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BEHAVIORAL PHARMACOLOGY

Peripherally Mediated Antinociception of the µ-Opioid Receptor Agonist 2-[(4,5-Epoxy-3-hydroxy-14-methoxy-17-methylmorphinan-6-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B.-L., Y.G.); Department of Surgical Sciences, Section of Orthopaedics, Karolinska Institutet, Orthopaedic Research Laboratory M3:02, Karolinska Hospital, Stockholm, Sweden (I.B.-L.); and Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (M.S., J.S., P.W., H.S.)

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 2-[(4,5-epoxy-3-hydroxy-14-methoxy-17-methylmorphinan-6-yl)amino]acetic acid (HS-731) after 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 with 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 to 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.), whereas 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.

Address correspondence to: Dr. Indre Bileviciute-Ljungar, Department of Rehabilitation Medicine Stockholm, Bldg. 32, Danderyd University Hospital, S-182 88 Stockholm, Sweden. E-mail: indre.ljungar{at}ds.se

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