Table of Contents

    Topic review

    Opioid Tolerance

    Subjects: Others
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    Submitted by: Tomohiko Aoe


    Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. The US Food and Drug Administration (FDA) define opioid tolerance as follows (;

    Patients are considered opioid tolerant if they are taking, for 1 week or longer, at least:

    - Oral morphine–60 mg daily

    - Transdermal fentanyl–25 mcg/h

    - Oral oxycodone–30 mg daily

    - Oral hydromorphone–8mgdaily

    - Oral oxymorphone–25mgdaily

    - Equianalgesic daily dose of another opioid

    1. Introduction

    Opioids such as fentanyl and morphine are widely used as excellent analgesics for both acute pain (e.g., during surgery) and chronic pain (e.g., in cancer patients) [1][2]. However, the increases in addiction and overdose death due to opioid misuse arising from prescriptions made by medical institutions, especially in the United States where opioid analgesics have been heavily used in recent years, have become serious social problems. US government agencies have declared the Opioid Crisis as a national emergency [3][4]. Chronic use of opioids induces tolerance that reduces analgesic effects, and opioid-induced hyperalgesia increases painful sensation throughout the entire body [5], resulting in increased opioid doses, more addiction, and even shorter life span [6][7]. About 16,000 deaths, or 36% of the 44,000 drug overdose deaths in the United States in 2013, were associated with prescribed opioids (2013 National Survey on Drug Use and Health). Approximately 9.9 million people aged 12 or older in 2018 misused prescription pain relievers, corresponding to 3.6% of the US population (2018 National Survey on Drug Use and Health).

    Opioid tolerance develops due to multifaceted mechanisms such as altered intracellular signal transductions in sensory neurons, inflammation of neurons and glial cells, and reconstitution of neural circuits [8]. Opioids act via mu opioid receptors (MORs) expressed on the plasma membrane of primary sensory neurons, as well as various neurons in the cerebrum, brainstem, and dorsal horn of the spinal cord; opioid binding to MORs suppresses ascending nociceptive transmission and enhances descending pain inhibitory pathways, resulting in analgesia. MORs activate various signaling molecules through heterotrimeric guanine nucleotide-binding proteins (G proteins) [9], leading to an analgesic effect. MOR activation also induces G-protein-coupled receptor kinases to phosphorylate MORs [10][11], which can then be recognized by β-arrestins and internalized by clathrin-coated vesicles [12]. Transient uncoupling of MORs from signaling pathways due to their phosphorylation and subsequent intracellular trafficking causes opioid desensitization. β-arrestin-2 deletion enhances morphine analgesia and prevents the development of tolerance, but not dependence [12][13]. Most internalized MORs eventually return to the cell surface, resulting in re-sensitization [14][15][16]. Chronic morphine tolerance may accompany adaptations of the intracellular signal transduction of post-MOR activation, including increased activity of protein kinase A [17] and protein kinase C [18], and up-regulation of N-methyl-D-aspartate receptor signaling [19][20][21][22]. Chronic morphine treatment also activates the glycogen synthase kinase 3β (GSK3β) and Src kinase pathways, while inhibition of these kinases has been shown to diminish morphine tolerance and restore analgesia [23][24][25].

    2. Data, Model, Applications and Influences

    Dobashi et al. previously reported that signaling from the endoplasmic reticulum (ER) contributed to the development of morphine tolerance [24]. Accumulation of misfolded proteins in the ER induced the unfolded protein response (UPR) that causes diverse pathological conditions. Persistent overload of misfolded proteins causes a diverse array of disorders due to impaired functional protein synthesis and cell death [26][27], including neurodegenerative disease [28], dilated cardiomyopathy [29], and renal disease [30]. Another distinct mechanism by which ER stress causes human disease is that the UPR alters signaling pathways required for important cellular functions [31]. Obesity causes ER stress that induces the UPR, which may attenuate insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate-1. Crosstalk between the UPR and insulin receptor signaling has been shown to cause insulin resistance in type II diabetes [32]. Chronic morphine administration may alter signal transduction due to persistent MOR activation [33]. In addition, MOR signaling may induce the UPR via calcium (Ca2+) kinetics, and the ER is the main store of Ca2+. MOR activation induces the ER to release Ca2+ into the cytoplasm [34]. ER chaperones including BiP are Ca2+-binding proteins, and the release of Ca2+ may disturb protein folding and induce the UPR. It has been shown that ER stress activates Src kinase [35] and GSK3β [[36][37]. MOR-signaling also induces the activation of these kinases, which has been associated with tolerance formation [23][24][25]. GSK3β plays important roles in a variety of human disorders, including inflammation, Alzheimer’s disease, mood disorders, diabetes, and cancer [38]. Thus, a mechanism similar to that occurring in type II diabetes might underlie the crosstalk between the UPR and analgesic signal transduction through MORs.

    Okuyama et al. examined the effects of pharmacological chaperones on opioid tolerance development by assessing thermal nociception in mice [39]. The pharmacological chaperones, such as 4-phenyl butyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) facilitate protein folding in the ER, and function as proteostasis regulators [40]. Pharmacological chaperones suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Those results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse.

