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Advances in Pain Research: Mechanisms and Modulation of Chronic Pain pp 125–139Cite as

Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1099))

Abstract

Opioid analgesics remain the most effective and widely used analgesics for the management of moderate to severe pain, including cancer pain and chronic non-cancer pain. However, the efficacy of long-term opioid analgesics is attenuated by tolerance and/or hyperalgesia after long-term use, preventing adequate pain relief under stable opioid dosages for chronic pain patients. Classical neuron-centered concepts about tolerance, such as internalization of opioid receptors, upregulation of N-methyl-D-aspartate receptor function, or downregulation of glutamate transporter activity, can only partially explain the phenomenon of tolerance. Recent evidence revealing glial activation and upregulation of inflammatory mediators in the rodent central nervous system has confirmed the pivotal role of neuroinflammation in neuropathic pain or opioid tolerance, or both. However, human evidence is still sparse.

Based on our clinical practice, we conducted translational research by investigating the cerebrospinal fluid (CSF) cytokine and chemokine profiles of opioid-tolerant patients after research ethic committee approval. CSF samples from opioid-tolerant patients and opioid-naive subjects were compared. We found CXCL1, CXCL12, and leukemia inhibitory factor (LIF) were significantly upregulated among the opioid-tolerant patients and positively correlated with the opioid dosage.

We translated these findings back to lab animal experiment; after induction of tolerance by morphine infusion, the spinal cord expression of CXCL1, CXCL12, and LIF were all upregulated. Although CXCL1 and CXCL12 infusion alone did not affect baseline tail-flick latency, morphine analgesic efficacy dropped significantly after intrathecal infusion of CXCL1 and CXCL12. After establishing tolerance by intrathecal continuous infusion of morphine, tolerance development was accelerated by co-administration of CXCL1 and CXCL12. In parallel, the effect was attenuated by co-administration of CXCL1- or CXCL12-neutralizing antibody or concordant receptor antagonists.

On the contrary, although chronic morphine administration still induced LIF upregulation in rat spinal cords, intrathecal injection of LIF potentiated the analgesic action of morphine and delayed the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other pro-inflammatory cytokines.

CXCL1, CXCL12, and LIF are upregulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance were affected by modulating the intrathecal CXCL1/CXCR2, CXCL12/CXCR4, and LIF signaling and could be novel drug targets for the treatment of opioid tolerance.

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References

  1. Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115(6):1363–1381. https://doi.org/10.1097/ALN.0b013e318238bba6

    Article  CAS  PubMed  Google Scholar 

  2. Beitner-Johnson D, Guitart X, Nestler EJ (1993) Glial fibrillary acidic protein and the mesolimbic dopamine system: regulation by chronic morphine and Lewis-Fischer strain differences in the rat ventral tegmental area. J Neurochem 61(5):1766–1773

    Article  CAS  PubMed  Google Scholar 

  3. Berta T, Liu T, Liu YC, Xu ZZ, Ji RR (2012) Acute morphine activates satellite glial cells and up-regulates IL-1beta in dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain 8:18. https://doi.org/10.1186/1744-8069-8-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA (2009) Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol Pain 5:48. https://doi.org/10.1186/1744-8069-5-48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chapman CR, Lipschitz DL, Angst MS, Chou R, Denisco RC, Donaldson GW, … Weisner CM (2010) Opioid pharmacotherapy for chronic non-cancer pain in the United States: a research guideline for developing an evidence-base. J Pain 11(9):807–829. doi:https://doi.org/10.1016/j.jpain.2010.02.019

    Article  PubMed  Google Scholar 

  6. Che X, Ye W, Panga L, Wu DC, Yang GY (2001) Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 902(2):171–177

    Article  CAS  PubMed  Google Scholar 

  7. Clark AK, Old EA, Malcangio M (2013) Neuropathic pain and cytokines: current perspectives. J Pain Res 6:803–814. https://doi.org/10.2147/JPR.S53660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, … Feng JQ (2008) A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 22(1):114–123. doi:https://doi.org/10.1016/j.bbi.2007.07.014

    Article  CAS  PubMed  Google Scholar 

  9. Dubovy P, Klusakova I, Svizenska I, Brazda V (2010) Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain. Histochem Cell Biol 133(3):323–337. https://doi.org/10.1007/s00418-010-0675-0

