Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies
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.
KeywordsOpioid tolerance Neuroinflammation Chemokine Cytokine Translational research
- 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 CrossRefPubMedCentralGoogle 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 CrossRefPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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):3715–3720CrossRefPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefGoogle Scholar