Interaction of Opioids with TLR4—Mechanisms and Ramifications

Cancers - Tập 13 Số 21 - Trang 5274
Mai Mahmoud Gabr1, Iqira Saeed1, Jared A. Miles1, Benjamin P. Ross1, P. Nicholas Shaw1, Markus W. Hollmann2, Marie‐Odile Parat1
1School of Pharmacy, The University of Queensland, St Lucia, QLD 4072, Australia
2Academic Medical Center, Department of Anaesthesiology, 1100DD Amsterdam, The Netherlands

Tóm tắt

The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.

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Tài liệu tham khảo

Caso, 2016, Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases, Neurosci. Biobehav. Rev., 64, 134, 10.1016/j.neubiorev.2016.02.013

Pandey, 2018, TLR4 Polymorphisms and Expression in Solid Cancers, Mol. Diagn. Ther., 22, 683, 10.1007/s40291-018-0361-9

Vijay, 2018, Toll-like receptors in immunity and inflammatory diseases: Past, present, and future, Int. Immunopharmacol., 59, 391, 10.1016/j.intimp.2018.03.002

Alexander, 2001, Bacterial lipopolysaccharides and innate immunity, J Endotoxin Res., 7, 167

2015, Toll-like receptors: Activation, signalling and transcriptional modulation, Cytokine, 74, 181, 10.1016/j.cyto.2015.02.025

Li, 2017, The role of toll-like receptor 4 in tumor microenvironment, Oncotarget, 8, 66656, 10.18632/oncotarget.19105

Mai, 2013, Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: Its expression and effects in the ten most common cancers, Onco Targets, 6, 1573

Khademalhosseini, 2019, Toll-like receptor 4 and breast cancer: An updated systematic review, Breast Cancer, 26, 265, 10.1007/s12282-018-00935-2

Sato, 2009, Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment, Cancer Microenviron., 2, 205, 10.1007/s12307-009-0022-y

Molteni, 2006, Melanoma cell lines are responsive in vitro to lipopolysaccharide and express TLR-4, Cancer Lett., 235, 75, 10.1016/j.canlet.2005.04.006

Ikebe, 2009, Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway, J. Surg. Oncol., 100, 725, 10.1002/jso.21392

Liao, 2012, Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes alphavbeta3-mediated adhesion and invasive migration, Breast Cancer Res Treat, 133, 853, 10.1007/s10549-011-1844-0

Chung, 2016, Enhanced TLR4 Expression on Colon Cancer Cells After Chemotherapy Promotes Cell Survival and Epithelial–Mesenchymal Transition through Phosphorylation of GSK3β, Anticancer Res., 36, 3383

Sun, 2016, Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling, Exp. Cell Res., 347, 274, 10.1016/j.yexcr.2016.07.009

Kang, 2013, HMGB1 in Cancer: Good, Bad, or Both?, Clin. Cancer Res., 19, 4046, 10.1158/1078-0432.CCR-13-0495

Schlueter, 2005, Angiogenetic Signaling through Hypoxia: HMGB1: An Angiogenetic Switch Molecule, Am. J. Pathol., 166, 1259, 10.1016/S0002-9440(10)62344-9

Yu, 2014, Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein, Nat. Commun., 5, 5256, 10.1038/ncomms6256

Afsharimoghaddam, 2016, Controversial roles played by toll like receptor 4 in urinary bladder cancer; A systematic review, Life Sci., 158, 31, 10.1016/j.lfs.2016.06.013

Apetoh, 2007, Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy, Nat. Med., 13, 1050, 10.1038/nm1622

Matzner, 2015, Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects, Int. J. Cancer, 138, 1754, 10.1002/ijc.29885

Das, 1995, Modulatory effects of [Met5]-enkephalin on interleukin-1 beta secretion from microglia in mixed brain cell cultures, J. Neuroimmunol., 62, 9, 10.1016/0165-5728(95)00083-E

Kong, 1997, Inhibition of lipopolysaccharide-induced nitric oxide and cytokine production by ultralow concentrations of dynorphins in mixed glia cultures, J. Pharmacol. Exp. Ther., 280, 61

Liu, 2000, Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation, J. Pharmacol. Exp. Ther., 293, 607

