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At least 721 records · Page 40Linked to original sources
PubMed1998

Anesthesia in a Baird's tapir (Tapirus bairdii).

A Baird's tapir (Tapirus bairdii) was satisfactorily immobilized on two occasions with i.m. detomidine (0.065-0.13 mg/kg) and butorphanol (0.13-0.2 mg/kg). On the second occasion, anesthesia was induced by i.v. administration of ketamine (2.2 mg/kg). Twenty minutes later, endotracheal intubation was performed after an additional i.v. injection of ketamine (1.5 mg/kg). Anesthesia was maintained with isoflurane, which provided excellent conditions for radiology and surgery. Anesthesia was associated with hypoxemia when the tapir was allowed to breathe air and with hypoventilation. Mean arterial pressure remained satisfactory. No antagonist drugs were administered, and recovery from anesthesia was rapid and smooth.

Analgesics↗
PubMed1991

Cross-tolerance and enhanced sensitivity to the response rate-decreasing effects of opioids with varying degrees of efficacy at the mu receptor.

The purpose of the present experiment was to determine whether the effects of opioids with varying degrees of efficacy at the mu receptor are differentially altered in morphine-tolerant pigeons. To this end, dose-effect curves were determined for high, intermediate, and low efficacy mu agonists in pigeons responding under a schedule of food presentation prior to, during, and after exposure to a regimen of chronic morphine administration. In pigeons treated with 56 mg/kg/daily morphine, the dose-effect curves for the rate-decreasing effects of the high-efficacy mu agonists morphine and fentanyl were shifted to the right of their prechronic positions (i.e., tolerance). A small degree of tolerance was also conferred to the intermediate-efficacy mu agonists (-)-pentazocine and (-)-metazocine, but not to nalbuphine or butorphanol. In contrast to the effects obtained with these mu agonists, the chronic morphine regimen shifted the dose-effects curves of the mu antagonist naloxone and the low-efficacy mu agonists nalorphine and levallorphan to the left of their prechronic positions (i.e., enhanced sensitivity). These findings demonstrate that morphine tolerance confers cross-tolerance to other high efficacy mu agonists, enhanced sensitivity to mu antagonists and low efficacy mu agonists, and little or no cross-tolerance to intermediate efficacy mu agonists. Disadvantages of using schedule-controlled responding to examine the effects of intermediate efficacy mu agonists are discussed.

Animals↗
PubMed1995

A method to estimate the potency of the mu-component of an opioid having mixed mu-, and kappa- and/or delta-agonist activities.

The SC administration of either typical mu-agonists such as morphine, pethidine, fentanyl and levorphanol or a mixed mu- and delta-agonist like [D-Ala2, D-Leu5]-enkephalin to 10-day-old rats produced loss of righting reflex. Additionally, the loss of righting reflex induced by these opioid agonists was antagonized by naloxone, an opioid antagonist having a preference for mu-receptors, but by neither nor-binaltorphimine nor naltrindole, a specific kappa- or delta-antagonist, respectively, indicating that the loss of righting reflex was produced by the interaction of an opioid with mu-receptors. Moreover, the potency of each opioid agonist relative to that of morphine estimated by the present in vivo method was similar to that determined by the traditional in vitro isolated preparation. In contrast to mu-agonists, neither typical kappa-agonists such as U-50, 488H, ketocyclazocine, pentazocine and butorphanol, nor a selective delta-agonist like [D-Pen2, D-Pen5]-enkephalin affected the righting reflex of 10-day-old rats, indicating that mu-agonists, but neither kappa- nor delta-agonists, produced the naloxone-reversible loss of righting reflex in infant rats. By employing the present in vivo method to estimate the mu-agonist activity of an opioid with mixed agonist activities, it was indicated that the mu-agonist activity of ethylketocyclazocine, which had been employed as a representative kappa-agonist, was essentially the same as that of morphine, a representative mu-agonist.

Animals↗
PubMed1994

Antagonism of the discriminative stimulus effects of the kappa-opioid agonist spiradoline.

