Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon

Zernig, Gerald; Saria, Alois; Kraßnig, Roland; Schmidhammer, Helmut

doi:10.1016/s0024-3205(00)00510-5

Cited by 18 publications

(20 citation statements)

References 10 publications

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“…Administration of a low dose (20 g/kg s.c.) of 14-methoxymetopon produced a significant attenuation of nociceptive behavior in inflamed paws, demonstrated by increased HWL on application of pressure or heat, showing similar potency to morphine (2 mg/kg s.c.). The profile of the antinociceptive activity of 14-methoxymetopon identified in this study confirms previous reports on acute nociception using different pain stimuli and animal species (rat and mouse) (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003). The analgesic effects of 14-methoxymetopon were reversed by naloxone and naltrexone, two opioid antagonists that readily cross the blood-brain barrier (Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003), indicating that 14-methoxymetopon has central actions.…”

Section: Discussionsupporting

confidence: 89%

“…The profile of the antinociceptive activity of 14-methoxymetopon identified in this study confirms previous reports on acute nociception using different pain stimuli and animal species (rat and mouse) (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003). The analgesic effects of 14-methoxymetopon were reversed by naloxone and naltrexone, two opioid antagonists that readily cross the blood-brain barrier (Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003), indicating that 14-methoxymetopon has central actions. In the present study, a peripherally selective opioid antagonist, naloxone methiodide (Brown and Goldberg, 1985), was used to assess the site of action of 14-methoxymetopon after s.c. administration in rats with unilateral carrageenan-induced hyperalgesia.…”

Section: Discussionsupporting

confidence: 89%

“…In addition, antinociceptive effects on inflammatory pain after s.c. administration of 14-methoxymetopon ( Fig. 1) (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003), a centrally acting -opioid receptor agonist, are described.…”

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Peripherally Mediated Antinociception of the μ-Opioid Receptor Agonist 2-[(4,5α-Epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

Bilevičiūtė-Ljungar¹,

Spetea²,

Guo³

et al. 2005

J Pharmacol Exp Ther

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Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally mediated antinociception produced by the -opioid receptor agonist 2-[(4,5␣-epoxy-3-hydroxy-14␤-methoxy-17-methylmorphinan-6␤-yl)amino]acetic acid (HS-731) after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection and compared with those of centrally acting -opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time course of action was different, in that HS-731 (20 g/kg s.c.) produced significant longlasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 g/kg) and morphine (2 mg/kg) reached their peak of action at 10 to 30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 g/kg s.c.), whereas it was ineffective against 14-methoxymetopon (20 g/kg s.c.). Moreover, the antinociception produced by 100 g/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the -opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation.Traditionally, analgesic effects of opioids have been associated with activation of opioid receptors in the central nervous system (CNS) (Reisine and Pasternak, 1996). Several studies, however, have challenged the notion that opioids act to produce antinociception exclusively through central mechanisms. Peripheral antinociception in response to different noxious stimuli (e.g., heat, pressure, and chemicals) has been demonstrated in a variety of models and species in which opioids are applied locally at doses that are systemically

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

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Peripherally Mediated Antinociception of the μ-Opioid Receptor Agonist 2-[(4,5α-Epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

Bilevičiūtė-Ljungar¹,

Spetea²,

Guo³

et al. 2005

J Pharmacol Exp Ther

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“…5,14-O-Dimethyloxymorphone (14-methoxymetopon) is a highly potent and selective -opiate agonist (Schmidhammer et al, 1990;Fü rst et al, 1993;Freye et al, 2000;Zernig et al, 2000;King et al, 2003;Bileviciute-Ljungar et al, 2006) with a unique pharmacology and extraordinary analgesic potency that sets it apart from traditional agonists. Despite its high analgesic potency, it displays little respiratory depression, bradycardia, or sedation compared with sufentanil.…”

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confidence: 99%

Separation of Binding Affinity and Intrinsic Activity of the Potent μ-Opioid 14-Methoxymetopon

Mahurter¹,

Garceau²,

Marino³

et al. 2006

J Pharmacol Exp Ther

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Receptor binding studies of 5,14-O-dimethyloxymorphone (14-methoxymetopon) in brain membranes have established its high affinity for -binding sites, but its analgesic potency far exceeds the modest increase in binding affinity relative to other opioids. The current study has established the selectivity of -ol]-enkephalin (DAMGO) showed similar efficacies, as determined by maximal stimulation, but 14-methoxymetopon was up to 65-fold more potent than DAMGO. The greatest difference was seen with mMOR-1E and the least with mMOR-1C, which displayed only a 10-fold difference. These potency differences in the stimulation of [ 35 S]GTP␥S binding far exceeded the differences in binding affinity. The differences between 14-methoxymetopon and DAMGO remained after normalizing the potency shifts based upon receptor binding affinities and varied from 1.2-fold with mMOR-1C to 21-fold for mMOR-1 and 42-fold with mMOR-1F.

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“…1), a highly selective -opioid receptor agonist (Fü rst et al, 1993;Spetea et al, 2003). This opioid was described as an extremely potent centrally acting analgesic, being 300-to 20,000-fold more potent than morphine, depending upon the analgesic paradigm used (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003).…”

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confidence: 99%

Peripheral versus Central Antinociceptive Actions of 6-Amino Acid-Substituted Derivatives of 14-O-Methyloxymorphone in Acute and Inflammatory Pain in the Rat

Fürst

Riba

Friedmann

et al. 2004

J Pharmacol Exp Ther

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Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon

Cited by 18 publications

References 10 publications

Peripherally Mediated Antinociception of the μ-Opioid Receptor Agonist 2-[(4,5α-Epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

Peripherally Mediated Antinociception of the μ-Opioid Receptor Agonist 2-[(4,5α-Epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

Separation of Binding Affinity and Intrinsic Activity of the Potent μ-Opioid 14-Methoxymetopon

Peripheral versus Central Antinociceptive Actions of 6-Amino Acid-Substituted Derivatives of 14-O-Methyloxymorphone in Acute and Inflammatory Pain in the Rat

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