    Opioids such as oxycodone and fentanyl have been prescribed for chronic pain, but the efficacy of long-term therapy has not been demonstrated [41][42][43]. High doses of opioid preparations for chronic pain can cause unfavorable side effects such as tolerance, hyperalgesia, addiction, and even death [44][45][46]. Buprenorphine, methadone, and naltrexone are currently used to reduce opioid use [46][47]. Buprenorphine and methadone are less preferred options because they themselves are opioids. Pharmacological chaperones such as PBA and TUDCA ameliorate opioid tolerance and maintain morphine’s analgesia. Moreover, the analgesic effect of opioids could be recovered by pharmacological ER chaperone administration even after tolerance had been induced [39]. Both PBA and TUDCA have few clinical side effects and may be effective treatments for opioid misuse through the reduction of opioid usage. Pharmacological chaperones may represent a promising therapeutic option for maintaining opioid analgesia without increasing prescriptions.

    The entry is from 10.3390/ijms21207536


    1. Somogyi, A.A.; Barratt, D.T.; Coller, J.K. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007, 81, 429-444.
    2. Ghelardini, C.; Di Cesare Mannelli, L.; Bianchi, E. The pharmacological basis of opioids. Clin Cases Miner Bone Metab 2015, 12, 219-221.
    3. Rutkow, L.; Vernick, J.S. Emergency Legal Authority and the Opioid Crisis. N Engl J Med 2017.
    4. Volkow, N.D.; Collins, F.S. The Role of Science in Addressing the Opioid Crisis. N Engl J Med 2017, 377, 391-394, doi:10.1056/NEJMsr1706626.
    5. Kim, S.H.; Stoicea, N.; Soghomonyan, S.; Bergese, S.D. Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol 2014, 5, 108.
    6. Chan, P.; Lutfy, K. Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System. Prog Mol Biol Transl Sci 2016, 137, 203-227, doi:10.1016/bs.pmbts.2015.10.005.
    7. Volkow, N.D.; McLellan, A.T. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med 2016, 374, 1253-1263.
    8. Aoe, T. Development of Opioid Tolerance and Endoplasmic Reticulum Stress. Journal of Pain & Relief 2015, 4.
    9. Dickinson, P.; Kimber, W.L.; Kilanowski, F.M.; Webb, S.; Stevenson, B.J.; Porteous, D.J.; Dorin, J.R. Enhancing the efficiency of introducing precise mutations into the mouse genome by hit and run gene targeting. Transgenic Res 2000, 9, 55-66.
    10. Zhang, J.; Ferguson, S.S.; Barak, L.S.; Bodduluri, S.R.; Laporte, S.A.; Law, P.Y.; Caron, M.G. Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc Natl Acad Sci U S A 1998, 95, 7157-7162.
    11. Johnson, E.E.; Christie, M.J.; Connor, M. The role of opioid receptor phosphorylation and trafficking in adaptations to persistent opioid treatment. Neurosignals 2005, 14, 290-302.
    12. Bohn, L.M.; Lefkowitz, R.J.; Gainetdinov, R.R.; Peppel, K.; Caron, M.G.; Lin, F.T. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999, 286, 2495-2498.
    13. Bohn, L.M.; Gainetdinov, R.R.; Lin, F.T.; Lefkowitz, R.J.; Caron, M.G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000, 408, 720-723.
    14. Gintzler, A.R.; Chakrabarti, S. Post-opioid receptor adaptations to chronic morphine; altered functionality and associations of signaling molecules. Life Sci 2006, 79, 717-722.
    15. Martini, L.; Whistler, J.L. The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol 2007, 17, 556-564.
    16. Zollner, C.; Mousa, S.A.; Fischer, O.; Rittner, H.L.; Shaqura, M.; Brack, A.; Shakibaei, M.; Binder, W.; Urban, F.; Stein, C., et al. Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest 2008, 118, 1065-1073.
    17. Araldi, D.; Ferrari, L.F.; Levine, J.D. Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain. J Neurosci 2015, 35, 12502-12517.
    18. Granados-Soto, V.; Kalcheva, I.; Hua, X.; Newton, A.; Yaksh, T.L. Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion. Pain 2000, 85, 395-404.
    19. Trujillo, K.A.; Akil, H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991, 251, 85-87.
    20. Adam, F.; Bonnet, F.; Le Bars, D. Tolerance to morphine analgesia: evidence for stimulus intensity as a key factor and complete reversal by a glycine site-specific NMDA antagonist. Neuropharmacology 2006, 51, 191-202.
    21. Al-Hasani, R.; Bruchas, M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 2011, 115, 1363-1381.
    22. Colvin, L.A.; Bull, F.; Hales, T.G. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 2019, 393, 1558-1568.
