Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans

The objective of the present study was to evaluate the effects of EMD 61753 (asimadoline), a K-opioid receptor agonist with restricted access to the c entral nervous system, on postoperative pain in patients who underwent knee surgery and on nociceptive thresholds and inflammation in rats treated wit h Freund's complete adjuvant. Patients treated with EMD 61753 (10 mg p.o.) tended to report an increase in pain, as evaluated by a visual analog scale and by the time to the first request for and the total amount of supplemen tal analgesic medication. The global tolerability of EMD 61753 was assessed as significantly inferior to that of a placebo by the investigator. In rat s, the bilateral intraplantar (i.pl.) injection of EMD 61753 (0.1-3.2 mg) r esulted in dose-dependent antinociception in both inflamed and noninflamed paws, with a peak at 5 min after injection, as evaluated by the paw pressur e method. However, at later time points (1 h-4 days), a significant decreas e in the paw pressure threshold was observed, confirming its tendency towar d a hyperalgesic action in humans. This was accompanied by an increase in p aw volume and paw temperature, with a peak at 6 h after injection. EMD 6175 3 (1.6 mg)-induced analgesia was blocked by the peripheral opioid receptor antagonist naloxone methiodide (2.5-10 mg/kg s.c.) and by the kappa-recepto r antagonist nor-binaltorphimine (0.1 mg; i.pl.). In contrast, EMD 61753 (1 .6 mg)-induced hyperalgesia and increases in paw volume and paw temperature were blocked neither by naloxone methiodide (10-40 mg/kg s.c.) nor by dizo cilpine maleate (0.003-0.009 mg i,pl.), a N-methyl-D-aspartic acid receptor antagonist. These data show differentially mediated peripheral actions of EMD 61753: K-opioid receptor-induced analgesia and nonopioid, non-N-methyl- D-aspartic acid hyperalgesic and proinflammatory effects.