Etorphines: μ-opioid receptor-selective antinociception and low physical dependence capacity

Aceto, Mario D.; Harris, Louis S.; Bowman, Edward R.

doi:10.1016/s0014-2999(97)81924-3

Cited by 49 publications

(45 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the eD 50 value of 030418 was in the microgram range and was calculated as approximately 1100-1500 times that of the standard morphine hydrochloride. experimental data regarding the potency of dihydroetorphine and morphine were consistent with those of Aceto et al [34] . In addition, 030418 had more potent and powerful antinociceptive effects in vivo than its parent compound thienorphine, which has previously been demonstrated to be a partial opioid agonist, with an eD 50 value in the milligram range in the mouse antinociceptive tests [15] .…”

Section: Discussionsupporting

confidence: 89%

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Wen¹,

Yu²,

Li³

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine. Methods: The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5′-O-(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations. Results: The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K i values in the nanomolar range. In [ 35 S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing. Conclusion:The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N 17 position and the high hydrophobicity of the C 7 -thiophene group in its chemical structure.

show abstract

Section: Discussionsupporting

confidence: 89%

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Wen¹,

Yu²,

Li³

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…The effect reached its peak at 10 to 30 min and declined rapidly thereafter. The fast onset with an early maximum effect that disappears shortly after drug application is a typical feature of the time course of action of opioid drugs (i.e., morphine, fentanyl, and etorphine) that mediate analgesia via central mechanisms and has been depicted under normal and inflammatory conditions (Millan et al, 1987;Aceto et al, 1997;Fü rst et al, 2005). In contrast, s.c. HS-731 acted considerably longer (up to 4 h) and dose-dependent reduction of carrageenan-induced hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

“…The rapid onset with a maximum effect early, which waned very shortly after drug administration, is a typical characteristic of the time course of action of opioid agonists (e.g., morphine, fentanyl, and etorphine) that mediate analgesia via central mechanisms and were described under both normal and inflammatory conditions (Millan et al, 1987;Aceto et al, 1997). In contrast, the new opioids administered s.c. acted longer with some delay in onset.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

Etorphines: μ-opioid receptor-selective antinociception and low physical dependence capacity

Cited by 49 publications

References 27 publications

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

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

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

Contact Info

Product

Resources

About