Nociceptin and the ORL-1 ligand [Phe1ψ (CH2-NH)Gly2]nociceptin(1-13)NH2 exert anti-opioid effects in the Freund's adjuvant-induced arthritic rat model of chronic pain

摘要

Stimulation of the opioid receptor-like1 (ORL-1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated.The present study was undertaken to assess the action of NC in the Freund's adjuvant-induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL-1 ligand, [Phe1ψ(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), were also studied alone or in association with morphine.NC (1–30 nmol, i.c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (−4.5±0.9 vs −0.7±0.8 s of vehicle-treated animals). [F/G]NC(1-13)NH2 (0.01–10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (−3.3±0.6 vs −0.3±0.5 s of vehicle-treated animals; 10 nmol).Both NC (0.01–10 nmol, i.c.v.) and [F/G]NC(1-13)NH2 (0.01–1 nmol, i.c.v), 30 min after morphine (3 mg kg−1, s.c.) induced an immediate and short-lived reversal of morphine effects (2.6±0.3 vs 10.4±1.0 and 1.2±1.5 vs 9.3±1.1 s of morphine alone, respectively), therefore displaying anti-opioid activity.In the Freund's adjuvant-induced rat model of arthritis, both NC and [F/G]NC(1-13)NH2 act as anti-opioid peptides. Furthermore, NCNH2 and [F/G]NC(1-13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL-1 antagonist are necessary to better understand the role of NC in pain mechanisms.