Chronic pain is a major health issue in our society that clearly impacts quality of life. Thirty to forty percent of the population in the United States suffer from chronic pain and its total cost have been estimated at 560-635 billion dollars annually. Even if research progresses to develop novel analgesics, opioids remain the gold standard to treat pain. However, opioid treatment is associated with several adverse side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). OIH is of major importance and the use of morphine continues to increase. Analgesia tolerance corresponds to a progressive decrease of analgesia produced by a given dose of opioid upon chronic administration, resulting in the need to increase the dosage in order to maintain the initial analgesic effect. OIH usually clinically presents itself as the development of hypersensitivity to painful stimuli. OIH is well established in humans in different types of pain such as post-surgical pain, cancer pain and musculoskeletal pain.[2-4] Hence, clinicians face a dilemma to decided to either treat or not treat chronic pain with opioids which the knowledge of the patient developing pain hypersensitivity that may develop into opioid dependence. OIH is not yet completely understood and different mechanisms have been identified for this adaptive process to occur following opioid administration. These included the sensitization of primary afferent neurons and enhanced release of glutamate, hyperexcitability of second order neurons to excitatory neurotransmitters. However, more recently glial cells have been shown to play an important role in OIH. Receptors expressed in both microglia and astrocytes become activated in OIH.
Long-term potentiation (LTP) is a sensitization of synapse (homo- and heterosynaptic) that enhances the strength of the synapse and its signal transduction. Increase LTP can cause hypersensitivity and may lead to hyperalgesia and has been shown to be involved in OIH. In addition to glutamate-NMDA receptor mediated LTP in OIH, glial cells and released pro-inflammatory mediator have also been implicated in LTP in OIH. For example, cytokines interleukin-1beta (IL-1β) and tumor necrosis factor-α (TNF-α) can enhance post-synaptic potentials leading to neuronal excitation in the spinal cord. Cytokines in the central nervous system act mostly through the activation of glial cells to induce the release of other mediators that trigger LTP and hyperexcitability or neurons that leads to OIH. The pro-inflammatory cytokine, IL-1β plays a major role in host defense and inflammation and is associated with inflammatory pain and opioid analgesia. In rodent models, peripheral administration of IL-1β produced hyperalgesia and reduced morphine analgesia while contributing to morphine tolerance.[8,9] At the molecular level, the interaction of IL-1β and the opioid system is shown by the finding that IL-1β increased the levels of mu opioid receptor (MOR) mRNA in primary astrocytes, neurons and in neural microvascular endothelial cells.[10-12] Other cytokines, including IFNα, TNFα, IL-4 and IL-6, also increase the expression of MOR in neuroblastoma cells and peripheral immune cells.[13-15] These results and others show that cytokines interact with endogenous opioid systems but explicit molecular mechanisms remain elusive. Interleukin-1beta mediates its effects through the interleukin-1 receptor type 1 (IL1R1) protein, which is a member of the Toll-like/IL-1R1 (TIR) domain family of membrane receptors. Like the Toll-like receptors, the IL1R1 receptor signals through a complex of accessory proteins and downstream signaling events including activation of the JAK-STAT, MAPK, and NF-κB pathways. Functional studies in cell lines show that transcription factors from the JAK-STAT, MAPK and NF-κB signaling pathways alter MOR gene transcription after cytokine stimulation.[10,18,19]
The NOD-like receptor protein 3 (NLRP3) inflammasome and downstream release of IL-1β are involved in pain conditions such as post-operative pain, post-herpetic neuralgia, diabetic peripheral neuropathy and spinal cord injury and if not controlled can lead to neuropathic pain. In these and other forms of pain conditions, opioid such as morphine remains the gold standard analgesic and opioid use for pain management has dramatically increased, with little assessment of the pathological consequences on the primary pain condition. Recent data has shown that prolonged treatment with morphine doubled the duration of pain associate with nerve injury independent of opioid-receptor selectivity. Morphine-mediated persistence of pain was attenuated following co-administration with the IL-1 receptor antagonist (IL-1ra). Prolonged morphine use can activate glial toll-like receptors such as the toll-like receptor 4 (TLR4) which following priming ensures neurotoxicity, immune mediated amplification of nociceptive signaling in the spinal cord.[5,21-23] Evidence has also shown that morphine can directly compromise opioid-induced analgesia by promoting proinflammation via a TLR4 dependent mechanism and can potentiate mechanical allodynia.[24,25]
Reactive microglia has been implicated in playing a key role in morphine-mediated persistent pain conditions as demonstrated with the use of glial cell blockers.[26-29] It is noteworthy that while there are many reports that have described the importance of neuroinflammation in analgesic tolerance, since 2002 only a dozen few have focused on immune mechanism for OIH with four of the studies showing that the blockade of IL-1β reduced OIH.[30-33] In astrocytes, morphine exposure has shown to trigger astrocytes activation and lead to the upregulation of IL-1β. Also, more recently, ultra-low dose morphine induced OIH was found to selectively activate astrocytes. Together, this indicates that concurrent activation of microglia and astrocytes are involved in OIH.
