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James H. Woods - One of the best experts on this subject based on the ideXlab platform.

  • Buprenorphine Antagonism of Mu Opioids in the Rhesus Monkey TaiIWithdrawaI Procedure1
    1995
    Co-Authors: Ellen A. Walker, Gerald Zernig, James H. Woods
    Abstract:

    The apparent in vivo dissociation constant (1<A) and relative efficacy values for alfentanil, Etonitazene, morphine, and nal-buphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal pro-cedure. Initial time course studies of buprenorphine alone mdi-cated that 3.2 and 10 mg/kg produced increases in tail-with-drawal latencies when studied with 48#{176}Cwater for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55#{176}Cwater. Buprenorphine produced dose-de-pendent shifts to the right for the antinociceptive effects of alfentanil, Etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48#{176}Cwater and those of alfentanil and Etonitazene in 55#{176}C water. Buprenorphine administration decreased the receptor

  • Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding
    Life Sciences, 1995
    Co-Authors: Gerald Zernig, Tom Issaevitch, Jillian Helen Broadbear, T F Burke, John W. Lewis, George A. Brine, James H. Woods
    Abstract:

    Abstract In order to quantitate the extent to which opioid agonist potencies obtained in behavioral assays are determined by the apparent in vivo affinity and efficacy of the agonist, the antinociceptive effects of the mu opioid agonists morphine, fentanyl, Etonitazene, and NIH 10741 were assessed before and after administration of the insurmountable mu opioid antagonist clocinnamox (CCAM) in a 55 °C warm-water tail withdrawal test in Swiss albino mice. Under control conditions, all four mu opioid agonists produced a full antinociceptive response with the following ED 50 values (in mg/kg): morphine, 12; fentanyl, 0.47; Etonitazene, 0.039; NIH 10741, 0.0051. Analysis of CCAM's effects according to Black and Leff gave the following agonist efficacy or tau values: Morphine, 4; fentanyl 15, Etonitazene, 7; and NIH 10741, 59. The respective ka values were (in mg/kg): morphine, 29; fentanyl, 7.3; Etonitazene, 0.22; and NIH 10741, 0.30. The major determinant of the experimentally observed ED50 values seemed to be the apparent in vivo affinity of the respective agonist and not its efficacy. ka values (expressed as mol/kg) correlated with the K i values (in mol/1) obtained with [ 3 H]DAMGO radioligand inding (r = 0.96 for pK A vs. pK i ), although being on average 11,000-fold higher. Values for q, the available receptor fraction as determined in the behavioral experiments, correlated strongly (r = 0.96) with the q values determined by ex vivo [ 3 H]DAMGO- and [ 3 H]naltrexone equilibrium binding ( i.e. , B max ,clocinnamox/B max ,control), the relationship approaching unity.

  • Agonist and antagonist effects of dynorphin A-(1-13) in a thermal antinociception assay in rhesus monkeys.
    The Journal of pharmacology and experimental therapeutics, 1995
    Co-Authors: Eduardo R. Butelman, James H. Woods
    Abstract:

    The agonist and antagonist effects of intravenously administered dynorphin A-(1-13) were characterized in the warm water (50 and 55 degrees C) tail withdrawal assay of antinociception in rhesus monkeys. The peptide dose-dependently elevated tail withdrawal latencies in 50 degrees C water, but was ineffective in 55 degrees C water. The antinociceptive effect of dynorphin was surmountably antagonized by quadazocine (0.1 mg/kg) and nor-binaltorphimine (3.2 mg/kg), but was not antagonized by clocinnamox (0.1 mg/kg); this pattern of antagonism is consistent with a kappa-opioid receptor mediated effect. Pretreatment with dynorphin A-(1-13) (0.032-3.2 mg/kg) antagonized the antinociceptive effects of U50,488 and U69,593 in 55 degrees C water, suggesting a low efficacy action of the peptide at the receptors activated by these kappa agonists. However, dynorphin A-(1-13) (3.2 mg/kg) did not antagonize other kappa agonists: bremazocine (0.018-0.056 mg/kg) and enadoline (0.0056-0.018 mg/kg). Taken together, these dynorphin A-(1-13) findings support the notion of functional kappa-opioid receptor subtypes, and it appears that dynorphin A-(1-13) has limited efficacy at one of these sites. Finally, dynorphin A-(1-13) (0.32 mg/kg) also antagonized the antinociceptive effects of the mu-agonist Etonitazene (0.0018-0.01 mg/kg).

  • Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice.
    The Journal of pharmacology and experimental therapeutics, 1994
    Co-Authors: T F Burke, James H. Woods, John W. Lewis, Fedor Medzihradsky
    Abstract:

    The effects of the systemically active irreversible opioid receptor antagonist clocinnamox (C-CAM; 14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N- cyclopropylmethyl normorphinone mesylate) on mu receptor binding to cerebral membranes and on mu opioid analgesia were assessed using mice. After systemic administration, C-CAM produced a dose-dependent decrease in the Bmax values of both [3H]DAMGO ([D-Ala2, N-MePhe4, Gly5-ol][tyrosyl-3,5-3H]enkephalin) and [3H]naltrexone without affecting the Kd value of either ligand. After administration of 3.2 mg/kg of C-CAM, [3H]DAMGO binding recovered gradually, returning to control levels by 8 days. This time course of recovery was similar to that observed with 3.2 mg/kg of C-CAM against morphine analgesia in the warm-water tail-withdrawal assay. The analgesic effect of the mu agonist Etonitazene also was assessed in the assay. C-CAM produced dose-dependent rightward and slight downward shifts of the Etonitazene dose-effect curve. The analgesic activity of Etonitazene had still not returned to base-line levels 12 days after administration of 32 mg/kg of C-CAM, a time at which [3H]DAMGO binding had returned to control levels. In addition, the apparent pA2 values of Etonitazene with naltrexone in the tail-withdrawal assay were assessed at 4, 8 and 12 days after the administration of 32 mg/kg of C-CAM, and none were found to be different from the control pA2 value. These results support the notion that C-CAM is an irreversible mu receptor antagonist and suggest that post-treatment, perhaps newly synthesized, mu receptors are similar to mu receptors in control membranes.

  • Butorphanol: Characterization of Agonist and Antagonist Effects in Rhesus Monkeys1’2’3
    1994
    Co-Authors: Eduardo R. Butelman, Gerald Zernig, Gail Winger, James H. Woods
    Abstract:

    The effects of butorphanol were studied in assays of antinoci-ception, respiratory depression, sedation, diuresis and reinforc-ing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003-0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50#{176}Cwater but not in 55#{176}C. Over a similar dose range, butorphanol caused substantial respiratory depression, without an obvious plateau. Con-strained quadazocine apparent pA analysis on the respiratory depressant and antinociceptive effects of butorphanol yielded different values between the two assays (respiratory depres-sion pA = 6.61; antinociception pA = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of Etonitazene in 55#{176}Cwater, but caused a nonparallel leftward shift in the U50,488 dose-effect curve; both effects were probably due t

J. W. Lewis - One of the best experts on this subject based on the ideXlab platform.

  • Clocinnamox antagonism of opioid suppression of schedule-controlled responding in rhesus monkeys
    Psychopharmacology, 1996
    Co-Authors: E. R. Butelman, J H Woods, S. S. Negus, J. W. Lewis
    Abstract:

    The antagonist effects of clocinnamox were evaluated against opioid agonists, acting at μ, κ and ∂-receptors, in rhesus monkeys ( n =3–4) responding under a fixed-ratio 30 (FR 30) schedule for food delivery. Clocinnamox (0.032–0.1 mg/kg) dose-dependently antagonized fentanyl (0.001–0.32 mg/kg) after either a 3-h or 1-day pretreatment; there was substantial recovery of agonist potency by 1 week after clocinnamox. Etonitazene (0.0001–0.01 mg/kg) was also antagonized by clocinnamox (0.1 mg/kg), but to a lesser extent than fentanyl. The smaller extent of antagonism was not due to the appearance of non μ-opioid response-decreasing effects of Etonitazene, since the competitive antagonist quadazocine (0.1 mg/kg) shifted the Etonitazene dose-effect curve in the presence of clocinnamox (0.1 mg/kg). Clocinnamox (0.1–0.32 mg/kg) did not antagonize the rate-suppressing effects of the ∂-agonist BW373U86 (0.0.01-1.0 mg/kg) or the κ-agonist U69,593 (0.001–0.032 mg/kg). These results are consistent with previous in vivo and in vitro evidence that characterized clocinnamox as an insurmountable antagonist, with selectivity for μ-over κ- and δ-receptors.

