RATIONALE: Despite numerous investigations, the mechanisms underlying the development of opioid tolerance are far from clear. However, several in vitro studies implicated a protective role of agonist-induced micro-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of micro-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in micro-opioid receptor expressing HEK293 cells. OBJECTIVES: The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo. METHODS: The opioid effects were quantified using the hot plate, electric tail root stimulation, and the locomotor activity chamber in male Wistar rats. Dose-response curves were generated for each test drug. To induce tolerance, equieffective doses of etonitazene, morphine, and buprenorphine were administered daily for 29 days. RESULTS: We found that chronic treatment with the non-internalizing drugs buprenorphine and morphine resulted in a greater development of tolerance than etonitazene. In addition, the sensitization to the locomotor stimulant effect was high after buprenorphine and morphine, but was lacking after chronic etonitazene application. CONCLUSION: The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.
RATIONALE: Despite numerous investigations, the mechanisms underlying the development of opioid tolerance are far from clear. However, several in vitro studies implicated a protective role of agonist-induced micro-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of micro-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in micro-opioid receptor expressing HEK293 cells. OBJECTIVES: The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo. METHODS: The opioid effects were quantified using the hot plate, electric tail root stimulation, and the locomotor activity chamber in male Wistar rats. Dose-response curves were generated for each test drug. To induce tolerance, equieffective doses of etonitazene, morphine, and buprenorphine were administered daily for 29 days. RESULTS: We found that chronic treatment with the non-internalizing drugs buprenorphine and morphine resulted in a greater development of tolerance than etonitazene. In addition, the sensitization to the locomotor stimulant effect was high after buprenorphine and morphine, but was lacking after chronic etonitazene application. CONCLUSION: The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.
Authors: D E Keith; S R Murray; P A Zaki; P C Chu; D V Lissin; L Kang; C J Evans; M von Zastrow Journal: J Biol Chem Date: 1996-08-09 Impact factor: 5.157
Authors: Jamie McPherson; Guadalupe Rivero; Myma Baptist; Javier Llorente; Suleiman Al-Sabah; Cornelius Krasel; William L Dewey; Chris P Bailey; Elizabeth M Rosethorne; Steven J Charlton; Graeme Henderson; Eamonn Kelly Journal: Mol Pharmacol Date: 2010-07-20 Impact factor: 4.436
Authors: John T Williams; Susan L Ingram; Graeme Henderson; Charles Chavkin; Mark von Zastrow; Stefan Schulz; Thomas Koch; Christopher J Evans; Macdonald J Christie Journal: Pharmacol Rev Date: 2013-01-15 Impact factor: 25.468
Authors: Leslie I Curtin; Julie A Grakowsky; Mauricio Suarez; Alexis C Thompson; Jean M DiPirro; Lisa B E Martin; Mark B Kristal Journal: Comp Med Date: 2009-02 Impact factor: 0.982
Authors: Joseph A Kim; Selena Bartlett; Li He; Carsten K Nielsen; Amy M Chang; Viktor Kharazia; Maria Waldhoer; Chrissi J Ou; Stacy Taylor; Madeline Ferwerda; Dragana Cado; Jennifer L Whistler Journal: Curr Biol Date: 2008-01-22 Impact factor: 10.834