.1 mg/kg), butorphanol (1.0 mg/kg), oxilorphan (3.0 mg/kg) and levallorphan (3.0 mg/kg). Time course experiments revealed that the duration of complete stimulus control was relatively short: 1 hour after 0.1 mg/kg of cyclazocine and 3.0 mg/kg of oxilorphan and 0.5 hour after 0.1 mg/kg of ketocyclazocine. Naloxone produced a dose-related antagonism of the stimulus control by cyclazocine and butorphanol which was complete at 1.0 mg/kg. In contrast, as much as 10 mg/kg of naloxone only partially blocked stimulus control by ketocyclazocine and failed to modify stimulus control by oxilorphan and levallorphan. The monkeys showed partial generalization to other drugs with activity as narcotic agonists, antagonists or both (e.g., morphine, naloxone, pentazocine, nalbuphine, nalmexone and nalorphine), but little or no generalization to the nonopioid psychoactive drugs, d-amphetamine, mescaline, pentobarbital and scopolamine. This discrimination paradigm appears to have potential as a model for the quantitative assessment of the discriminative stimulus properties of narcotic antagonist analgesics.

Animals↗
PubMed1983

Behavioral studies of shaking behavior induced by thyrotropin-releasing hormone and morphine withdrawal in rats.

A behavioral study was performed in an attempt to understand the neuronal mechanisms involved in wet dog body shaking in rats induced by the administration of thyrotropin-releasing hormone (TRH). The body shaking evoked by TRH (10 mg/kg, i.p.) was not affected by pretreatment with methysergide, scopolamine, levallorphan or phentolamine, but was inhibited by clonidine, haloperidol and reserpine. Body shaking behavior was also elicited by injection of levallorphan to morphine-dependent rats. The morphine-withdrawal body shaking was antagonized by pretreatment with TRH in the doses (10, 20 mg/kg, i.p.) which alone induced body shaking. A dose of TRH (10 mg/kg, i.p.) which induces body shaking in control rats, was without effect in morphine-dependent rats that had undergone withdrawal. The present results imply that TRH-induced body shaking is not associated with the increased activity of serotonergic, cholinergic and enkephalinergic neurons in the brain, and also its mechanisms seem to be different from that of morphine-withdrawal body shaking.

Animals↗
PubMed1994

Kappa agonist and antagonist properties of mixed action opioids in a pigeon drug discrimination procedure.

Previous investigations indicate that mixed action opioids (i.e., opioids with activity at a combination of opioid receptor sites or a combination of opioid and nonopioid sites) often possess kappa-like stimulus effects in the rat and monkey, but mu-like stimulus effects in pigeons. In the present investigation, the kappa agonist and antagonist actions of a series of mixed action opioids were examined in pigeons trained to discriminate a 0.017-mg/kg dose of the kappa agonist bremazocine from saline. The mixed-action opioids (-)-n-allylnormetazocine, (-)-cyclazocine, (-)-metazocine, levallorphan, buprenorphine, nalbuphine, butorphanol and nalorphine failed to substitute for the bremazocine stimulus. When administered in combination with the training dose of bremazocine, each of these opioids produced a dose-related antagonism of the bremazocine stimulus. With the exceptions of butorphanol and (-)-metazocine, the antagonist effects of these opioids were surmountable. Buprenorphine, (-)-n-allylnormetazocine and levallorphan produced their kappa antagonist effects at doses approximately 2 to 3 log units lower than those that decreased rates of responding when these opioids were administered alone, whereas approximately 1 log unit separated the kappa antagonist and rate-decreasing effects of nalorphine, nalbuphine and (-)-cyclazocine. In contrast, the kappa antagonist effects of butorphanol and (-)-metazocine were observed only at doses of markedly decreased response rates. A somewhat different profile was obtained with ethylketocyclazocine and ketocyclazocine in that these mixed action opioids produced partial substitution for and partial antagonism of the bremazocine stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences.