E. R. Butelman - One of the best experts on this subject based on the ideXlab platform.

  • Clocinnamox antagonism of opioid suppression of schedule-controlled responding in rhesus monkeys
    Psychopharmacology, 1996
    Co-Authors: E. R. Butelman, J H Woods, S. S. Negus, J. W. Lewis
    Abstract:

    The antagonist effects of clocinnamox were evaluated against opioid agonists, acting at μ, κ and ∂-receptors, in rhesus monkeys ( n =3–4) responding under a fixed-ratio 30 (FR 30) schedule for food delivery. Clocinnamox (0.032–0.1 mg/kg) dose-dependently antagonized fentanyl (0.001–0.32 mg/kg) after either a 3-h or 1-day pretreatment; there was substantial recovery of agonist potency by 1 week after clocinnamox. Etonitazene (0.0001–0.01 mg/kg) was also antagonized by clocinnamox (0.1 mg/kg), but to a lesser extent than fentanyl. The smaller extent of antagonism was not due to the appearance of non μ-opioid response-decreasing effects of Etonitazene, since the competitive antagonist quadazocine (0.1 mg/kg) shifted the Etonitazene dose-effect curve in the presence of clocinnamox (0.1 mg/kg). Clocinnamox (0.1–0.32 mg/kg) did not antagonize the rate-suppressing effects of the ∂-agonist BW373U86 (0.0.01-1.0 mg/kg) or the κ-agonist U69,593 (0.001–0.032 mg/kg). These results are consistent with previous in vivo and in vitro evidence that characterized clocinnamox as an insurmountable antagonist, with selectivity for μ-over κ- and δ-receptors.

  • Opioid thermal antinociception in rhesus monkeys : receptor mechanisms and temperature dependency
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: E. A. Walker, E. R. Butelman, B R Decosta, J H Woods
    Abstract:

    The antinociceptive effects of the opioid agonists Etonitazene and alfentanil, as well as the agonist/antagonists nalbuphine, [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were studied in the warm water (48 degrees and 55 degrees C) tail-withdrawal assay in rhesus monkeys. Etonitazene and alfentanil produced dose-dependent increases in tail-withdrawal latency up to the maximum possible latency of 20 sec in 48 degrees and 55 degrees C water. Nalbuphine, GPA 1657 and profadol produced the maximum possible effect only at 48 degrees C, and were ineffective at 55 degrees C. The opioid antagonist quadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazocine with alfentanil, Etonitazene and nalbuphine were homogeneous (7.3-7.7 mol/kg), suggesting their effects were probably mediated by mu opioid receptors. The apparent pA2 value for GPA 1657 was significantly lower (6.2 mol/kg), suggesting GPA 1657 may have produced antinociception by a non mu receptor-mediated mechanism. The selective delta antagonist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effect of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (nor-BNI, 3.2 mg/kg) caused a small rightward shift in the GPA 1657 dose-effect curve. Nalbuphine, GPA 1657 or profadol produced a rightward shift in the alfentanil dose-effect curve in 55 degrees C water, consistent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinociceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.

J H Woods - One of the best experts on this subject based on the ideXlab platform.

  • Clocinnamox antagonism of opioid suppression of schedule-controlled responding in rhesus monkeys
    Psychopharmacology, 1996
    Co-Authors: E. R. Butelman, J H Woods, S. S. Negus, J. W. Lewis
    Abstract:

    The antagonist effects of clocinnamox were evaluated against opioid agonists, acting at μ, κ and ∂-receptors, in rhesus monkeys ( n =3–4) responding under a fixed-ratio 30 (FR 30) schedule for food delivery. Clocinnamox (0.032–0.1 mg/kg) dose-dependently antagonized fentanyl (0.001–0.32 mg/kg) after either a 3-h or 1-day pretreatment; there was substantial recovery of agonist potency by 1 week after clocinnamox. Etonitazene (0.0001–0.01 mg/kg) was also antagonized by clocinnamox (0.1 mg/kg), but to a lesser extent than fentanyl. The smaller extent of antagonism was not due to the appearance of non μ-opioid response-decreasing effects of Etonitazene, since the competitive antagonist quadazocine (0.1 mg/kg) shifted the Etonitazene dose-effect curve in the presence of clocinnamox (0.1 mg/kg). Clocinnamox (0.1–0.32 mg/kg) did not antagonize the rate-suppressing effects of the ∂-agonist BW373U86 (0.0.01-1.0 mg/kg) or the κ-agonist U69,593 (0.001–0.032 mg/kg). These results are consistent with previous in vivo and in vitro evidence that characterized clocinnamox as an insurmountable antagonist, with selectivity for μ-over κ- and δ-receptors.

  • Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure.
    The Journal of pharmacology and experimental therapeutics, 1995
    Co-Authors: E. A. Walker, Gerald Zernig, J H Woods
    Abstract:

    The apparent in vivo dissociation constant (KA) and relative efficacy values for alfentanil, Etonitazene, morphine, and nalbuphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal procedure. Initial time course studies of buprenorphine alone indicated that 3.2 and 10 mg/kg produced increases in tail-withdrawal latencies when studied with 48 degrees C water for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55 degrees C water. Buprenorphine produced dose-dependent shifts to the right for the antinociceptive effects of alfentanil, Etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48 degrees C water and those of alfentanil and Etonitazene in 55 degrees C water. Buprenorphine administration decreased the receptors available for agonist interaction to approximately 2%. The average apparent in vivo dissociation constant (KA) values for alfentanil, Etonitazene, morphine and nalbuphine were 3.3, 0.073, 60 and 31 mg/kg, respectively. High efficacy estimates were determined for alfentanil (149-203) and Etonitazene (174-203), whereas lower efficacy estimates were determined for nalbuphine (57) and morphine (17). The apparent in vivo dissociation constant of a pseudoirreversible antagonist (KB) value for buprenorphine averaged 0.15 mg/kg across agonists, temperatures and buprenorphine doses. These data extend and emphasize the significance of in vivo estimates of affinity and relative efficacy for drug classification.

  • Opioid thermal antinociception in rhesus monkeys : receptor mechanisms and temperature dependency
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: E. A. Walker, E. R. Butelman, B R Decosta, J H Woods
    Abstract:

    The antinociceptive effects of the opioid agonists Etonitazene and alfentanil, as well as the agonist/antagonists nalbuphine, [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were studied in the warm water (48 degrees and 55 degrees C) tail-withdrawal assay in rhesus monkeys. Etonitazene and alfentanil produced dose-dependent increases in tail-withdrawal latency up to the maximum possible latency of 20 sec in 48 degrees and 55 degrees C water. Nalbuphine, GPA 1657 and profadol produced the maximum possible effect only at 48 degrees C, and were ineffective at 55 degrees C. The opioid antagonist quadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazocine with alfentanil, Etonitazene and nalbuphine were homogeneous (7.3-7.7 mol/kg), suggesting their effects were probably mediated by mu opioid receptors. The apparent pA2 value for GPA 1657 was significantly lower (6.2 mol/kg), suggesting GPA 1657 may have produced antinociception by a non mu receptor-mediated mechanism. The selective delta antagonist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effect of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (nor-BNI, 3.2 mg/kg) caused a small rightward shift in the GPA 1657 dose-effect curve. Nalbuphine, GPA 1657 or profadol produced a rightward shift in the alfentanil dose-effect curve in 55 degrees C water, consistent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinociceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.

Frank R. George - One of the best experts on this subject based on the ideXlab platform.

  • Opioid operant self-administration, analgesia, stimulation and respiratory depression inμ-deficient mice
    Psychopharmacology, 1995
    Co-Authors: Gregory I. Elmer, Jeanne O. Pieper, Steven R. Goldberg, Frank R. George
    Abstract:

