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PubMed1986

[Tifluadom, a benzodiazepine with opioid-like activity: study of its central mechanism of action in conscious dogs].

A derivative of the 1,4-benzodiazepine series with reported opioid activity was evaluated in regard to its effect on central nervous activity in the awake canine. Additionally a possible benzodiazepine- or opioid-receptor interaction was evaluated by using specific antagonists. In 10 experiments increasing doses of tifluadom (5, 10, 20, 40, 80 micrograms/kg) modified somato-sensory-evoked potentials (SEP) inducing a dose-related latency change (40-80 micrograms/kg) and a suppression (80 micrograms/kg) of the P50-peak. Both effects are interpreted as a modification of stimuli reaching the somatosensory cortex. EEG-spectral analysis was characterized by a dose-related decrease of power in the higher frequency range (13-40 Hz) accompanied by an increase of power in the lower band (0.5-3.5 Hz). This effect was paralleled by deep sedation. The specific benzodiazepine antagonist Ro 15-1788 (240 micrograms/kg) was ineffective in reversing central nervous EEG- and SEP-changes. Naloxone (20 micrograms/kg) induced a short-term (5 min) arousal and a partial reversal of SEP-changes. The specific opioid-kappa-antagonist Mr 2266 (20 micrograms/kg) however, induced a long lasting return of power spectra and SEP-changes back to control. This results suggest that tifluadom, although being structurally a benzodiazepine, interacts with an opioid sub-receptor of the kappa-type, which is known to induce sedation and supraspinal analgesia without respiratory depression.

Animals↗
PubMed1987

Kappa opioids in rhesus monkeys. II. Analysis of the antagonistic actions of quadazocine and beta-funaltrexamine.

In rhesus monkeys, kappa opioid agonists have been shown to increase urinary output, increase tail-withdrawal latencies from warm water and produce distinct discriminative stimulus effects. In order to explore further the relation between these effects and activity at the kappa opioid receptor type, the antagonist activity of quadazocine against several kappa opioid agonists was examined with the tail-withdrawal and drug-discrimination procedures. Quadazocine dose dependently antagonized the increases in tail-withdrawal latency produced by the kappa agonists bremazocine, ethylketazocine and U-50, 488, as well as the discriminative stimulus effects of these drugs. The dose-ratio analysis of Schild revealed apparent pA2 values for quadazocine in combination with bremazocine, ethylketazocine and U-50, 488 of 6.1, 6.4 and 6.4, respectively, with the tail-withdrawal procedure and 6.3, 6.4 and 6.1, respectively, with the drug-discrimination procedure. Quadazocine also antagonized the effects of a mu agonist (morphine) in the tail-withdrawal procedure, and the apparent pA2 value for these data was 8.2. The activity of the mu-selective alkylating agent, beta-funaltrexamine (beta-FNA), was examined alone and in combination with the kappa agonist ethylketazocine in the urinary-output, tail-withdrawal and drug-discrimination procedures. At about 30 to 60 min postinjection, beta-FNA alone produced ethylketazocine-appropriate responding under the drug-discrimination procedure and increased urine output but did not increase tail-withdrawal latencies. At 24 to 48 hr postinjection, beta-FNA did not antagonize effects of ethylketazocine in any of the three procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Kappa opioids in rhesus monkeys. III. Dependence associated with chronic administration.

The kappa opioid agonists, Mr 2033 and U-50, 488, or the mu opioid agonist, morphine, were administered chronically to three separate groups of rhesus monkeys. Tolerance developed to the overt signs of intoxication produced by each compound. Monkeys receiving morphine were not cross-tolerant to Mr 2033 or to U-50, 488, and monkeys receiving U-50, 488 were not cross-tolerant to morphine. Monkeys given Mr 2033 chronically were, however, cross-tolerant to morphine. When administration of U-50,488 was interrupted, or the monkeys receiving this compound were given an opioid antagonist, withdrawal behaviors were displayed that were qualitatively different from deprivation or antagonist-induced morphine withdrawal. These signs were suppressed by kappa agonists but not by morphine. Deprivation-induced withdrawal from Mr 2033 resulted in signs similar to those shown by U-50,488-dependent monkeys and some signs were observed in withdrawn morphine-dependent monkeys. Several antagonists, including the mu-selective antagonist beta-funaltrexamine, precipitated signs of withdrawal normally associated with morphine dependence in Mr 2033-dependent monkeys. Withdrawal from Mr 2033 was suppressed by kappa agonists in a stereoselective manner, and by morphine. The asymmetrical cross-tolerance and cross-dependence between Mr 2033 and morphine, and the appearance of morphine-like signs during precipitated withdrawal, suggest that Mr 2033 is kappa receptor selective but not specific. Dependence to U-50,488, however, was qualitatively and pharmacologically distinct from morphine-dependence and is apparently a consequence of specific activity at kappa receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

