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-ENKâ¢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.
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