    It is commonly thought that μ -receptors play an important role in the reinforcing effects of opioids. In the present study, inbred strains widely divergent in CNS opiate receptor densities were used to investigate the influence of genetic variation in receptor concentration on opioid-reinforced behavior. In particular, the CXBK/ByJ mice were used as an investigative tool because of their significantly lower number of CNS μ opioid receptors. The behavioral pharmacology of opioids in the μ -deficient CXBK/ByJ mice was compared to other commonly used inbred mouse strains, C57BL/6J and BALB/cJ, and the opiate receptor rich CXBH/ByJ mice. Operant opioid reinforced behavior, opioid-induced locomotor stimulation, analgesia and respiratory depression were investigated in all four inbred strains. To assess the acquisition and maintenance of opioid reinforced behavior, oral self-administration of the potent benzimidazole opioid, Etonitazene, was determined using an operant fixed-ratio schedule of reinforcement (FR 8). Acquisition of Etonitazene-reinforced behavior was established in all four strains including the μ -deficient CXBK/ByJ mice. However, there were significant genetic differences in the amount of drug intake during the maintenance of opioid-reinforced behavior and extinction behavior following vehicle substitution. For example, drug intake was significantly greater in the BK versus BH mice during the maintenance phase and an extinction burst was seen in the BH but not the BK mice following vehicle substitution. Thus, μ -receptor density may not account for individual variability in the acquisition of opioid-reinforced behavior under these conditions. Sensitivity to Etonitazene-induced respiratory depression, stimulation of locomotor activity and analgesia were unrelated to drug intake during self-administration sessions across these four inbred strains. These data indicate that inherited differences in CNS μ -opiate receptor concentrations do not affect acquisition of Etonitazene-reinforced behavior.

  • Opioid operant self-administration, analgesia, stimulation and respiratory depression in mu-deficient mice.
    Psychopharmacology, 1995
    Co-Authors: Gregory I. Elmer, Jeanne O. Pieper, Steven R. Goldberg, Frank R. George
    Abstract:

    It is commonly thought thatμ-receptors play an important role in the reinforcing effects of opioids. In the present study, inbred strains widely divergent in CNS opiate receptor densities were used to investigate the influence of genetic variation in receptor concentration on opioid-reinforced behavior. In particular, the CXBK/ByJ mice were used as an investigative tool because of their significantly lower number of CNSμ opioid receptors. The behavioral pharmacology of opioids in theμ-deficient CXBK/ByJ mice was compared to other commonly used inbred mouse strains, C57BL/6J and BALB/cJ, and the opiate receptor rich CXBH/ByJ mice. Operant opioid reinforced behavior, opioid-induced locomotor stimulation, analgesia and respiratory depression were investigated in all four inbred strains. To assess the acquisition and maintenance of opioid reinforced behavior, oral self-administration of the potent benzimidazole opioid, Etonitazene, was determined using an operant fixed-ratio schedule of reinforcement (FR 8). Acquisition of Etonitazene-reinforced behavior was established in all four strains including theμ-deficient CXBK/ByJ mice. However, there were significant genetic differences in the amount of drug intake during the maintenance of opioid-reinforced behavior and extinction behavior following vehicle substitution. For example, drug intake was significantly greater in the BK versus BH mice during the maintenance phase and an extinction burst was seen in the BH but not the BK mice following vehicle substitution. Thus,μ-receptor density may not account for individual variability in the acquisition of opioid-reinforced behavior under these conditions. Sensitivity to Etonitazene-induced respiratory depression, stimulation of locomotor activity and analgesia were unrelated to drug intake during self-administration sessions across these four inbred strains. These data indicate that inherited differences in CNSμ-opiate receptor concentrations do not affect acquisition of Etonitazene-reinforced behavior.

  • Etonitazene delivered orally serves as a reinforcer for Lewis but not Fischer 344 rats
    Pharmacology Biochemistry and Behavior, 1992
    Co-Authors: Tsutomu Suzuki, Frank R. George, Richard A. Meisch
    Abstract:

    Oral Etonitazene self-administration was systematically investigated in two inbred strains of rats, Lewis (LEW) and Fischer 344 (F344). For LEW rats, Etonitazene maintained higher rates of lever pressing and was consumed in larger volumes than the water vehicle when the reinforcement schedule was fixed ratio (FR) 8. In contrast, with F344 rats responding did not systematically exceed water values at any Etonitazene concentration. LEW rats also drank substantially more Etonitazene than F344 rats, and at FR 8 only LEW rats showed the typical inverted U-shaped function between Etonitazene concentration and number of responses. For the LEW strain, response rate increased as FR size increased from FR 1 to FR 2 and FR 4, but decreased at FR 8. For the F344 strain, as FR size increased response rate showed small increases, but the response rates were far lower than those of the LEW strain. The results support the conclusion that Etonitazene was an effective reinforcer for LEW but not F344 rats. These findings demonstrate genetic differences in opioid reinforcement of operant behavior and indicate that genotype can be an important determinant of whether Etonitazene serves as a reinforcer.