In conclusion, my hypothesis is that opioid tolerance is a consequence of OIH. The increase in pain sensitivity caused by OIH masks opioid analgesia and if this continues would lead to opioid tolerance. At the molecular level, increased, chronic use of opioids would cause a decrease in MOR expression contributing to a loss of any analgesia mediated by opioids. Therefore, in the future it would be key to determine the cellular chronological order involved in increasing synaptic activity (i.e. LTP), which is normally mediated by increased levels of glutamate in the synaptic cleft and is removed by astrocytes. Current research shows that the common thread that may lead to OIH is the pro-inflammatory cytokine, IL-1β. Morphine alone can increase the expression and release of IL-1β from activated microglia and this increase may disrupt glutamate homeostasis. Recent evidence has shown that IL-1β can down-regulate the expression of GLT-1 and directly elevate the levels of glutamate and trigger the release of ATP from glia. Increased glutamate, ATP and reactive oxygen species may contribute to excitotoxicity and chronic inflammatory and therefore the cycle may continue until morphine is discontinued. Current and previous data supports the rationale to further examine whether the management of pain with opioids such as morphine contributes to a neuroinflammatory challenge that then leads to opioid tolerance and other pain comorbidities.
Financial support and sponsorship
Supported by the Marshall University, School of Pharmacy, Faculty Research Support (FRS) grant.
Conflict of interest
There are no conflicts of interest.
No patient involved.
This article does not contain any studies with human participants or animals.
- 1. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012;13:715-24.
- 2. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 2014;112:991-1004.
- 3. Carullo V, Fitz-James I, Delphin E. Opioid-induced hyperalgesia: a diagnostic dilemma. J Pain Palliat Care Pharmacother 2015;29:378-84.
- 4. Crofford LJ. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat Rev Rheumatol 2010;6:191-7.
- 5. Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev 2011;63:772-810.
- 6. Drdla R, Gassner M, Gingl E, Sandkuhler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science 2009;325:207-10.
- 7. Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, Wunderbaldinger G, Gassner M, Sandkuhler J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J Neurosci 2013;33:6540-51.
- 8. Ferreira SH, Lorenzetti BB, Bristow AF, Poole S. Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature 1988;334:698-700.
- 9. Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R. Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain 2005;115:50-9.
- 10. Mohan S, Davis RL, DeSilva U, Stevens CW. Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1beta: evidence for opioid-immune crosstalk. J Neuroimmunol 2010;227:26-34.
- 11. Ruzicka BB, Akil H. The interleukin-1beta-mediated regulation of proenkephalin and opioid receptor messenger RNA in primary astrocyte-enriched cultures. Neuroscience 1997;79:517-24.
- 12. Vidal EL, Patel NA, Wu G, Fiala M, Chang SL. Interleukin-1 induces the expression of mu opioid receptors in endothelial cells. Immunopharmacology 1998;38:261-6.
