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

Abstract

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

14-methoxymetopon, a highly potent μ opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats

“…Naltrexone, a relatively subtype nonselective opioid antagonist, completely blocked the facilitatory effect of systemic 14-MM on ethanol intake, confirming an opioid-mediated action of this derivative of the 14-alkoxymorphinan series of opioids. These findings are consistent with the in vitro pharmacological characteristics and reported μ-receptor mediated analgesic mechanisms of 14-MM (Bileviciute-Ljungar et al 2006;King et al 2003). The selectively high potency of 14-MM for μ receptors in vitro, known μ selectivity of 14-MM for antinociceptive action in vivo at doses comparable to the present study, and very high in vivo potencies of 14-MM seen in the current study collectively implicate a role for μ, rather than δ or κ, opioid receptors in the observed actions of 14-MM to increase drinking.…”

“…The early suppressive action of 14-MM was accompanied by anorexia and not reversed by a dose of naltrexone that could abolish the subsequent, behaviorally specific action of 14-MM to increase ethanol drinking. Thus, the μ agonist 14-MM altered ethanol intake on the same very high order of potency that it reportedly produces antinociception in rats (ED 50 =7-20 μg/kg s.c.; Bileviciute-Ljungar et al 2006;Furst et al 1993). The delayed induction of ethanol consumption was reversed by naltrexone, suggesting an opioid receptor mechanism.…”

“…Given systemically, 14-MM is 100-20,000-fold more potent than morphine in producing analgesia (Furst et al 1993), and up to one million-fold more potent than morphine following supraspinal or spinal central administration (King et al 2003). 14-MM analgesia has been proposed to be mediated predominantly by central μ1 receptors (King et al 2003;Bileviciute-Ljungar et al 2006). Consistent with this hypothesis and its pharmacological profile, 14-MM analgesia can be reversed by antisense oligonucleotides targeting the cloned μ-opioid receptor-1 or by selective μ or μ1, but not δ or κ, antagonists (Furst et al 1993;King et al 2003).…”

“…A possible explanation for this paradox and the inability of naltrexone to modulate the acute effects of 14-MM is that a nonopioid mediated mechanism mediates the early suppressive phase of 14-MM action. Alternatively, perhaps intermediate levels of opioid receptor activation are facilitatory for ethanol intake and levels at either extreme are suppressive, and the dose of naltrexone used was simply not sufficient to displace the functionally greater central levels of 14-MM that are present at opioid receptors during the first 30 min of ethanol access (Bileviciute-Ljungar et al 2006). In the latter explanation, an antagonist may reduce the reinforcing effects of ethanol by preventing activation of opioid receptors, whereas high agonist doses might saturate them, thereby substituting for (and removing) a reinforcement mechanism of ethanol drinking.…”

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

“…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.…”