κ-Opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice

Kuzmin, Alexander; Semenova, Svetlana; Gerrits, M.A.F.M.; Zvartau, Edwin; Ree, Jan M. van

doi:10.1016/s0014-2999(96)00961-2

Cited by 114 publications

(76 citation statements)

References 23 publications

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“…Thus, ATPM significantly attenuated the self-administration of heroin under an FR1 schedule of reinforcement. (Ϫ)U50,488H showed similar effects on heroin self-administration behavior as ATPM, which was consistent with the results reported in the literature (Kuzmin et al, 1997).…”

Section: In Vivo Studiessupporting

confidence: 91%

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

Wang

Tao²,

Li³

et al. 2009

J Pharmacol Exp Ther

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ATPM [(Ϫ)-3-amino-thiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed -and -opioid activity and identified to act as a full -agonist and a partial -agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (Ϫ)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by -and -, but not ␦-opioid, receptors. In addition to its agonist profile on the -receptor, ATPM also acted as a -antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED 50 value of sedation to that of antinociception than (Ϫ)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (Ϫ)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (Ϫ)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (Ϫ)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed -agonist and -agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect.-Agonists with some -activity appear to offer some advantages over selective -agonists for the treatment of heroin abuse.Previous studies in both nonhuman primates and rats have demonstrated that -agonists functionally attenuate many behavioral effects of cocaine, including behavioral sensitization (Ukai et al

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Section: In Vivo Studiessupporting

confidence: 91%

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

Wang

Tao²,

Li³

et al. 2009

J Pharmacol Exp Ther

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“…Interestingly, KOR agonists do not contribute to the classical drug-seeking behaviors. Unlike MOR agonists, KOR agonists do not cause drug dependence nor do they produce respiratory failure (46); U50,488H actually reduced cocaine and morphine self-administration in rat and mouse models (47). However, KOR activation has also been implicated in producing an array of undesirable side effects, including dysphoric and psychomimetic effects in human clinical studies (48,49).…”

Section: Discussionmentioning

confidence: 99%

Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration

Wu¹,

Zhang²,

Shkhyan³

et al. 2017

JCI Insight

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“…In addition, kappa opioid agonists have been found to decrease cocaine-seeking behavior in rodent models of intravenous (i.v.) self-administration and relapse, as well as place preference (Glick et al, 1995;Kuzmin et al, 1997;Schenk et al, 2001;Shippenberg et al, 2001). Kappa opioid agonists also produced dose-dependent and sustained decreases in cocaine self-administration in rhesus monkeys (Negus et al, 1997;Negus, 1998b, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

Mello

Mendelson

Sholar

et al. 2004

Neuropsychopharmacol

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Kappa opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and reduce cocaine selfadministration by rhesus monkeys. We compared the cardiovascular and subjective effects of acute doses of the mu/kappa opioid nalbuphine alone (5 mg/70 kg, intravenous (i.v.)), with cocaine alone (0.2 mg/kg, i.v.), and with nalbuphine þ cocaine in combination, under placebo-controlled, double-blind conditions. Subjects met American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV) criteria for current cocaine abuse. Nalbuphine serum levels exceeded 50 ng/ml within 10 min after injection, and cocaine plasma levels exceeded 130 ng/ml within 4 min. Cocaine's pharmacokinetic profile did not change after concurrent nalbuphine administration. The nalbuphine þ cocaine combination was safe and without synergistic effects on heart rate and systolic or diastolic blood pressure. Moreover, the addition of cocaine did not increase the subjective effects of nalbuphine. Visual Analog Scale (VAS) ratings of High, Euphoria, Stimulated, and Good Effect were equivalent after nalbuphine þ cocaine and nalbuphine alone, and both were significantly higher than after cocaine alone (area under the curve analysis) (po0.05-0.01). Peak VAS ratings of High, Stimulated, Good Effect, and Drug Effect were also significantly higher after nalbuphine þ cocaine than after cocaine alone (po0.01). Addiction Research Center Inventory (ARCI) scores were equivalent for nalbuphine þ cocaine and nalbuphine alone, but the PCAG, MBG, and amphetamine scores were significantly higher after both nalbuphine þ cocaine and nalbuphine alone than after cocaine alone (po0.01-0.003). Thus, there were no additive interactions between nalbuphine and cocaine on cardiovascular, subjective, or drug level measures after acute administration.

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κ-Opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice

Cited by 114 publications

References 23 publications

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

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