Peripherally mediated antinociception of the µ-opioid receptor agonist HS-731 after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation

Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally-mediated antinociception produced by the µ-opioid receptor agonist HS-731 (2-[(4,5 after subcutaneous (s.c.) and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection, and compared to those of centrally acting µ-opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time-course of action was different, in that HS-731 (20 µg/kg, s.c.) produced significant long-lasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 µg/kg) and morphine (2 mg/kg) reached their peak of action at 10–30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 µg/kg, s.c.), while it was ineffective against 14-methoxymetopon (20 µg/kg, s.c.). Moreover, the antinociception produced by 100 µg/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the µ-opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation. methiodide, demonstrating a peripheral opioid receptor-specific mechanism of action. The potent reduction of hyperalgesia after oral administration of HS-731 was also inhibited by s.c. naloxone methiodide indicating that oral HS-731 preferentially activates peripheral opioid receptors. The present results on the antagonism caused by naloxone methiodide corroborate and extend recent findings, in the tail-flick and the formalin test in rats (Fürst et al., 2005) on the peripheral site of action of systemic s.c. HS-731. In conclusion, the present study shows that the µ-opioid receptor agonist HS-731 dose-dependently produces potent and long-lasting peripherally mediated antinociception after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. In addition, the µ-opioid agonist 14-methoxymetopon induces antinociceptive effects in inflammatory hyperalgesia after s.c. administration, through central mechanisms. Our findings suggest that peripheral µ-opioid agonists such as HS-731 may find clinical applications as analgesics in inflammatory pain conditions. Opioid-induced CNS side effects, e.g. respiratory depression, sedation, tolerance and addiction, can be minimized with drugs which do not readily cross the blood-brain barrier after systemic administration.