    Article  CAS  PubMed  Google Scholar 

  10. Engert S, Wendland JR, Schwab A, Petersen M (2008) Leukemia inhibitory factor differentially regulates capsaicin and heat sensitivity in cultured rat dorsal root ganglion neurons. Neuropeptides 42(2):193–197. https://doi.org/10.1016/j.npep.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  11. Flugel A, Hager G, Horvat A, Spitzer C, Singer GM, Graeber MB et al (2001) Neuronal MCP-1 expression in response to remote nerve injury. J Cereb Blood Flow Metab 21(1):69–76. https://doi.org/10.1097/00004647-200101000-00009

    Article  CAS  PubMed  Google Scholar 

  12. Franciotta D, Zardini E, Ravaglia S, Piccolo G, Andreoni L, Bergamaschi R et al (2006) Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis. J Neurol Sci 247(2):202–207. https://doi.org/10.1016/j.jns.2006.05.049

    Article  CAS  PubMed  Google Scholar 

  13. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ et al (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29(13):4096–4108. https://doi.org/10.1523/JNEUROSCI.3623-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, … Ren K (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27(22):6006–6018. doi:https://doi.org/10.1523/JNEUROSCI.0176-07.2007

    Article  CAS  PubMed  Google Scholar 

  15. Hendriks JJ, Slaets H, Carmans S, de Vries HE, Dijkstra CD, Stinissen P, Hellings N (2008) Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. J Neuroimmunol 204(1–2):52–57. https://doi.org/10.1016/j.jneuroim.2008.07.015

    Article  CAS  PubMed  Google Scholar 

  16. Horvath RJ, DeLeo JA (2009) Morphine enhances microglial migration through modulation of P2X4 receptor signaling. J Neurosci 29(4):998–1005. https://doi.org/10.1523/JNEUROSCI.4595-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu XM, Liu YN, Zhang HL, Cao SB, Zhang T, Chen LP, Shen W (2015) CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats. J Neurochem 132(4):452–463. https://doi.org/10.1111/jnc.12985

    Article  CAS  PubMed  Google Scholar 

  18. Hutchinson MR, Northcutt AL, Chao LW, Kearney JJ, Zhang Y, Berkelhammer DL et al (2008) Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia. Brain Behav Immun 22(8):1248–1256. https://doi.org/10.1016/j.bbi.2008.07.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR (2011) Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev 63(3):772–810. https://doi.org/10.1124/pr.110.004135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK (2011) Increased expression of the chemokines CXCL1 and MIP-1alpha by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation 8:41. https://doi.org/10.1186/1742-2094-8-41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Johnson JL, Rolan PE, Johnson ME, Bobrovskaya L, Williams DB, Johnson K et al (2014) Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation. Transl Psychiatry 4:e482. https://doi.org/10.1038/tp.2014.121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J et al (2004) A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33):7353–7365. https://doi.org/10.1523/JNEUROSCI.1850-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Juni A, Klein G, Pintar JE, Kest B (2007) Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neuroscience 147(2):439–444. https://doi.org/10.1016/j.neuroscience.2007.04.030

    Article  CAS  PubMed  Google Scholar 

  24. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L (2011) A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14(2):145–161

    PubMed  Google Scholar 

  25. Lilius TO, Rauhala PV, Kambur O, Kalso EA (2009) Modulation of morphine-induced antinociception in acute and chronic opioid treatment by ibudilast. Anesthesiology 111(6):1356–1364. https://doi.org/10.1097/ALN.0b013e3181bdfa11

    Article  CAS  PubMed  Google Scholar 

  26. Lin CP, Kang KH, Lin TH, Wu MY, Liou HC, Chuang WJ et al (2015) Role of spinal CXCL1 (GROalpha) in opioid tolerance: a human-to-rodent translational study. Anesthesiology 122(3):666–676. https://doi.org/10.1097/ALN.0000000000000523

    Article  CAS  PubMed  Google Scholar 

  27. Lin CP, Kang KH, Tu HJ, Wu MY, Lin TH, Liou HC et al (2017) CXCL12/CXCR4 Signaling contributes to the pathogenesis of opioid tolerance: a translational study. Anesth Analg 124(3):972–979. https://doi.org/10.1213/ANE.0000000000001480