This study compared the potency of mixed-action opioids (i.e., agonist-antagonists) and pure antagonists to block the discriminative stimulus effects of spiradoline, a kappa-opioid agonist. Rats were trained to discriminate between 3.0 mg/kg spiradoline and saline (SC) in a two-choice discrete-trial procedure. Graded doses of test drugs were administered in combination with 3.0 mg/kg spiradoline and the dose that reduced selection of the spiradoline-appropriate choice lever by 50% (AD50) was calculated. Ten drugs blocked the discriminative effects of spiradoline in an orderly dose-dependent manner. They spanned a 150-fold potency range from diprenorphine (5 times as potent as naloxone) to nalbuphine (0.03 times as potent as naloxone). Antagonism was stereoselective: 0.1-1.0 mg/kg (-)-N-allylnormetazocine (NANM) reduced spiradoline-appropriate responding by 50% whereas 3.0 mg/kg (+)-NANM did not. (-)-Pentazocine (0.1-10 mg/kg) and butorphanol (0.1-3.0 mg/kg) also did not block the discriminative effects of spiradoline. Antagonism was surmountable when graded doses of spiradoline were tested with a fixed dose of diprenorphine, naloxone, or levallorphan. Apparent pKB values derived from the interactions between those three drugs and spiradoline were in accord with relative antagonist potencies based upon the AD50s. Because the potency of a competitive antagonist is determined by its receptor affinity, the relative potencies of mixed-action opioids and pure antagonists in blocking the discriminative stimulus effects of spiradoline can provide an estimate of the relative in vivo affinities of these drugs for the kappa-opioid receptor.

Analgesics↗
PubMed2002

Characterization of the discriminative stimulus effects of buprenorphine in pigeons.

RATIONALE: Buprenorphine is a low-efficacy mu opioid agonist that can reduce drug taking in opioid abusers; however, the mechanism by which buprenorphine modifies the actions of other drug taking and the consequences of repeated treatment with buprenorphine are not fully understood. OBJECTIVE: The purposes of this study were to evaluate the time- and dose-dependence of discriminative stimulus effects in pigeons receiving buprenorphine repeatedly and to examine possible interactions between buprenorphine and heroin. METHODS: Six pigeons discriminated between vehicle and 0.178 mg/kg buprenorphine while responding under an FR schedule for food. Substitution and drug combination studies characterized the potency and time course for buprenorphine, as well as interactions between buprenorphine and heroin. RESULTS: Stimulus control by buprenorphine was maintained throughout the study and was not changed by repeated daily dosing or by an acute injection of large doses of buprenorphine. Mu opioid agonists substituted for buprenorphine with the following order of potency: heroin > or = butorphanol > nalbuphine > or = morphine. Ketamine, enadoline, spiradoline, amphetamine and cocaine failed to substitute completely for buprenorphine. The discriminative stimulus effects of buprenorphine lasted 2-72 h, depending on dose, and naltrexone prevented but did not reverse the effects of buprenorphine. CONCLUSION: Despite a very long duration of action and apparent irreversibility, under these conditions in pigeons, buprenorphine does not modulate the discriminative stimulus effects of itself or heroin. Thus, simple agonism might account for the therapeutic effectiveness of buprenorphine in opioid abusers.

Animals↗
PubMed2005

Behavioral assessment of temporal summation in the rat: sensitivity to sex, opioids and modulation by NMDA receptor antagonists.

RATIONALE: Temporal summation of pain reflects a perceived increase in nociceptive sensitivity following repeated noxious stimulation that can last for approximately 15 s-2 min. This short-lasting change in nociceptive sensitivity has been used as a model to examine factors that influence the central processing of pain and the mechanisms underlying some chronic pain conditions. OBJECTIVE: The purpose of this study was to develop a behavioral procedure to induce temporal summation in rats and determine the sensitivity of temporal summation (i.e., decrease tail-withdrawal latency following repeated presentations of a nociceptive thermal stimulus) to various parametric manipulations, sex, modulation by the N-methyl-D-aspartate (NMDA) receptor system, and sensitivity to reversal by opioids. RESULTS: The magnitude of temporal summation generally decreased with increases in the inter-nociceptive stimulus interval, and increased with increases in both the nociceptive stimulus intensity and the number of nociceptive stimulus presentations. Temporal summation was short-lived, evident 3.0 s after the final nociceptive stimulus presentation, but not after 30 s. Males displayed slightly higher levels of temporal summation than females. The non-competitive NMDA antagonists ketamine (3.0-30 mg/kg), dizocilpine (0.03-0.1 mg/kg) and dextromethorphan (10-30 mg/kg) attenuated the level of temporal summation at doses that failed to produce antinociceptive effects (warm water tail-withdrawal procedure). In an antinociception procedure, the opioids morphine (3.0-10 mg/kg), buprenorphine (0.3-3.0 mg/kg), butorphanol (3.0-30 mg/kg) and spiradoline (10-30 mg/kg) were more potent in males, whereas these opioids were equally potent and effective in reducing the level of temporal summation in males and females. CONCLUSIONS: These findings suggest a number of similarities in the characteristics and receptor modulation of temporal summation in humans and rats, and that in this model of chronic pain there are no sex differences in opioid potency.