[Characteristics of the development of postural asymmetry in rats as affected by the opioids met-enkephalin and the kappa-agonist bremazocine].

It has been found that bremazocine and met-enkephalin induce postural asymmetry in spinal rats under subarachnoidal and intravenous administration. Intravenous administration of bremazocine to intact animals--even if after it (an hour later) their spinal cord is sectioned--produces no asymmetry, i. e. the spinal cord section is necessary for asymmetry development. The magnitude of postural asymmetry and the side of limb flexion are not constant for each animal, but they change in time. Though, on the average, the percent of asymmetric animals and the ratio of left and right flexions in each group of animals are practically constant. When the spinal cord is sectioned at the T1-T4 level, the bremazocine and metenkephalin induce mainly the right-leg flexion: when the section is made at the T5-T9 level, the left-leg is bent, i. e. the flexion side depends on the level of the section. It is suggested that the ability of opioids to induce postural asymmetry is based on lateralization of opioid receptors in the rat spinal cord.

Analgesics↗
PubMed1987

Bremazocine-induced urination in rats of different sizes.

The increased urine output after injection of the kappa agonist bremazocine was determined in rats of various body weights. Rats of all sizes were sensitive to the diuretic effect of bremazocine. The total diuretic effect was greater in heavier animals. The urine output plateaued between 4-5 ml/100 g body weight irrespective of body weight at the higher doses of bremazocine.

Analgesics↗
PubMed1986

[Reinforcing, but no analgesic, effect of opioid stimulation of the ventral tegmental area].

Analgesic and secondary reinforcing effects of morphine, bremazocine and phencyclidine microinjections into ventral tegmental area were studied in rats. The drugs under study failed to affect nociceptive reactions produced by thermal, mechanic and electrical stimuli. Morphine and phencyclidine have shown reinforcing properties in place preference paradigm. Ventral tegmental area seems to be a triggering zone of the reinforcing, and not analgesic effect of opioid agonists, with an important role of mu- and sigma-receptors revealed.

Analgesics↗
PubMed1986

Effects of bremazocine on passive avoidance behaviour in mice.

The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avoidance apparatus. In a first set of experiments, memory impairments following immediately posttraining bremazocine administration (0.025 and 0.05 but not 0.01 mg/kg), and memory improvements following immediately posttraining administration of the kappa-opioid-receptor antagonist MR-1452 (1.0 and 2.0 but not 0.5 mg/kg), were observed. No effect was evident when the drugs were injected starting 120 min after training. In a second set of experiments, the effects of bremazocine (0.05 mg/kg) were antagonized by a per se ineffective dose of MR-1452 (0.5 mg/kg), suggesting involvement of kappa-opioid-receptors. In a third set of experiments, the effects of bremazocine were enhanced by a per se ineffective (15 min) immobilization stress, and were decreased by familiarization with the passive avoidance apparatus. The results are discussed in terms of attenuation of emotionality following bremazocine administration.

Analgesics↗
PubMed1987

Effects of mixed agonist-antagonist opioids on the acquisition of conditional discriminations in monkeys.

Responding in patas monkeys was maintained under a multiple schedule of food presentation. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). The mixed agonist-antagonists dezocine, GPA 1657 and nalbuphine each produced dose-related decreases in the overall rate of responding in each component of the multiple schedule. In general each drug produced greater rate-decreasing effects in the learning than in the performance component, although this differential effect between components was less apparent with dezocine. In the learning component low doses of nalbuphine and GPA 1657 produced small increases in percentage of errors but had little or no effect on response rate. A similar effect was obtained with dezocine in only one of four subjects tested. At doses which produced comparable rate-decreasing effects dezocine also exerted the least disruptive effect on the within-session pattern of acquisition. High doses of each drug disrupted accuracy in each component of the multiple schedule. In contrast to the other drugs tested, buprenorphine had virtually no effect on response rate or percentage of errors in either component of the multiple schedule across a wide range of doses (0.01-3.2 mg/kg). The results suggest that, among the mixed agonist-antagonist, buprenorphine is unique in that it does not disrupt the acquisition or performance of complex discrimination in patas monkeys.

