Novel approach to demonstrate high efficacy of μ opioids in the rat vas deferens: A simple model of predictive value

• Published in: Brain research bulletin 2010-01, Vol.81 (1), p.178-184
• Main Authors: Riba, Pál, Friedmann, Tamás, Király, Kornél P, Al-Khrasani, Mahmoud, Sobor, Melinda, Asim, Muhammad F, Spetea, Mariana, Schmidhammer, Helmut, Furst, Susanna
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; Antinociception; Brain - drug effects; Brain - metabolism; Dose-Response Relationship, Drug; Efficacy; Enkephalin, Ala-MePhe-Gly- - metabolism; Enkephalin, Ala-MePhe-Gly- - pharmacology; Male; Mice; Mice, Inbred Strains; Models, Biological; Morphinans; Morphine - metabolism; Morphine - pharmacology; Morphine Derivatives - metabolism; Morphine Derivatives - pharmacology; Mouse vas deferens; Naltrexone - metabolism; Naltrexone - pharmacology; Neurology; Oxymorphone - analogs & derivatives; Oxymorphone - metabolism; Oxymorphone - pharmacology; Pain - drug therapy; Pain - metabolism; Rat vas deferens; Rats; Rats, Wistar; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism; Vas Deferens - drug effects; Vas Deferens - metabolism; μ Opioid receptors
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2009.09.011

Abstract 14- O -Methyloxymorphone and 14-methoxymetopon were reported as highly selective and potent μ opioid receptor agonists. The aim of this study was to demonstrate the opioid activity of these compounds in vitro and in vivo in comparison to oxymorphone, morphine and DAMGO. The μ opioid receptor efficacy, full or partial agonist nature of opioids was analyzed in the rat vas deferens (RVD) bioassay. Compared to oxymorphone, 14- O -methyloxymorphone and 14-methoxymetopon showed greater affinities to the rodent brain μ opioid receptors in receptor binding assays. In isolated organs 14- O -methyloxymorphone and 14-methoxymetopon were 3–10-fold more potent than the μ agonist opioid peptide, DAMGO. All tested compounds reached at least 70% maximum inhibition in mouse vas deferens (MVD) except morphine and oxymorphone. In the RVD, morphine could not exceed 50% inhibition of the twitches while 14- O -methyloxymorphone and 14-methoxymetopon showed inhibitory effects more than 70%. Oxymorphone reached only 4% maximal agonist effect and antagonized the inhibitory effect of DAMGO. The investigated morphinans produced dose-dependent antinociceptive activities in mice and rats. Both, 14- O -methyloxymorphone and 14-methoxymetopon are highly efficacious μ opioid receptor agonists in the RVD exhibiting full μ agonist properties. The RVD tissue contains μ receptors indicated by the comparable Ke values of the μ antagonist naltrexone against DAMGO in the MVD. RVD may be a good alternative to assess the μ receptor efficacy of opioid agonists providing a more physiological environment for the ligand–receptor interaction than other efficacy measuring methods such as the [35 S]GTPγS binding assay.