Liu, 2000, Reduction by naloxone of lipopolysaccharide-induced neurotoxicity in mouse cortical neuron-glia co-cultures, Neuroscience, 97, 749, 10.1016/S0306-4522(00)00057-9

Cheng, 2014, HSP60 is involved in the neuroprotective effects of naloxone, Mol. Med. Rep., 10, 2172, 10.3892/mmr.2014.2411

Bian, 1995, Effects of morphine and naloxone on proliferation of lymphocytes in vitro, Acta Pharmacol. Sin., 16, 315

Husted, 2005, A δ2-opioid agonist inhibits p38 MAPK and suppresses activation of murine macrophages, J. Surg. Res., 128, 45, 10.1016/j.jss.2005.04.003

Hyejin, 2013, Remifentanil attenuates human neutrophils activation induced by lipopolysaccharide, Immunopharmacol. Immunotoxicol., 35, 264, 10.3109/08923973.2013.767346

Bastami, 2013, Inhibitory effect of opiates on LPS mediated release of TNF and IL-8, Acta Oncol., 52, 1022, 10.3109/0284186X.2012.737932

Mottaz, 2017, Dose-dependent effects of morphine on lipopolysaccharide (LPS)-induced inflammation, and involvement of multixenobiotic resistance (MXR) transporters in LPS efflux in teleost fish, Environ. Pollut., 221, 105, 10.1016/j.envpol.2016.11.046

Back, 2010, Intra-articular opioid analgesia is effective in reducing pain and inflammation in an equine LPS induced synovitis model, Equine Vet. J., 42, 412, 10.1111/j.2042-3306.2010.00077.x

Lysle, 1999, Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes, J. Pharmacol. Exp. Ther., 288, 502

Ji, 2019, μ-Opioid receptor signalling via PI3K/Akt pathway ameliorates lipopolysaccharide-induced acute respiratory distress syndrome, Exp. Physiol., 104, 1555, 10.1113/EP087783

Davis, 2017, The opioid antagonist, β-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice, Physiol. Behav., 173, 52, 10.1016/j.physbeh.2017.01.037

Messmer, 2006, Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation, Mol. Med., 12, 284, 10.2119/2006-00043.Messmer

Wu, 2009, Effects of remifentanyl and fentanyl on LPS-induced cytokine release in human whole blood in vitro, Mol. Biol. Rep., 36, 1113, 10.1007/s11033-008-9286-4

Cheng, 2008, Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein, J. Exp. Med., 205, 2235, 10.1084/jem.20080132

Hutchinson, 2008, Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: Involvement of toll-like receptor 4 (TLR4), Eur. J. Neurosci., 28, 20, 10.1111/j.1460-9568.2008.06321.x

Hutchinson, 2010, Evidence that opioids may have toll-like receptor 4 and MD-2 effects, Brain Behav. Immun., 24, 83, 10.1016/j.bbi.2009.08.004

Stevens, 2013, Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4, Br. J. Pharmacol., 168, 1421, 10.1111/bph.12028

Cruz, 2013, Morphine prevents lipopolysaccharide-induced TNF secretion in mast cells blocking IκB kinase activation and SNAP-23 phosphorylation: Correlation with the formation of a β-arrestin/TRAF6 complex, J. Immunol., 191, 3400, 10.4049/jimmunol.1202658

Skolnick, 2014, Translational potential of naloxone and naltrexone as TLR4 antagonists, Trends Pharmacol. Sci., 35, 431, 10.1016/j.tips.2014.06.008

Selfridge, 2015, Structure–Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists, J. Med. Chem., 58, 5038, 10.1021/acs.jmedchem.5b00426

Wan, 2015, Morphine potentiates LPS-induced autophagy initiation but inhibits autophagosomal maturation through distinct TLR 4-dependent and independent pathways, Acta Physiol., 214, 189, 10.1111/apha.12506

Gessi, 2016, The activation of μ-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia, FEBS Lett., 590, 2813, 10.1002/1873-3468.12313

Fazalul Rahiman, S.S., Morgan, M., Gray, P., Shaw, P.N., and Cabot, P.J. (2016). Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells. PLoS ONE, 11.

