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Mary Jeanne Kreek - One of the best experts on this subject based on the ideXlab platform.
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κ-Opioid Receptor agonist-induced prolactin release in primates is blocked by dopamine D2-like Receptor Agonists
European Journal of Pharmacology, 2001Co-Authors: Eduardo R. Butelman, Mary Jeanne KreekAbstract:Abstract Kappa (κ)-opioid Receptor Agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine Receptor systems involved in drug reinforcement. κ-Opioid Receptor Agonists also modulate dopamine Receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a “biomarker” for the ability of κ-opioid Receptor Agonists (e.g., (+)-(5α,7α,8β)- N -methyl- N -[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine Receptor system in vivo in primates. The effectiveness of dopamine D 2 -like Receptor Agonists (quinpirole and (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032–0.1 mg/kg) in preventing U69,593–induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID 50 values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D 1 -Receptor agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating κ-opioid Receptor Agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with κ-opioid Receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of κ-opioid Receptor Agonists to modulate dopamine D 2 -like Receptor function, and may also be used to quantify dopamine D 2 -like Receptor agonist potency in primates.
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kappa-Opioid Receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like Receptor Agonists.
European journal of pharmacology, 2001Co-Authors: Eduardo R. Butelman, Mary Jeanne KreekAbstract:Kappa-opioid Receptor Agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine Receptor systems involved in drug reinforcement. kappa-Opioid Receptor Agonists also modulate dopamine Receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid Receptor Agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine Receptor system in vivo in primates. The effectiveness of dopamine D(2)-like Receptor Agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-Receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid Receptor Agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid Receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid Receptor Agonists to modulate dopamine D(2)-like Receptor function, and may also be used to quantify dopamine D(2)-like Receptor agonist potency in primates.
David M. Wood - One of the best experts on this subject based on the ideXlab platform.
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Synthetic Cannabinoid Receptor Agonists
Novel Psychoactive Substances, 2013Co-Authors: Volker Auwärter, Paul I. Dargan, David M. WoodAbstract:Since 2008 dozens of new synthetic cannabinoid Receptor agonist compounds have emerged as additives in so-called ‘Spice’ or ‘K2’ products. These synthetic cannabinoid Receptor Agonists have become a significant challenge for clinicians, forensic scientists, analytical toxicologists and legislative authorities. These products are often used as a cannabis substitute, particularly where individuals want to avoid detection in routine drug screening, which often do not include these compounds. Relatively little is known about the pharmacological properties of these drugs, particularly in humans. Most of the synthetic cannabinoid Receptor Agonists act as potent and efficacious Agonists at the cannabinoid Receptor type 1 (CB1) and hence elicit cannabis-like effects even after doses in the low milligram range. In addition to cannabis-like toxicity, these compounds are associated with stimulant effects (e.g. tachycardia, hypertension, agitation, convulsions) and other effects including hypokalaemia. There have been some studies and early case reports which suggest the potential for dependence associated with the use of synthetic cannabinoid Receptor Agonists.
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The impact of changes in UK classification of the synthetic cannabinoid Receptor Agonists in 'Spice'
International Journal of Drug Policy, 2011Co-Authors: Paul I. Dargan, Simon Hudson, John Ramsey, David M. WoodAbstract:Abstract Background Spice is the iconic brand name of a smokeable herbal mixture containing synthetic cannabinoid Receptor Agonists. It has been available on the Internet/in head shops in Europe since at least 2006. The synthetic cannabinoid Receptor agonist constituents of Spice were classified in the UK as Class B agents in December 2009. This study assessed the impact of this legislation on the synthetic cannabinoid Receptor Agonists present in Spice products and whether new synthetic cannabinoid Receptor Agonists outside of the legislation are now available. Methods Spice products were bought, prior to and after the change in the UK legislation, from a range of Internet legal high websites selling to UK consumers. Products were analysed using liquid chromatography high-resolution tandem mass spectrometry (LCMSMS). Identification of the synthetic cannabinoid Receptor agonist(s) detected was made by comparison to existing databases or by ‘in silico' methods. Results Sixteen products were purchased prior to the UK control of synthetic cannabinoid Receptor Agonists; all contained at least one synthetic cannabinoid Receptor agonist. 20 products were purchased after the UK control; no active compounds were detected in 3 (15%). The remaining 17 (85%) all contained at least one classified synthetic cannabinoid Receptor agonist. Additionally, 2 synthetic cannabinoid Receptor Agonists not covered under current UK generic legislation (AM-694 and the ‘novel Belarus compound') were detected. Conclusion Despite the UK ‘Spice' classification, classified synthetic cannabinoid Receptor Agonists continue to be supplied over the Internet to UK users. Furthermore, new synthetic cannabinoid Receptor Agonists not covered by the legislation are appearing. Consideration needs to be given to reviewing the UK legislation so that suppliers cannot circumvent it by supplying legal alternatives to the classified synthetic cannabinoid Receptor Agonists.
Frank Porreca - One of the best experts on this subject based on the ideXlab platform.