    Article  CAS  PubMed  Google Scholar 

  28. Luo X, Tai WL, Sun L, Qiu Q, Xia Z, Chung SK, Cheung CW (2014) Central administration of C-X-C chemokine receptor type 4 antagonist alleviates the development and maintenance of peripheral neuropathic pain in mice. PLoS One 9(8):e104860. https://doi.org/10.1371/journal.pone.0104860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mao J, Price DD, Mayer DJ (1994) Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 14(4):2301–2312

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Menichella DM, Abdelhak B, Ren D, Shum A, Frietag C, Miller RJ (2014) CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy. Mol Pain 10:42. https://doi.org/10.1186/1744-8069-10-42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36. https://doi.org/10.1038/nrn2533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Narita M, Mizoguchi H, Narita M, Nagase H, Suzuki T, Tseng LF (2001) Involvement of spinal protein kinase Cgamma in the attenuation of opioid mu-receptor-mediated G-protein activation after chronic intrathecal administration of [D-Ala2,N-MePhe4,Gly-Ol(5)] enkephalin. J Neurosci 21(11):3715–3720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Okie S (2010) A flood of opioids, a rising tide of deaths. N Engl J Med 363(21):1981–1985. https://doi.org/10.1056/NEJMp1011512

    Article  CAS  PubMed  Google Scholar 

  34. Pertovaara A, Wei H (2001) Peripheral effects of morphine in neuropathic rats: role of sympathetic postganglionic nerve fibers. Eur J Pharmacol 429(1–3):139–145

    Article  CAS  PubMed  Google Scholar 

  35. Pranzatelli MR, Tate ED, McGee NR, Colliver JA (2013) Cytokines, cytokine antagonists, and soluble adhesion molecules in pediatric OMS and other neuroinflammatory disorders. J Neurol Sci 326(1–2):53–58. https://doi.org/10.1016/j.jns.2013.01.011

    Article  CAS  PubMed  Google Scholar 

  36. Raghavendra V, Rutkowski MD, DeLeo JA (2002) The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci 22(22):9980–9989

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Raghavendra V, Tanga FY, DeLeo JA (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29(2):327–334. https://doi.org/10.1038/sj.npp.1300315

    Article  CAS  PubMed  Google Scholar 

  38. Reaux-Le Goazigo A, Rivat C, Kitabgi P, Pohl M, Melik Parsadaniantz S (2012) Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance. Eur J Neurosci 36(5):2619–2631. https://doi.org/10.1111/j.1460-9568.2012.08179.x

    Article  PubMed  Google Scholar 

  39. Reaux-Le Goazigo A, Van Steenwinckel J, Rostene W, Melik Parsadaniantz S (2013) Current status of chemokines in the adult CNS. Prog Neurobiol 104:67–92. https://doi.org/10.1016/j.pneurobio.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  40. Rivat C, Sebaihi S, Van Steenwinckel J, Fouquet S, Kitabgi P, Pohl M et al (2014) Src family kinases involved in CXCL12-induced loss of acute morphine analgesia. Brain Behav Immun 38:38–52. https://doi.org/10.1016/j.bbi.2013.11.010

    Article  CAS  PubMed  Google Scholar 

  41. Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R (2005) Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain 115(1–2):50–59. https://doi.org/10.1016/j.pain.2005.02.003

    Article  CAS  PubMed  Google Scholar 

  42. Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS (2011) Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg 112(2):454–459. https://doi.org/10.1213/ANE.0b013e3182025b15

    Article  CAS  PubMed  Google Scholar 

  43. Shen CH, Tsai RY, Wong CS (2012) Role of neuroinflammation in morphine tolerance: effect of tumor necrosis factor-alpha. Acta Anaesthesiol Taiwanica 50(4):178–182. https://doi.org/10.1016/j.aat.2012.12.004

    Article  Google Scholar 

  44. Shen W, Hu XM, Liu YN, Han Y, Chen LP, Wang CC, Song C (2014) CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord. J Neuroinflammation 11:75. https://doi.org/10.1186/1742-2094-11-75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Simamura E, Shimada H, Higashi N, Uchishiba M, Otani H, Hatta T (2010) Maternal leukemia inhibitory factor (LIF) promotes fetal neurogenesis via a LIF-ACTH-LIF signaling relay pathway. Endocrinology 151(4):1853–1862. https://doi.org/10.1210/en.2009-0985

