CI‐977, a novel and selective agonist for the κ‐opioid receptor

Hunter, John C.; Leighton, G.E.; Meecham, Ken; Boyle, S. J.; Horwell, David C.; Rees, David C.; Hughes, J.

doi:10.1111/j.1476-5381.1990.tb12110.x

Cited by 143 publications

(63 citation statements)

References 26 publications

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“…Centrally-acting K-opioid receptor agonists generally induce sedative effects at higher doses than central antinociceptive actions (Hayes et al, 1990;Hunter et al, 1990). The three K agonists we tested were effective in the rodent writhing test (Figure 3), and the present ID50 values for ICI 197067 and ICI 204448 in the mouse writhing test (0.02 and 1.9 mg kg-', s.c., respectively) are in good agreement with those published previously by others (0.05 (0.02-0.06) and 4.4 (2.5-7.4)mgkg-', s.c., respectively; Costello et al, 1988;Rogers et al, 1992).…”

Section: Discussionmentioning

confidence: 89%

“…We found that the action of EMD 60400 in these tests could be reversed by pretreatment with naloxone (1 mg kg-', s.c.), like Hunter et al (1990) who found that this dose of naloxone completely antagonized antinociception produced by CI-977, PD 117302, U 69593, U 50488 and other K-agonists in the rat paw pressure test. The observation that the action of EMD 60400 in the hyperalgesic pressure pain test can be completely antagonized by 0.2 mg kg-' naloxone s.c. may, however, indicate that this compound can also have activity at t-opioid receptors under some in vivo experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

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Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Barber

Bartoszyk

Greiner

et al. 1994

British J Pharmacology

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1 The pharmacological characteristics of the x-opioid receptor agonist, EMD 60400, have been investigated, with particular reference to its central and peripheral sites of action and its ability to influence nociception. The K agonists ICI 197067 and ICI 204448 10 Pharmacological and biochemical data therefore indicate that the three K-opioid receptor agonists tested here have different tendencies to elicit centrally-mediated sedation and putative aversion (ICI 197067 > EMD 60400 > ICI 204448) which correspond to their ability to cross the blood-brain barrier. EMD 60400 combines high affinity and selectivity for the K receptor with a degree of peripheral selectivity. The peripheral actions of systemically-applied EMD 60400 against hyperalgesic pressure pain and neurogenic inflammation are very probably mediated by opioid receptors on the endings of sensory nerve fibres.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Barber

Bartoszyk

Greiner

et al. 1994

British J Pharmacology

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“…Finally, the acute effects of the arylacetamide, enadoline, were examined. Like Mr2034, enadoline has high efficacy at k receptors, but it differs in that it also is highly selective for k receptors (Hunter et al, 1990). Both Mr2033 and enadoline dose dependently decreased cocaine self-administration during chronic treatment (Mello and Negus, 1998).…”

Section: Introductionmentioning

confidence: 99%

Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

Bowen

Negus

Zong

et al. 2002

Neuropsychopharmacol

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k-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed k/m receptor activity is unclear. The effects of three mixed k/m agonists (MCL-101, (À)cyclorphan, and Mr2034) and one k-selective agonist (enadoline) on cocaine selfadministration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all k agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (À)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration doseeffect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (À)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed k/m agonists produced fewer side effects (some salivation) than the k-selective agonist (sedation, salivation, emesis). However, none of these k agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, k and mixed k/m-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed k/m agonists appear to offer some advantages over selective k agonists as potential treatments for cocaine abuse.

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“…One reliable physiological indicator of kappa receptor activation is the production of diuresis. Increased urinary output has been observed after administration of selective kappa agonists, such U50,488 (Vonvoigtlander et al 1983), enadoline (CI-977) (Hunter et al 1990;Leander et al 1985), spiradoline (Rimoy et al 1991), and ethylketocyclazocine (Slizgi and Ludens 1982). The findings with butorphanol on urinary outcomes have been mixed.…”

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confidence: 99%

Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade

et al. 2007

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Rationale-Butorphanol exerts activity at mu, kappa and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans.Objectives-To determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu versus kappa receptors.Methods-Ten healthy adult inpatient volunteers (8 M, 2 F), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10 or 30 mg, p.o.) was administered 1 hr before butorphanol (0, 6 or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, subject-and observer-rated measures was collected before and for 4 hr after drug administration.Results-Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., "liking," "good drug effects") and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanolinduced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of these subjective responses.Conclusion-These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu versus kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.

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CI‐977, a novel and selective agonist for the κ‐opioid receptor

Cited by 143 publications

References 26 publications

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade

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