    23. Parkitna, J.R.; Obara, I.; Wawrzczak-Bargiela, A.; Makuch, W.; Przewlocka, B.; Przewlocki, R. Effects of glycogen synthase kinase 3beta and cyclin-dependent kinase 5 inhibitors on morphine-induced analgesia and tolerance in rats. J Pharmacol Exp Ther 2006, 319, 832-839.
    24. Dobashi, T.; Tanabe, S.; Jin, H.; Mimura, N.; Yamamoto, T.; Nishino, T.; Aoe, T. BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance. J Cell Mol Med 2010, 14, 2816-2826.
    25. Bull, F.A.; Baptista-Hon, D.T.; Sneddon, C.; Wright, L.; Walwyn, W.; Hales, T.G. Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation. Anesthesiology 2017, 127, 878-889.
    26. Kaufman, R.J. Orchestrating the unfolded protein response in health and disease. J Clin Invest 2002, 110, 1389-1398.
    27. Zhao, L.; Ackerman, S.L. Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol 2006, 18, 444-452.
    28. Jin, H.; Komita, M.; Aoe, T. The Role of BiP Retrieval by the KDEL Receptor in the Early Secretory Pathway and its Effect on Protein Quality Control and Neurodegeneration. Front Mol Neurosci 2017, 10, 222.
    29. Hamada, H.; Suzuki, M.; Yuasa, S.; Mimura, N.; Shinozuka, N.; Takada, Y.; Nishino, T.; Nakaya, H.; Koseki, H.; Aoe, T. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Mol Cell Biol 2004, 24, 8007-8017.
    30. Kimura, K.; Jin, H.; Ogawa, M.; Aoe, T. Dysfunction of the ER chaperone BiP accelerates the renal tubular injury. Biochem Biophys Res Commun 2008, 366, 1048-1053.
    31. Kokubun, H.; Jin, H.; Aoe, T. Pathogenic Effects of Impaired Retrieval between the Endoplasmic Reticulum and Golgi Complex. Int J Mol Sci 2019, 20, 5614.
    32. Ozcan, U.; Cao, Q.; Yilmaz, E.; Lee, A.H.; Iwakoshi, N.N.; Ozdelen, E.; Tuncman, G.; Gorgun, C.; Glimcher, L.H.; Hotamisligil, G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306, 457-461.
    33. Gintzler, A.R.; Chakrabarti, S. Opioid tolerance and the emergence of new opioid receptor-coupled signaling. Mol Neurobiol 2000, 21, 21-33.
    34. Araldi, D.; Khomula, E.V.; Ferrari, L.F.; Levine, J.D. Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. J Neurosci 2018, 38, 2226-2245.
    35. Tsai, Y.L.; Ha, D.P.; Zhao, H.; Carlos, A.J.; Wei, S.; Pun, T.K.; Wu, K.; Zandi, E.; Kelly, K.; Lee, A.S. Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-beta signaling. Proc Natl Acad Sci U S A 2018, 115, E4245-E4254.
    36. Song, L.; De Sarno, P.; Jope, R.S. Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem 2002, 277, 44701-44708.
    37. Qu, L.; Huang, S.; Baltzis, D.; Rivas-Estilla, A.M.; Pluquet, O.; Hatzoglou, M.; Koumenis, C.; Taya, Y.; Yoshimura, A.; Koromilas, A.E. Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev 2004, 18, 261-277.
    38. Jope, R.S.; Yuskaitis, C.J.; Beurel, E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 2007, 32, 577-595.
    39. Okuyama, Y.; Jin, H.; Kokubun, H.; Aoe, T. Pharmacological Chaperones Attenuate the Development of Opioid Tolerance. Int J Mol Sci 2020, 21.
    40. Liguori, L.; Monticelli, M.; Allocca, M.; Hay Mele, B.; Lukas, J.; Cubellis, M.V.; Andreotti, G. Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations. Int J Mol Sci 2020, 21.
    41. Chou, R.; Turner, J.A.; Devine, E.B.; Hansen, R.N.; Sullivan, S.D.; Blazina, I.; Dana, T.; Bougatsos, C.; Deyo, R.A. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015, 162, 276-286.
    42. Krebs, E.E.; Gravely, A.; Nugent, S.; Jensen, A.C.; DeRonne, B.; Goldsmith, E.S.; Kroenke, K.; Bair, M.J.; Noorbaloochi, S. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA 2018, 319, 872-882.
    43. Morasco, B.J.; Smith, N.; Dobscha, S.K.; Deyo, R.A.; Hyde, S.; Yarborough, B.J.H. Outcomes of prescription opioid dose escalation for chronic pain: results from a prospective cohort study. Pain 2020, 161, 1332-1340.
    44. Ekholm, O.; Kurita, G.P.; Hojsted, J.; Juel, K.; Sjogren, P. Chronic pain, opioid prescriptions, and mortality in Denmark: A population-based cohort study. Pain 2014, 155, 2486-2490.
    45. Kaplovitch, E.; Gomes, T.; Camacho, X.; Dhalla, I.A.; Mamdani, M.M.; Juurlink, D.N. Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study. PLoS One 2015, 10, e0134550, doi:10.1371/journal.pone.0134550.
    46. Babu, K.M.; Brent, J.; Juurlink, D.N. Prevention of Opioid Overdose. N Engl J Med 2019, 380, 2246-2255.
    47. Wakeman, S.E.; Barnett, M.L. Primary Care and the Opioid-Overdose Crisis - Buprenorphine Myths and Realities. N Engl J Med 2018, 379, 1-4.
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