The stimulus effects of selective, high efficacy mu opioids and mixed action opioids with varying degrees of intrinsic efficacy at the mu receptor were examined in pigeons trained to discriminate between saline and either 0.056 (low) or 0.18 (high) mg/kg of fentanyl. The stimulus profiles produced by the various opioids could be separated into three groups: 1) opioids that substituted completely for both training doses of fentanyl, with steep slopes and little interanimal differences in the lowest dose (lowest discriminable dose) that produced complete substitution (fentanyl, morphine and l-alpha-acetylmethadol); 2) opioids that substituted completely for the low training dose and produced high levels of substitution for the high training dose, with relatively shallow slopes and interanimal differences in the lowest discriminable dose (butorphanol, buprenorphine, ethylketocyclazocine, ketocyclazocine, proxorphan, (-)-pentazocine and (-)-metazocine); and 3) opioids that substituted completely for the low training dose, with relatively shallow slopes and large interanimal differences in the lowest discriminable dose. Each of these opioids also antagonized the high-dose fentanyl stimulus with large interanimal differences in the lowest antagonist dose (nalbuphine, nalorphine, (-)-cyclorphan, (-)-cyclazocine, (-)-n-ally-normetazocine and levallorphan). These patterns of substitution and antagonism most likely reflect differences in the intrinsic efficacy of these drugs at the mu receptor, with low intrinsic efficacy associated with shallow dose-effect functions, large interanimal differences in the drug's lowest discriminable dose and low levels of substitution for the high-dose fentanyl stimulus. During antagonism tests with naloxone, two patterns were observed: 1) opioids against which naloxone had apparent pA2 values of approximately 7.0, with little interanimal differences and with the slopes of the Schild plots approximating -1.0 (fentanyl and morphine) and 2) opioids against which naloxone had apparent pA2 values an order of magnitude higher, with large interanimal differences and with the slopes of Schild plots being relatively shallow (butorphanol, nalbuphine, nalorphine and levallorphan). The present findings emphasize the importance of training dose, intrinsic efficacy and interanimal differences when analyzing drug discrimination data.

Animals↗
PubMed1997

Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity.

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.

Analgesics↗
PubMed1999

Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor.

A C6 glioma cell line stably transfected with the human kappa opioid receptor (kappaOR) was used to characterize receptor binding and G protein activation via the kappaOR by a comprehensive series of opioid ligands. The ligand-binding affinity for [3H]5alpha,7alpha, 8beta(-)-N-methyl-N-(7-Cl-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl)benzene acetamide (U69593) was similar to that observed in monkey brain membranes and was 10-fold lower in the presence of sodium and GDP. Both peptide and nonpeptide agonists maximally stimulated [35S]GTPgammaS binding. The stimulation of [35S]GTPgammaS binding was blocked by pretreatment of cells with pertussis toxin. Partial stimulation of [35S]GTPgammaS binding via the kappaOR was observed for several ligands that are antagonists at the mu opioid receptor, suggesting an additional mechanism of drug action. The ability of isomers of tifluadom and levallorphan to stimulate [35S]GTPgammaS binding indicates that the chiral carbon of levallorphan, a benzomorphan derivative, imparts a greater degree of stereoselectivity than does the chiral carbon in the benzodiazepine derivative tifluadom. In addition, (-)tifluadom, the less potent isomer of tifluadom, which is also a gamma-aminobutyric acidA receptor agonist, stimulated [35S]GTPgammaS binding. In contrast, d-pentazocine, (+)SKF10047, (+)cyclazocine, and d-ethylketocyclazocine displayed no agonist activity. kappaOR-selective antagonist norbinaltorphimine competitively inhibited the stimulation of [35S]GTPgammaS binding by the active isomers of ethylketocyclazocine, cyclazocine, and nalorphine to the same degree, indicating that all three ligands are eliciting an effect via the kappaOR. The results suggest that these cells express a homogeneous population of kappaOR, and that their [35S]GTPgammaS-binding properties make them an excellent means to assess kappaOR efficacy.

Analgesics, Opioid↗
PubMed1976

The effect of morphine on the activity evoked in ventrolateral tract axons of the cat spinal cord.

The effect of morphine on the activity in ventrolateral tract axons was studied in intercollicularly decerebrate cats with and without spinal section. Activity was elicited by electrical stimulation of Adelta- and C-fibres in the sural nerves. In spinal animals, morphine injected intravenously in a dose as low as 0.5 mg/kg reduced the post-stimulus discharge of impulses recorded in ventrolateral tract axons below the site of transection. The depression was not only abolished but reversed by levallorphan and naloxone. Pretreatment with reserpine did not diminish the effect of morphine. The effect of morphine was considerably weaker in decerebrate cats. Reversible block of the spinal cord produced by cold revealed that morphine reduced inhibition from the brain stem controlling the impulse transmission to ventrolateral tract axons. It is concluded that a spinal effect contributes to the analgesic action of morphine.

Afferent Pathways↗