title: Peripheral antinociceptive efficacy and potency of a novel opioid compound 14-O-MeM6SU in comparison to known peptide and non-peptide opioid agonists in a rat model of inflammatory pain.
abstract: This study compared the peripheral analgesic effects of a novel opioid agonist 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), to that of non-peptide (morphine, fentanyl) and peptide opioid agonists (Met-enkephalin; met-ENK and β-endorphin; β-END) in a model of localized inflammatory pain evoked by intraplantar (i.pl.) Freund's complete adjuvant (FCA). Nociceptive responses to local opioid agonists were measured by pressure paw-withdrawal procedures. In addition, the antinociceptive efficacy and potency of these test compounds in vivo was compared to that in vitro using the rat vas deferens (RVD) bioassay. Intraplantar 14-O-MeM6SU (0.32-2.53 nmol/rat), morphine (14.95-112.15 nmol/rat), fentanyl (0.19-2.36 nmol/rat), met-ENK (0.10-10 nmol/rat) and β-END (0.77-5.00 nmol/rat) dose dependently increased paw pressure thresholds exclusively in inflamed hindpaws. At higher doses analgesic effects were also seen in noninflamed paws for 14-O-MeM6SU, morphine and fentanyl but not for met-ENK or β-END. The maximal possible local analgesic effect (%) measured in inflamed paws was 50.6 ± 2.7, 18.23 ± 1.78, 37.44 ± 2.17, 36.00 ± 1.43, and 40.69 ± 0.91 for 14-O-MeM6SU, morphine, fentanyl, met-ENK and β-END, respectively. Interestingly, i.pl. administered opioid peptides met-ENK and β-END displayed a peripheral analgesic ceiling effect. This local antinociception was antagonized by co-administered opioid antagonist naloxone-methiodide (NAL-M). Similar to the analgesic testing, the RVD showed the following efficacy order of the test compounds: 14-O-MeM6SU>β-END>fentanyl>met-ENK≫morphine. Taken together, 14-O-MeM6SU was more potent than morphine, fentanyl and met-ENK and β-END and displayed superiority in the maximum antinociceptive effects. The superiority of local antinociceptive effects of 14-O-MeM6SU might be due to both pharmacodynamic and pharmacokinetic factors.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Augustnburgerplatz 113353 Berlin, Germany.
authors.forename: Baled I
authors.initials: BI
authors.lastname: Khalefa
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Lackó
authors.forename: Sándor
authors.initials: S
authors.lastname: Hosztafi
authors.forename: Pál
authors.initials: P
authors.lastname: Riba
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D009119:Muscle Contraction / Q000187:drug effects; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: C579042:14-O-methylmorphine-6-O-sulfate; D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D018847:Opioid Peptides; D011957:Receptors, Opioid; D003061:Codeine