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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 122 (1995), S. 336-345 
    ISSN: 1432-2072
    Keywords: Drug discrimination ; 8-OH-DPAT ; Ipsapirone ; Morphine ; Fentanyl ; U50,488 ; Bremazocine ; Drug interactions ; Rats ; Time course
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The ratedecreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Key words Butorphanol ; Cross tolerance ; Dependence ; Relative efficacy ; Opioid ; Rat ; Tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of the present investigation was to examine the development of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of butorphanol, an opioid with low relative efficacy at the mu receptor. The mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufentanil, and the kappa opioid U50,488 dose-dependently suppressed responding under all conditions examined. In rats administered the low maintenance dose of butorphanol, tolerance developed to the effects of butorphanol, buprenorphine and morphine, but not to fentanyl and sufentanil. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degree to which tolerance developed was greater for butorphanol and buprenorphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats administered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when tested at both 23 and 47 h following the previous maintenance dose of butorphanol, suggesting that these changes were not due to any acute pharmacological interactions between butorphanol and the test compound (i.e., antagonism). Tolerance was also conferred to the kappa opioid U50,488 in both groups of rats, and in rats administered the high maintenance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence developed in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-suppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependence was apparent in rats administered the low maintenance dose of butorphanol. These data suggest that during chronic treatment with butorphanol, (1) greater degrees of tolerance are conferred to drugs possessing low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opioid dependence.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: BW373U86 ; Fentanyl ; Morphine ; Nalbuphine ; Drug discrimination ; Pigeons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED50 values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2072
    Keywords: Key words Antinociception ; Butorphanol ; Relative efficacy ; Opioid ; Rat ; Stimulus intensity ; Tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. Objective: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. Methods: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50°C (low temperature) and 55°C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (–)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. Results: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (–)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (–)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. Conclusions: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Key words Drug discrimination ; Opioids ; Pigeons ; Irreversible antagonists ; Intrinsic efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible μ opioid antagonist beta-funaltrexamine (βFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The µ opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the δ opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of βFNA. Antagonist effects of βFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of βFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of βFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of βFNA as low as 5 mg/kg. The δ opioid BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg βFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the µ opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the µ opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the µ opioid receptor is: l-methadone=fentanyl≥buprenorphine≥morphine≥ butorphanol〉nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of βFNA in the pigeon suggests that the recovery of µ opioid receptor function varies across species.
    Type of Medium: Electronic Resource
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