Piotrowska, 2017, Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners, Neural Plast., 2017, 1

Wang, 2016, Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4, Br. J. Pharmacol., 173, 856, 10.1111/bph.13394

Xie, 2017, Activation of μ-opioid receptor and Toll-like receptor 4 by plasma from morphine-treated mice, Brain Behav. Immun., 61, 244, 10.1016/j.bbi.2016.12.002

Montesinos, 2017, Nalmefene Prevents Alcohol-Induced Neuroinflammation and Alcohol Drinking Preference in Adolescent Female Mice: Role of TLR4, Alcohol. Clin. Exp. Res., 41, 1257, 10.1111/acer.13416

Cant, 2017, Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors, Front. Immunol., 8, 809, 10.3389/fimmu.2017.00809

Rahiman, 2017, Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway, Peptides, 90, 48, 10.1016/j.peptides.2017.02.004

Lei, 2018, Remifentanil attenuates lipopolysaccharide-induced oxidative injury by downregulating PKCβ2 activation and inhibiting autophagy in H9C2 cardiomyocytes, Life Sci., 213, 109, 10.1016/j.lfs.2018.10.041

Zhang, 2019, Remifentanil Protects against Lipopolysaccharide-Induced Inflammation through PARP-1/NF-κB Signaling Pathway, Mediat. Inflamm., 2019, 3013716, 10.1155/2019/3013716

Zhou, 2020, Oxycodone suppresses the lipopolysaccharide-induced neuroinflammation by downregulating nuclear factor-κB in hippocampal astrocytes of Sprague–Dawley rats, NeuroReport, 31, 99, 10.1097/WNR.0000000000001376

Zeng, 2020, Kappa Opioid Receptor on Pulmonary Macrophages and Immune Function, Transl. Perioper. Pain Med., 7, 225

Choubey, A., Dehury, B., Kumar, S., Medhi, B., and Mondal, P. (2020). Naltrexone a potential therapeutic candidate for COVID-19. J. Biomol. Struct. Dyn., 1–8.

Cui, 2021, Beta-endorphin inhibits the inflammatory response of bovine endometrial cells through δ opioid receptor in vitro, Dev. Comp. Immunol., 121, 104074, 10.1016/j.dci.2021.104074

Li, 2021, Oxycodone attenuates vascular leak and lung inflammation in a clinically relevant two-hit rat model of acute lung injury, Cytokine, 138, 155346, 10.1016/j.cyto.2020.155346

Cheng, 2021, δ-Opioid receptor activation ameliorates lipopolysaccharide-induced inflammation and apoptosis by inhibiting the MAPK/caspase-3 pathway in BV2 microglial cells, Exp. Brain Res., 239, 401, 10.1007/s00221-020-05983-9

Vaidya, 2021, Attenuation of ongoing neuropathic pain by peripheral acting opioid involves activation of central dopaminergic neurocircuitry, Neurosci. Lett., 754, 135751, 10.1016/j.neulet.2021.135751

Luan, 2021, Butorphanol Promotes Macrophage Phenotypic Transition to Inhibit Inflammatory Lung Injury via κ Receptors, Front. Immunol., 12, 2660, 10.3389/fimmu.2021.692286

Liu, 2000, Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide, J. Pharmacol. Exp. Ther., 295, 125

Chin, 2016, Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth, Sci. Rep., 6, 36112, 10.1038/srep36112

Xie, 2018, Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile, Clin. Cancer Res., 24, 2319, 10.1158/1078-0432.CCR-18-0172

Watkins, 2009, The “Toll” of opioid-induced glial activation: Improving the clinical efficacy of opioids by targeting glia, Trends Pharmacol. Sci., 30, 581, 10.1016/j.tips.2009.08.002

Watkins, 2014, In vivo veritas: (+)-Naltrexone’s actions define translational importance, Trends Pharmacol. Sci., 35, 432, 10.1016/j.tips.2014.07.002

Lewis, 2010, Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta, Neuroscience, 165, 569, 10.1016/j.neuroscience.2009.10.011

Wang, 2012, Morphine activates neuroinflammation in a manner parallel to endotoxin, Proc. Natl. Acad. Sci. USA, 109, 6325, 10.1073/pnas.1200130109

Liang, 2016, Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia, Purinergic. Signal., 12, 637, 10.1007/s11302-016-9525-4