Animals↗
PubMed1985

Antagonistic and rate-suppressing effects of opioid antagonists in the pigeon.

Pigeons trained to peck a key on a fixed-ratio 20 schedule of food presentation were used to evaluate the antagonistic and rate-suppressing effects of several opioid antagonists. Antagonism was measured as an increase in the dose of morphine necessary to suppress responding. Antagonist pretreatments increased the suppressing dose of morphine, although the magnitude of the increase varied markedly among different antagonists. Rank order of the maximum increase in the suppressing dose of morphine that each antagonist produced was: naltrexone = WIN 44,441 greater than beta-funaltrexamine greater than naloxone = buprenorphine greater than MR 2266 greater than diprenorphine. The time course of morphine antagonism also differed among antagonists. For example, buprenorphine was not an effective antagonist when administered 10 min before morphine, but was effective when administered either 2 or 12 hr before morphine. beta-Funaltrexamine and WIN 44,441 had the longest durations of antagonist action; each antagonized the rate-suppressing effects of morphine from 10 min to 24 hr. The effective antagonistic dose range (i.e., doses which blocked the rate-suppressing effects of morphine without affecting response rate when administered alone) and maximum increase in the suppressing dose of morphine were highly correlated, suggesting that the direct effects of most of these antagonists on responding may limit their effectiveness as morphine antagonists.

Animals↗
PubMed1984

A novel phencyclidine analog interacts selectively with mu opioid receptors.

A new potent analgesic drug, 1-(1-phenylcyclohexyl)-4-phenyl-4-piperidinol (PCP-4-Ph-4-OH), derived from phencyclidine was tested for its interactions with different types of opioid receptors. The antinociceptive effect of PCP-4-Ph-4-OH in the mouse writhing test (ED50 = 0.3 mg/kg) is reversed by low doses of naloxone (pA2 = 6.98). The potency of PCP-4-Ph-OH in the inhibition of the electrically induced contractions of the guinea-pig ileum (IC50 = 17 nM) is 8-fold higher than that in the mouse vas deferens preparation (IC50 = 130 nM). The concentration of naloxone required to double the IC50 (Ke) of PCP-4-Ph-4-OH is 1.5 to 1.9 nM in both preparations. In opioid radioreceptor assays, PCP-4-Ph-4-OH displays 60- to-300 fold higher affinity for the [3H] dihydromorphine (mu) and D-[3H]Ala2-MePhe-Gly-ol5-enkephalin (mu) binding sites than for D-[3H]Ala2-D-Leu5-enkephalin (delta) sites in rat brain and [3H]bremazocine (kappa) sites in guinea-pig cerebellar membrane preparations. These results suggest that PCP-4-Ph-4-OH interacts with high affinity and selectivity with mu opioid receptors.

Analgesia↗
PubMed1984

[Binding sites of opiates and endogenous opioids in the oocytes of the toad Bufo viridis].

The binding of labelled naloxone, morphine and (D-Ala2,D-Leu5)enkephalin (DADL) to oocyte membranes of the toad Bufo viridis was investigated. The opiate antagonist naloxone binds to the membranes much more effectively than morphine or DADL. The binding of [3H]naloxone is reversible and saturating. The bound [3H]naloxone is readily replaced by unlabelled naloxone or bremazocine (kappa-agonist), far less effectively by morphine (mu-agonist) and SKF 10.047 (sigma-agonist) and is not practically replaced by DADL (delta-agonist), beta-endorphin (epsilon-agonist) and other neuropeptides. Analysis of experimental results in Scatchard plots revealed two types of binding sites with a high (Kd = 15 nM) and low (Kd = 10(3) nM) affinity for naloxone. The number of sites responsible for the binding of naloxone possessing a high affinity is 16 pmol-/mg of oocyte homogenate protein, i.e., 20-50 times as great as in the toad or rat brain. Trypsin and p-chloromercurybenzoate decrease the binding of [3H]naloxone. The oocyte extract is capable of replacing the membrane-bound [3H]naloxone, on the one hand, and of inhibiting the smooth muscle contracture of the rabbit vas deferens, on the other. This inhibition is reversed by naloxone and can also be induced by bremazocine, but not by morphine, DADL and SKF 10.047. In all probability oocytes contain compounds that are similar to opiate kappa-agonists. It may also be possible that these compounds mediate their effects via specific receptors and are involved in the control over maturation of oocytes and early development of toad eggs.