Analgesics, Opioid↗
PubMed2007

Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats.

RATIONALE: Sex differences in the potency of the antinociceptive effects of kappa opioids have been reported in various acute pain models with evidence suggesting that these sex differences are mediated by activity in the N-methyl-D: -aspartate (NMDA) system. OBJECTIVES: The purpose of the present study was to evaluate sex differences in the antihyperalgesic actions of selected kappa and mixed-action opioids in a persistent pain model and determine if the NMDA system modulates these effects in a sexually dimorphic manner. METHODS: Using gonadally intact male and female F344 rats, hyperalgesia was induced by local administration of capsaicin in the tail, after which the tail was immersed in a mildly noxious thermal stimulus (45 degrees C water), and tail-withdrawal latency measured. Opioids were then administered systemically (s.c.) and locally (in the tail) alone, and in selected combinations with the noncompetitive NMDA antagonist dextromethorphan. RESULTS: When administered systemically and locally, the kappa opioids spiradoline, U69,593 and U50,488, and the mixed-action opioids butorphanol and nalbuphine, produced dose-dependent antihyperalgesic effects. Whereas the kappa opioids were generally more potent in males, sex differences were not observed with the mixed-action opioids. Peripheral receptor activity was confirmed for local administration of kappa opioids by the antagonism observed after local, but not intracerebroventricular (i.c.v.), administration of the kappa antagonist nor-binaltorphamine (nor-BNI). Dextromethorphan was equally potent in attenuating the antihyperalgesia induced by kappa opioids in both males and females. CONCLUSIONS: These findings demonstrate sex differences in kappa opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of kappa opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.

Analgesics, Opioid↗
PubMed2001

Three-choice discrimination in pigeons is based on relative efficacy differences among opioids.

RATIONALE: Drug discrimination assays can provide important information on receptor selectivity and relative efficacy to guide the classification and characterization of opioid agonists. OBJECTIVES: A three-choice discrimination was established among high efficacy opioid agonist morphine, low efficacy opioid agonist nalbuphine, and saline to examine the conditions under which differences in relative efficacy might serve as a basis for stimulus control. METHODS: Seven White Carneau pigeons were trained to discriminate among 5.6 mg/kg nalbuphine, 3.2 mg/kg morphine, and saline under fixed ratio 30 (FR30) schedules of food reinforcement. Substitution and antagonism experiments were then conducted with mu, kappa, and delta opioids and naltrexone, respectively and the percent responding appropriate to the training stimuli was determined. RESULTS: Low, intermediate, and high doses of morphine produced > or = 80% saline-, > or = 60% nalbuphine-, and > or = 96% morphine-appropriate responding, respectively. Low and high doses of nalbuphine produced > or = 80% saline- and nalbuphine-appropriate responding, respectively. In substitution tests, low doses of fentanyl and etorphine produced partial nalbuphine-appropriate responding (20-60%) and high doses produced > or = 60-80% morphine-appropriate responding. Intermediate doses of buprenorphine and dezocine produced > or = 60-80% nalbuphine-appropriate responding and high doses produced > or = 80% morphine-appropriate responding. The lower efficacy agonists butorphanol, nalorphine, and levallorphan produced > or = 40-80% nalbuphine-appropriate responding. The kappa agonists spiradoline and U50,488 produced approximately > or = 50% nalbuphine-appropriate responding whereas d-amphetamine, saline, and delta agonists BW373U86 and SNC 80 produced > or = 80% saline-appropriate responding. Naltrexone produced > or = 80% saline-appropriate responding and reversed the stimulus effects of morphine and nalbuphine. CONCLUSIONS: The discrimination between morphine and nalbuphine in pigeons is predominantly based on the relative efficacy differences between morphine, a higher-efficacy mu agonist and nalbuphine, a lower-efficacy mu agonist.