Iqbal, 2020, Lipopolysaccharide and Morphine-3-Glucuronide-Induced Immune Signalling Increases the Expression of Polysialic Acid in PC12 Cells, Mol. Neurobiol., 57, 964, 10.1007/s12035-019-01791-7

Shah, 2016, A structural insight into the negative effects of opioids in analgesia by modulating the TLR4 signaling: An in silico approach, Sci. Rep., 6, 39271, 10.1038/srep39271

Grace, 2014, Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae, Neuroscience, 280, 299, 10.1016/j.neuroscience.2014.09.020

Hutchinson, 2010, Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences, Neuroscience, 167, 880, 10.1016/j.neuroscience.2010.02.011

Hutchinson, 2012, Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement, J. Neurosci., 32, 11187, 10.1523/JNEUROSCI.0684-12.2012

Lewis, 2013, Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain, Brain Behav. Immun., 30, 24, 10.1016/j.bbi.2013.01.005

Zhang, 2018, Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists, J. Chem. Inf. Modeling, 58, 816, 10.1021/acs.jcim.7b00717

Park, 2009, The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex, Nature, 458, 1191, 10.1038/nature07830

Kawai, 2006, TLR signaling, Cell Death Differ., 13, 816, 10.1038/sj.cdd.4401850

Chen, 2006, Nuclear factor kappaB signaling in opioid functions and receptor gene expression, J. Neuroimmune Pharmacol. Off. J. Soc. NeuroImmune Pharmacol., 1, 270, 10.1007/s11481-006-9028-0

Roy, 1998, Morphine Modulates NFκB Activation in Macrophages, Biochem. Biophys. Res. Commun., 245, 392, 10.1006/bbrc.1998.8415

Welters, 2000, Morphine inhibits NF-kappaB nuclear binding in human neutrophils and monocytes by a nitric oxide-dependent mechanism, Anesthesiology, 92, 1677, 10.1097/00000542-200006000-00027

Azuma, 2002, Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells, Scand. J. Immunol., 56, 260, 10.1046/j.1365-3083.2002.01128.x

Zhang, 2020, Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility, Front. Immunol., 11, 1455, 10.3389/fimmu.2020.01455

Pan, 2016, Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation, J. Neuroinflamm., 13, 294, 10.1186/s12974-016-0754-9

Chen, 2021, Involvement of TCF7L2 in generation of morphine-induced antinociceptive tolerance and hyperalgesia by modulating TLR4/NF-κB/NLRP3 in microglia, Toxicol. Appl. Pharmacol., 416, 115458, 10.1016/j.taap.2021.115458

Hutchinson, 2008, Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia, Brain Behav. Immun., 22, 1178, 10.1016/j.bbi.2008.05.004

Summer, 2015, Opioid-Induced Alterations of TLR4 Protein Expression in a Human Microglial Cell Line, FASEB J., 29, 770

Liu, 2018, Effect of Endomorphin-1 on Maturation and Expression of TLR4 in Peripheral Blood Dendritic Cells Induced by High Glucose, Zhongguo Shi Yan Xue Ye Xue Za Zhi, 26, 886

Schwarz, 2013, Adolescent Morphine Exposure Affects Long-Term Microglial Function and Later-Life Relapse Liability in a Model of Addiction, J. Neurosci., 33, 961, 10.1523/JNEUROSCI.2516-12.2013

Meng, J., Yu, H., Ma, J., Wang, J., Banerjee, S., Charboneau, R., Barke, R.A., and Roy, S. (2013). Morphine Induces Bacterial Translocation in Mice by Compromising Intestinal Barrier Function in a TLR-Dependent Manner. PLoS ONE, 8.