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cb2 cannabinoid Receptor Agonists pain relief without psychoactive effects
Current Opinion in Pharmacology, 2003Co-Authors: Philip T Malan, Mohab M Ibrahim, Todd W Vanderah, Alexandros Makriyannis, Frank PorrecaAbstract:Abstract Cannabinoid Receptor Agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid Agonists that selectively target CB2 (peripheral) cannabinoid Receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB2 Receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB2 Receptor Agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.
David R. Maguire - One of the best experts on this subject based on the ideXlab platform.
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Antinociceptive effects of mixtures of mu opioid Receptor Agonists and cannabinoid Receptor Agonists in rats: Impact of drug and fixed-dose ratio.
European Journal of Pharmacology, 2017Co-Authors: David R. MaguireAbstract:Pain is a significant clinical problem, and there is a need for effective pharmacotherapies with fewer adverse effects than currently available drugs (e.g., mu opioid Receptor Agonists). Cannabinoid Receptor Agonists enhance the antinociceptive effects of mu opioid Receptor Agonists, but it remains unclear which drugs and in what proportion will yield the most effective and safest treatments. The antinociceptive effects of the mu opioid Receptor Agonists etorphine and morphine alone and in combination with the cannabinoid Receptor Agonists Δ9-THC and CP55940 were studied in male Sprague-Dawley rats (n = 16) using a warm water tail withdrawal procedure. The ratio of opioid to cannabinoid (3:1, 1:1, and 1:3) varied for each mixture. Drugs administered alone or as pairwise mixtures of an opioid and a cannabinoid dose-dependently increased tail withdrawal latency. Mixtures with morphine produced supra-additive (CP55940) and additive (Δ9-THC) effects, whereas mixtures with etorphine and either cannabinoid were sub-additive. The interactions were not different among ratios for a particular mixture. The nature of the interaction between opioids and cannabinoids with regard to antinociceptive effects varies with the particular drugs in the mixture, which can have implications for designing combination therapies for pain.
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Interactions between cannabinoid Receptor Agonists and mu opioid Receptor Agonists in rhesus monkeys discriminating fentanyl
European Journal of Pharmacology, 2016Co-Authors: David R. MaguireAbstract:Cannabinoid Receptor Agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid Receptor Agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid Receptor agonist CP55940 increase the potency of some mu opioid Receptor Agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid Receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability.
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Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: David R. MaguireAbstract:Cannabinoid Receptor Agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid Receptor Agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy Agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid Receptor Agonists alone and in combination with cannabinoid Receptor Agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid Receptor Agonists increase the antinociceptive potency of higher efficacy opioid Receptor Agonists more than lower efficacy Agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.
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Interactions between μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: David R. Maguire, Wenjuan YangAbstract:Cannabinoid Receptor Agonists enhance the antinociceptive effects of μ-opioid Receptor Agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid Receptor Agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of μ-opioid Receptor Agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1–5.6 mg/kg s.c.), CP 55,940 (0.0032–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01–0.032 mg/kg s.c.) and WIN 55,212 (0.1–1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32–32.0 µg/kg/infusion i.v.), CP 55,940 (0.001–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid Receptor Agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of μ-opioid Receptor Agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid Receptor Agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability.
Eduardo R. Butelman - One of the best experts on this subject based on the ideXlab platform.
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κ-Opioid Receptor agonist-induced prolactin release in primates is blocked by dopamine D2-like Receptor Agonists
European Journal of Pharmacology, 2001Co-Authors: Eduardo R. Butelman, Mary Jeanne KreekAbstract:Abstract Kappa (κ)-opioid Receptor Agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine Receptor systems involved in drug reinforcement. κ-Opioid Receptor Agonists also modulate dopamine Receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a “biomarker” for the ability of κ-opioid Receptor Agonists (e.g., (+)-(5α,7α,8β)- N -methyl- N -[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine Receptor system in vivo in primates. The effectiveness of dopamine D 2 -like Receptor Agonists (quinpirole and (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032–0.1 mg/kg) in preventing U69,593–induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID 50 values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D 1 -Receptor agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating κ-opioid Receptor Agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with κ-opioid Receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of κ-opioid Receptor Agonists to modulate dopamine D 2 -like Receptor function, and may also be used to quantify dopamine D 2 -like Receptor agonist potency in primates.
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kappa-Opioid Receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like Receptor Agonists.
European journal of pharmacology, 2001Co-Authors: Eduardo R. Butelman, Mary Jeanne KreekAbstract:Kappa-opioid Receptor Agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine Receptor systems involved in drug reinforcement. kappa-Opioid Receptor Agonists also modulate dopamine Receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid Receptor Agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine Receptor system in vivo in primates. The effectiveness of dopamine D(2)-like Receptor Agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-Receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid Receptor Agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid Receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid Receptor Agonists to modulate dopamine D(2)-like Receptor function, and may also be used to quantify dopamine D(2)-like Receptor agonist potency in primates.