Animals↗
PubMed1984

Opioid drugs cause bile duct obstruction during hepatobiliary scans.

Hepatobiliary scans using Tc-IDA are reliable in making the diagnosis of acute cholecystitis. Commonly, opioid drugs are administered in patients with acute cholecystitis to relieve pain. Opioid drugs cause biliary sphincter spasm. Whether these drugs adversely affect hepatobiliary scans is unknown. We studied 13 healthy volunteer subjects, performing three hepatobiliary scans in each one. Scans were performed without opioid drugs and 30 minutes after intramuscularly administered meperidine, morphine, hydroxyzine, hydroxyzine plus meperidine, butorphanol, and nalbuphine. Opioid drugs markedly delayed clearance of Tc-IDA from the common bile duct, simulating common bile duct obstruction. Hydroxyzine alone caused an insignificant delay. We have concluded that opioid drugs cause bile duct obstruction in healthy persons. If opioid drugs are administered before a diagnostic hepatobiliary scan, delayed clearance of Tc-IDA from the common bile duct might lead to an erroneous diagnosis and indicate a potentially unnecessary common bile duct exploration. Opioid drugs should not be administered for several hours before a diagnostic hepatobiliary scan.

Acute Disease↗
PubMed1986

Irreversible selective blockade of kappa-opioid receptors in the guinea-pig ileum.

The irreversible non-selective opioid antagonist beta-chlornaltrexamine (beta-CNA) was used in combination with selective mu receptor protection by [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO) to produce an effective kappa receptor antagonism in the guinea-pig field-stimulated ileum preparation. Using a standard pre-treatment of 10(-7) M beta-CNA incubated for 15 min, DAG (10(-6)-10(-4) M) protected the response to the mu agonist normorphine while reducing the antagonism of the kappa agonist U50488 to a lesser extent. The concentration of DAGO which produced the most selective protection was 10(-5) M. This method was used to find the kappa selectivity of a series of opioid agonists. Of the compounds tested, butorphanol, dynorphin-(1-17), U50488, tifluadom, bremazocine and Mr 2034 were the most kappa-selective. The correlation with kappa agonist selectivity in vitro and effects in vitro on urine output in the rat is demonstrated.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Pharmacological properties of R-84760, a novel kappa-opioid receptor agonist.

The pharmacological properties of a structurally novel kappa-opioid receptor agonist, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride (R-84760), were examined. In an opioid receptor binding assay with a guinea pig brain membrane fraction, R-84760 showed a 5 times higher affinity for the kappa-opioid receptor than CI-977, the most potent reference kappa-opioid receptor agonist, and selectivity of R-84760 for the kappa-opioid receptor was higher than that of U-69593, a highly selective kappa-opioid receptor agonist. R-84760 was functionally 2.5 times more potent than CI-977 as a kappa-opioid receptor agonist in rabbit vas deferens. Subcutaneously administered R-84760 had an antinociceptive effect in the phenylquinone writhing test in mice and its potency was 5-846 times higher than those of CI-977, U-50488, morphine, pentazocine and butorphanol. On oral administration, R-84760 was 20-2077 times more potent than the same reference drugs. The antinociceptive effect of R-84760 was not antagonized by naloxone in a dose at which naloxone antagonized the effect of morphine, but on the other hand nor-binaltorphimine antagonized the effect of R-84760 at a dose which did not affect the effect of morphine. R-84760 and the reference kappa-opioid receptor agonists produced sedative and diuretic effects in mice with the same order of potency as for the antinociceptive effect. Tolerance to the antinociceptive effect of R-84760 barely developed, and naloxone-induced jumping tests for morphine-like physical dependence of R-84760 gave negative results.

