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.