BACKGROUND AND PURPOSE: Oxycodone and morphine are μ-opioid receptor agonists prescribed to control moderate-to-severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein-gated inwardly rectifying potassium (K(IR)3 also known as GIRK) channels in their antinociceptive effects. EXPERIMENTAL APPROACH: Opioid-induced antinociceptive effects were assessed in mice, using the tail-flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of K(IR)3.1 channels with tertiapin-Q (30 pmol per mouse, i.c.v. and i.t.) and K(IR)3.1-specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration in the mouse femur bone cancer and neuropathic pain models. KEY RESULTS: The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by K(IR)3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by K(IR)3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin-Q. CONCLUSION AND IMPLICATIONS: These results demonstrate that K(IR)3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal K(IR)3.1 channels are responsible for the unique analgesic profile of oxycodone.
BACKGROUND AND PURPOSE:Oxycodone and morphine are μ-opioid receptor agonists prescribed to control moderate-to-severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein-gated inwardly rectifying potassium (K(IR)3 also known as GIRK) channels in their antinociceptive effects. EXPERIMENTAL APPROACH: Opioid-induced antinociceptive effects were assessed in mice, using the tail-flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of K(IR)3.1 channels with tertiapin-Q (30 pmol per mouse, i.c.v. and i.t.) and K(IR)3.1-specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration in the mouse femur bone cancer and neuropathic pain models. KEY RESULTS: The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by K(IR)3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by K(IR)3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin-Q. CONCLUSION AND IMPLICATIONS: These results demonstrate that K(IR)3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal K(IR)3.1 channels are responsible for the unique analgesic profile of oxycodone.
Authors: Igor Mitrovic; Marta Margeta-Mitrovic; Semon Bader; Markus Stoffel; Lily Y Jan; Allan I Basbaum Journal: Proc Natl Acad Sci U S A Date: 2002-12-20 Impact factor: 11.205
Authors: Stephen P H Alexander; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; John C McGrath; William A Catterall; Michael Spedding; John A Peters; Anthony J Harmar; N Abul-Hasn; C M Anderson; C M H Anderson; M S Araiksinen; M Arita; E Arthofer; E L Barker; C Barratt; N M Barnes; R Bathgate; P M Beart; D Belelli; A J Bennett; N J M Birdsall; D Boison; T I Bonner; L Brailsford; S Bröer; P Brown; G Calo; W G Carter; W A Catterall; S L F Chan; M V Chao; N Chiang; A Christopoulos; J J Chun; J Cidlowski; D E Clapham; S Cockcroft; M A Connor; H M Cox; A Cuthbert; F M Dautzenberg; A P Davenport; P A Dawson; G Dent; J P Dijksterhuis; C T Dollery; A C Dolphin; M Donowitz; M L Dubocovich; L Eiden; K Eidne; B A Evans; D Fabbro; C Fahlke; R Farndale; G A Fitzgerald; T M Fong; C J Fowler; J R Fry; C D Funk; A H Futerman; V Ganapathy; B Gaisnier; M A Gershengorn; A Goldin; I D Goldman; A L Gundlach; B Hagenbuch; T G Hales; J R Hammond; M Hamon; J C Hancox; R L Hauger; D L Hay; A J Hobbs; M D Hollenberg; N D Holliday; D Hoyer; N A Hynes; K-I Inui; S Ishii; K A Jacobson; G E Jarvis; M F Jarvis; R Jensen; C E Jones; R L Jones; K Kaibuchi; Y Kanai; C Kennedy; I D Kerr; A A Khan; M J Klienz; J P Kukkonen; J Y Lapoint; R Leurs; E Lingueglia; J Lippiat; S J Lolait; S C R Lummis; J W Lynch; D MacEwan; J J Maguire; I L Marshall; J M May; C A McArdle; J C McGrath; M C Michel; N S Millar; L J Miller; V Mitolo; P N Monk; P K Moore; A J Moorhouse; B Mouillac; P M Murphy; R R Neubig; J Neumaier; B Niesler; A Obaidat; S Offermanns; E Ohlstein; M A Panaro; S Parsons; R G Pwrtwee; J Petersen; J-P Pin; D R Poyner; S Prigent; E R Prossnitz; N J Pyne; S Pyne; J G Quigley; R Ramachandran; E L Richelson; R E Roberts; R Roskoski; R A Ross; M Roth; G Rudnick; R M Ryan; S I Said; L Schild; G J Sanger; K Scholich; A Schousboe; G Schulte; S Schulz; C N Serhan; P M Sexton; D R Sibley; J M Siegel; G Singh; R Sitsapesan; T G Smart; D M Smith; T Soga; A Stahl; G Stewart; L A Stoddart; R J Summers; B Thorens; D T Thwaites; L Toll; J R Traynor; T B Usdin; R J Vandenberg; C Villalon; M Vore; S A Waldman; D T Ward; G B Willars; S J Wonnacott; E Wright; R D Ye; A Yonezawa; M Zimmermann Journal: Br J Pharmacol Date: 2013-12 Impact factor: 8.739
Authors: Chuang Lyu; Jan Mulder; Swapnali Barde; Kristoffer Sahlholm; Hugo Zeberg; Johanna Nilsson; Peter Århem; Tomas Hökfelt; Kaj Fried; Tie-Jun Sten Shi Journal: Mol Pain Date: 2015-07-22 Impact factor: 3.395