Amino Acid Sequence↗
PubMed1993

Liquid chromatography-mass spectrometry for the determination of medetomidine and other anaesthetics in plasma.

A liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric method is presented for the simultaneous determination of medetomidine and other anaesthetic drugs in solutions and dog plasma. The drugs examined were flumazenil, butorphanol, atropine, ketamine, xylazine, medetomidine, atipamezole and midazolam. The separation was carried out on a reversed-phase column using methanol-0.1 M ammonium acetate (3:2) as eluent.

Anesthetics↗
PubMed1988

Reversal by beta-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig.

The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions.

Abdomen↗
PubMed1994

Changes in plasma cortisol concentrations before, during and after analgesia, anaesthesia and anaesthesia plus ovariohysterectomy in bitches.

Plasma cortisol concentrations were determined before, during and after analgesia, anaesthesia and anaesthesia plus ovariohysterectomy in six New Zealand border collie cross bitches. The treatments were: control, analgesia with butorphanol, anaesthesia with thiopentone sodium, halothane and oxygen and anaesthesia plus surgery. In addition, each bitch was given an ACTH challenge. All the bitches showed transient increases in plasma cortisol concentrations and the integrated cortisol responses (calculated as the area under the cortisol curve above the pre-treatment concentration) for 6.25 hours after treatment increased in the order: control, anaesthesia, analgesia, surgery. The control group had increased cortisol concentrations attributable to the excitement from handling. The plasma cortisol concentrations of the group subjected to surgery were greater than the other groups for at least 6.25 hours, with an approximately four-fold increase above pre-treatment values, but they had returned to pre-treatment levels after 24 hours.

Analgesia↗
PubMed1989

Depression of hepatic glutathione by opioid analgesic drugs in mice.

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.

Alanine Transaminase↗
PubMedDate not supplied

Relationship between obstetric analgesia and time of effective breast feeding.

The Infant Breast-feeding Assessment Tool (IBFAT) was used to assess the time of effective breast feeding in 48 healthy term infants born to mothers having their first or second baby. Infants of mothers who received an analgesia (butorphanol or nalbuphine) in labor (n = 26) were compared with infants whose mothers did not receive any labor analgesia (n = 22). Timing of the administration of labor analgesia was also examined with infants whose mothers received no analgesia or analgesia within an hour of birth compared with infants whose mothers received analgesia more than one hour before birth. Infants of first-time breast-feeding mothers took longer to establish effective feeding compared with infants of second-time breast-feeding mothers. Male infants also took longer. Labor analgesia significantly affected mother-rated IBFAT scores when initiation time was considered. Infants who received analgesia within an hour of birth, or no analgesia, and who initiated breast feeding early, established effective feeding significantly earlier than infants with longer duration of analgesia and later initiation of breast feeding.

Adult↗
PubMed1981

A simple, reliable method for predicting the physical dependence liability of narcotic antagonist analgesics in the rat.

The rat intraperitoneal infusion procedure was used to chronically administer drugs for evaluation of the physical dependence liability of narcotic antagonist analgesics. Three methods were used to assess dependence liability: presence of withdrawal signs upon abrupt cessation of chronic infusion (primary dependence), attenuation of the withdrawal signs produced by cessation of chronic morphine infusion (morphine substitution), and production of withdrawal signs when chronically morphine-fused rats were administered the drugs (precipitated withdrawal). Butorphanol, nalbuphine and pentazocine all caused a mild withdrawal in the rat primary dependence model which agrees with the conclusions from experiments with monkey and man. None of these agents substituted for morphine in the rat and three appeared to precipitate withdrawal. Two experimental drugs, Codorphone and TR5400, did not induce primary dependence in the rat, and in chroni-morphinized rats, they precipitated a withdrawal syndrome comparable to naloxone. Another experimental drug, TR5257, substituted for morphine. The correlation between these observations in the rat and previously published data from the monkey are excellent. It is proposed that the rat could be used as a reliable indicator of potential physical dependence liability for the narcotic antagonist analgesics.

Analgesics, Opioid↗
PubMed1981

Morphine-like stimulus effects in the monkey: opioids with antagonist properties.

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.

Animals↗