Development of tolerance and sensitization to different opioid agonists in rats

Psychopharmacology (Berl). 2006 Jun;186(2):177-84. doi: 10.1007/s00213-006-0365-8. Epub 2006 Mar 30.


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.

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Benzimidazoles / pharmacology
  • Buprenorphine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Tolerance*
  • Electric Stimulation
  • Endocytosis / drug effects
  • Hot Temperature
  • Hyperalgesia / chemically induced*
  • Male
  • Morphine / pharmacology
  • Motor Activity / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, mu / agonists*


  • Analgesics, Opioid
  • Benzimidazoles
  • Receptors, Opioid, mu
  • Buprenorphine
  • Morphine
  • etonitazene