    Article  CAS  PubMed  Google Scholar 

  46. Song P, Zhao ZQ (2001) The involvement of glial cells in the development of morphine tolerance. Neurosci Res 39(3):281–286

    Article  CAS  PubMed  Google Scholar 

  47. Spofford CM, Mohan S, Kang S, Jang JH, Brennan TJ (2011) Evaluation of leukemia inhibitory factor (LIF) in a rat model of postoperative pain. J Pain 12(7):819–832. https://doi.org/10.1016/j.jpain.2011.02.351

    Article  CAS  PubMed  Google Scholar 

  48. Stein C, Reinecke H, Sorgatz H (2010) Opioid use in chronic noncancer pain: guidelines revisited. Curr Opin Anaesthesiol 23(5):598–601. https://doi.org/10.1097/ACO.0b013e32833c57a8

    Article  PubMed  Google Scholar 

  49. Stein C, Schafer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nat Med 9(8):1003–1008. https://doi.org/10.1038/nm908

    Article  CAS  PubMed  Google Scholar 

  50. Tai YH, Wang YH, Wang JJ, Tao PL, Tung CS, Wong CS (2006) Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats. Pain 124(1–2):77–86. https://doi.org/10.1016/j.pain.2006.03.018

    Article  CAS  PubMed  Google Scholar 

  51. Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251(4989):85–87

    Article  CAS  PubMed  Google Scholar 

  52. Tu HJ, Kang KH, Ho SY, Liou HC, Liou HH, Lin CP, Fu WM (2016) Leukemia inhibitory factor (LIF) potentiates antinociception activity and inhibits tolerance induction of opioids. Br J Anaesth 117(4):512–520. https://doi.org/10.1093/bja/aew247

    Article  CAS  PubMed  Google Scholar 

  53. Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR (2011) Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc 110(8):487–494. https://doi.org/10.1016/S0929-6646(11)60074-0

    Article  PubMed  PubMed Central  Google Scholar 

  54. White FA, Bhangoo SK, Miller RJ (2005a) Chemokines: integrators of pain and inflammation. Nat Rev Drug Discov 4(10):834–844. https://doi.org/10.1038/nrd1852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. White FA, Jung H, Miller RJ (2007) Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 104(51):20151–20158. https://doi.org/10.1073/pnas.0709250104

    Article  PubMed  PubMed Central  Google Scholar 

  56. White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M et al (2005b) Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A 102(39):4092–14097. https://doi.org/10.1073/pnas.0503496102

    Article  CAS  Google Scholar 

  57. Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA (2011) CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun 25(3):565–573. https://doi.org/10.1016/j.bbi.2010.12.014

    Article  CAS  PubMed  Google Scholar 

  58. Zhang ZJ, Cao DL, Zhang X, Ji RR, Gao YJ (2013) Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154(10):2185–2197. https://doi.org/10.1016/j.pain.2013.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao CM, Guo RX, Hu F, Meng JL, Mo LQ, Chen PX et al (2012) Spinal MCP-1 contributes to the development of morphine antinociceptive tolerance in rats. Am J Med Sci 344(6):473–479. https://doi.org/10.1097/MAJ.0b013e31826a82ce

    Article  PubMed  Google Scholar 

  60. Zhou L, Zhang Q, Stein C, Schafer M (1998) Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther 286(2):1000–1006

    CAS  PubMed  Google Scholar 

  61. Zwijnenburg PJ, de Bie HM, Roord JJ, van der Poll T, van Furth AM (2003) Chemotactic activity of CXCL5 in cerebrospinal fluid of children with bacterial meningitis. J Neuroimmunol 145(1–2):148–153

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan

    Chih-Peng Lin & Dai-Hua Lu

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  1. Chih-Peng Lin
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Editors and Affiliations

  1. Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Bai-Chuang Shyu

  2. Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan

    Makoto Tominaga

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Lin, CP., Lu, DH. (2018). Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies. In: Shyu, BC., Tominaga, M. (eds) Advances in Pain Research: Mechanisms and Modulation of Chronic Pain. Advances in Experimental Medicine and Biology, vol 1099. Springer, Singapore. https://doi.org/10.1007/978-981-13-1756-9_11

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