- 13. Borner C, Hollt V, Kraus J. Involvement of activator protein-1 in transcriptional regulation of the human mu-opioid receptor gene. Mol Pharmacol 2002;61:800-5.
- 14. Im HJ, Kang SW, Loh HH. Opioid receptor gene: cytokine response element and the effect of cytokines. Brain Res 1999;829:174-9.
- 15. Kraus J, Borner C, Giannini E, Hickfang K, Braun H, Mayer P, Hoehe MR, Ambrosch A, Konig W, Hollt V. Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J Biol Chem 2001;276:43901-8.
- 16. O’Neill LA. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol 2002;270:47-61.
- 17. Hibi M, Hirano T. Signal transduction through cytokine receptors. Int Rev Immunol 1998;17:75-102.
- 18. Kraus J, Borner C, Giannini E, Hollt V. The role of nuclear factor kappaB in tumor necrosis factor-regulated transcription of the human mu-opioid receptor gene. Mol Pharmacol 2003;64:876-84.
- 19. Kraus J, Borner C, Lendeckel U, Hollt V. Interferon-gamma down-regulates transcription of the mu-opioid receptor gene in neuronal and immune cells. J Neuroimmunol 2006;181:13-8.
- 20. Kleibeuker W, Gabay E, Kavelaars A, Zijlstra J, Wolf G, Ziv N, Yirmiya R, Shavit Y, Tal M, Heijnen CJ. IL-1 beta signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2. Brain Behav Immun 2008;22:200-8.
- 21. Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, Fabisiak TJ, Anderson ND, Cheng K, Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH, Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 2016;113:E3441-50.
- 22. Nicotra L, Loram LC, Watkins LR, Hutchinson MR. Toll-like receptors in chronic pain. Exp Neurol 2012;234:316-29.
- 23. Peirs C, Seal RP. Targeting Toll-like receptors to treat chronic pain. Nat Med 2015;21:1251-2.
- 24. Loram LC, Grace PM, Strand KA, Taylor FR, Ellis A, Berkelhammer D, Bowlin M, Skarda B, Maier SF, Watkins LR. Prior exposure to repeated morphine potentiates mechanical allodynia induced by peripheral inflammation and neuropathy. Brain Behav Immun 2012;26:1256-64.
- 25. Wang X, Loram LC, Ramos K, de Jesus AJ, Thomas J, Cheng K, Reddy A, Somogyi AA, Hutchinson MR, Watkins LR, Yin H. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A 2012;109:6325-30.
- 26. Jiang C, Xu L, Chen L, Han Y, Tang J, Yang Y, Zhang G, Liu W. Selective suppression of microglial activation by paeoniflorin attenuates morphine tolerance. Eur J Pain 2015;19:908-19.
- 27. Cai Y, Kong H, Pan YB, Jiang L, Pan XX, Hu L, Qian YN, Jiang CY, Liu WT. Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation 2016;13:53.
- 28. Hayashi Y, Morinaga S, Zhang J, Satoh Y, Meredith AL, Nakata T, Wu Z, Kohsaka S, Inoue K, Nakanishi H. BK channels in microglia are required for morphine-induced hyperalgesia. Nat Commun 2016;7:11697.
- 29. Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX, Feng JQ. A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 2008;22:114-23.
- 30. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 2004;24:7353-65.
- 31. Johnson JL, Rolan PE, Johnson ME, Bobrovskaya L, Williams DB, Johnson K, Tuke J, Hutchinson MR. Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation. Transl Psychiatry 2014;4:e482.
- 32. Raghavendra V, Rutkowski MD, DeLeo JA. The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci 2002;22:9980-9.
- 33. Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, Rice KC, Watkins LR. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 2010;165:569-83.
- 34. Berta T, Liu T, Liu YC, Xu ZZ, Ji RR. Acute morphine activates satellite glial cells and up-regulates IL-1beta in dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain 2012;8:18.
- 35. Sanna MD, Ghelardini C, Galeotti N. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia. Pain 2015;156:1265-75.