14-methoxymetopon and Pain

Still nowadays pain is one of the most common disabling conditions and yet it remains too often unsolved. Analgesic opioid drugs, and mainly MOR agonists such as morphine, are broadly employed for pain management. MOR activation, however, has been seen to cause not only analgesia but also undesired side effects. A potential pain treatment option is represented by the simultaneous targeting of different opioid receptors. In fact, ligands possessing multitarget capabilities led to an improved pharmacological fingerprint. This review focuses on the examination of multitarget opioid ligands which have been distinguished in peptide and non-peptide and further listed as bivalent and bifunctional ligands. Moreover, the potential of these compounds, both as analgesic drugs and pharmacological tools to explore heteromer receptors, has been stressed.

Topics: Analgesics, Opioid; Animals; Humans; Ligands; Molecular Structure; Pain; Receptors, Opioid

14-O-Methyloxymorphone and 14-methoxymetopon were reported as highly selective and potent micro 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 micro 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 micro opioid receptors in receptor binding assays. In isolated organs 14-O-methyloxymorphone and 14-methoxymetopon were 3-10-fold more potent than the micro 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 micro opioid receptor agonists in the RVD exhibiting full micro agonist properties. The RVD tissue contains mu receptors indicated by the comparable K(e) values of the micro antagonist naltrexone against DAMGO in the MVD. RVD may be a good alternative to assess the mu 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]GTPgammaS binding assay.

Topics: Analgesics, Opioid; Animals; Brain; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Mice; Mice, Inbred Strains; Models, Biological; Morphine; Morphine Derivatives; Naltrexone; Oxymorphone; Pain; Rats; Rats, Wistar; Receptors, Opioid, mu; Vas Deferens

We have studied the effects of 14-methoxymetopon (HS 198), a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity of adult male rats. The prototype mu agonist morphine was used as the drug of reference. Besides we addressed the effects of HS 198 on the serum corticosterone levels and on serotonergic systems of discrete brain regions. Both drugs were administered subcutaneously. Morphine (5 mg/kg) and HS 198 (30 microg/kg) induced a similar effect on the nociceptive test, with both drugs significantly increasing the threshold for the vocalization afterdischarge, which is related to the emotional component of pain. In the plus-maze, morphine (5 mg/kg) and HS 198 (20 and 30 microg/kg) induced similar increases in the percentages of entries and time in the open arms, two parameters related to the anxiety state of the animals. The results indicate that HS 198 is far more potent than morphine in reducing the emotive/affective component of pain and in inducing an anxiolytic effect. HS 198 (30 microg/kg) also induced parallel increases in the serum corticosterone levels and the hypothalamic serotonin content. A possible correlation between the anxiolytic action of the drug and its effect on the hypothalamic serotonergic system is suggested.

Topics: Animals; Anxiety; Brain; Corticosterone; Electric Stimulation; Hypothalamo-Hypophyseal System; Male; Maze Learning; Morphine; Morphine Derivatives; Narcotics; Neural Pathways; Pain; Pain Measurement; Raphe Nuclei; Rats; Serotonin; Vocalization, Animal