Animals↗
PubMed1983

Mr 2033 CL--a novel non-morphine-like opioid analgesic.

Mr 2033 CL is a very potent non-morphine-like opioid analgesic as shown in different test models and animal species. On a weight for weight basis, it is about 20 times more potent than morphine. The analgesic effects of Mr 2033 CL are supposed to be different from those of morphine and bremazocine because of individual sensitivity against selective antagonists like naloxone and Mr 2266 CL. Mr 2033 CL does not induce the Straub tail phenomenon and increased circling movements in mice, catatonia in rats, and stupor in rabbits which are characteristic for mu agonists. Moreover, Mr 2033 CL does not have a morphine-like abuse potential in rats, dogs and rhesus monkeys. CNS-depressive effects were observed in different species. Respiratory depression and inhibition of intestinal transit seem to be of minor degree. In contrast to morphine, Mr 2033 CL provokes diuresis in rats. Binding studies in rats as well as dependence studies in rats and rhesus monkeys characterize Mr 2033 CL as a predominant kappa agonist with morphine antagonistic properties.

Analgesics, Opioid↗
PubMed1983

Further study of kappa opioids on increased urination.

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two kappa agonists, U-50,488H and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at kappa opioid receptors. Mu agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas kappa agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. Kappa agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas mu agonists were still effective in decreasing urination. The data are consistent with the hypothesis that kappa agonists inhibit release of vasopressin from the neurohypophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on mu and kappa receptors in vivo.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1983

A kappa opioid effect: increased urination in the rat.

The effects of various opioids (mu agonists, kappa agonists and mixed agonists/antagonists) were determined on urination in the normally dehydrated rat. Opioids considered as kappa agonists (bremazocine, ethylketazocine and ketazocine) produced a marked dose-related increase in urination. The mixed agonists/antagonists (cyclazocine, butorphanol and nalorphine) produced less urination than the kappa agonists, but more than the mu agonists (morphine and l-methadone). The mu agonists did not increase urine output compared with controls. The increased urination effect was blocked by opioid antagonists in a potency order which indicated that the effect was due to an action at a kappa opioid receptor. The data suggest the hypothesis that dynorphin, a kappa agonist, acts as an endogenous ligand for an autoreceptor which inhibits the corelease of dynorphin and antidiuretic hormone from the neurohypophysis. This decrease in antidiuretic hormone levels produces the increased urination. Increased urination is a simple in vivo test for studying the actions of compounds at kappa opioid receptors.

Animals↗
PubMed1983

Actions of opiate antagonists with selective receptor interactions in hemorrhagic shock.

The broad-spectrum opiate antagonist naloxone has been shown previously to reverse hypotension and improve survival in hemorrhaged animals. Three new opiate antagonists with different receptor affinities and activities were utilized to investigate the role of the "mu"- and "kappa"-receptors in hemorrhagic shock. Cats in hemorrhagic shock (40 mm Hg for 150 min) and shamshock controls were given J-7747 (delta-antagonist), C-7000 (delta-antagonist and k-agonist) or MR-2266 (k-antagonist). Shock cats given the delta-antagonist J-7747 had a significantly higher final MABP than cats given vehicle as did the cats given C-7000, the delta-antagonist k-agonist. However, the k-antagonist MR-2266 did not result in a significantly greater MABP than untreated hemorrhaged cats. Both J-7747 and C-7000 significantly prevented the increase in plasma MDF activity observed in untreated shock cats, but MR-2266 did not. These results indicate that opiate receptors other than at k-receptor sites are involved in the pathophysiology of hemorrhagic shock. Our findings also introduce the possibility of the therapeutic use of opiate antagonist-analgesics that induce analgesia via the kappa receptor.

Animals↗