Development of tolerance and sensitization to different opioid agonists in rats.
BACKGROUND
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.


OBJECTIVE
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.


CONCLUSIONS
The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.
Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. gisela.grecksch@medizin.uni-magdeburg.de
Gisela
G
Grecksch
Katharina
K
Bartzsch
Antje
A
Widera
Axel
A
Becker
Volker
V
Höllt
Thomas
T
Koch
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D002047:Buprenorphine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004558:Electric Stimulation; D004705:Endocytosis / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists*
D000701:Analgesics, Opioid; D001562:Benzimidazoles; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D009020:Morphine; C084835:etonitazene