Yang, 2019, Indispensable role of β-arrestin2 in the protection of remifentanil preconditioning against hepatic ischemic reperfusion injury, Sci. Rep., 9, 2087, 10.1038/s41598-018-38456-9

Lin, 2013, κ-Opioid receptor stimulation modulates TLR4/NF-κB signaling in the rat heart subjected to ischemia–reperfusion, Cytokine, 61, 842, 10.1016/j.cyto.2013.01.002

Tanga, 2004, Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain, Neurochem. Int., 45, 397, 10.1016/j.neuint.2003.06.002

Raghavendra, 2004, Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS, Eur. J. Neurosci., 20, 467, 10.1111/j.1460-9568.2004.03514.x

Kigerl, 2007, Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury, J. Neurochem., 102, 37, 10.1111/j.1471-4159.2007.04524.x

Ellis, 2016, Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury, Brain Behav. Immun., 58, 348, 10.1016/j.bbi.2016.08.004

Liang, 2018, Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein-Biased Ligand in Mice, Anesth. Analg., 129, 1414, 10.1213/ANE.0000000000003662

Franchi, 2012, Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages, Brain Behav. Immun., 26, 480, 10.1016/j.bbi.2011.12.010

Aguado, 2018, Toll-like receptor 4 deficient mice do not develop remifentanil-induced mechanical hyperalgesia, Eur. J. Anaesthesiol., 35, 1, 10.1097/EJA.0000000000000803

Jacobsen, 2014, Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction, Int. Rev. Neurobiol., 118, 129, 10.1016/B978-0-12-801284-0.00006-3

Farzi, 2015, Toll-like receptor 4 contributes to the inhibitory effect of morphine on colonic motility in vitro and in vivo, Sci. Rep., 5, 9499, 10.1038/srep09499

Beckett, 2018, Differential effect of morphine on gastrointestinal transit, colonic contractions and nerve-evoked relaxations in Toll-Like Receptor deficient mice, Sci. Rep., 8, 5923, 10.1038/s41598-018-23717-4

Wu, 2004, Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord, J. Pharmacol. Exp. Ther., 310, 240, 10.1124/jpet.104.065334

Wu, 2005, Antianalgesia: Stereoselective Action of dextro-Morphine over levo-Morphine on Glia in the Mouse Spinal Cord, J. Pharmacol. Exp. Ther., 314, 1101, 10.1124/jpet.105.087130

Wu, 2006, dextro- and levo-morphine attenuate opioid δ and κ receptor agonist produced analgesia in μ-opioid receptor knockout mice, Eur. J. Pharmacol., 531, 103, 10.1016/j.ejphar.2005.12.012

Johnston, 2003, Acute and conditioned sickness reduces morphine analgesia, Behav. Brain Res., 142, 89, 10.1016/S0166-4328(02)00398-4

Johnston, 2005, Inhibition of morphine analgesia by LPS: Role of opioid and NMDA receptors and spinal glia, Behav. Brain Res., 156, 75, 10.1016/j.bbr.2004.05.006

Wu, 2006, dextro-Naloxone or levo-naloxone reverses the attenuation of morphine antinociception induced by lipopolysaccharide in the mouse spinal cord via a non-opioid mechanism, Eur. J. Neurosci., 24, 2575, 10.1111/j.1460-9568.2006.05144.x

Meller, 1994, The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat, Neuropharmacology, 33, 1471, 10.1016/0028-3908(94)90051-5

Mika, 2013, Importance of glial activation in neuropathic pain, Eur. J. Pharmacol., 716, 106, 10.1016/j.ejphar.2013.01.072

Jha, 2012, Glia as a Link between Neuroinflammation and Neuropathic Pain, Immune Netw., 12, 41, 10.4110/in.2012.12.2.41

Song, 2001, The involvement of glial cells in the development of morphine tolerance, Neurosci. Res., 39, 281, 10.1016/S0168-0102(00)00226-1

Raghavendra, 2002, The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats, J. Neurosci. Off. J. Soc. Neurosci., 22, 9980, 10.1523/JNEUROSCI.22-22-09980.2002

Raghavendra, 2003, Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: Mechanistic implications of spinal glia and proinflammatory cytokines, Pain, 104, 655, 10.1016/S0304-3959(03)00138-6

Raghavendra, 2004, Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats, Neuropsychopharmacology, 29, 327, 10.1038/sj.npp.1300315

Buchanan, 2010, Toll-like receptor 4 in CNS pathologies, J. Neurochem., 114, 13, 10.1111/j.1471-4159.2010.06736.x

Liu, 2012, Emerging role of Toll-like receptors in the control of pain and itch, Neurosci. Bull., 28, 131, 10.1007/s12264-012-1219-5

Kofler, 2011, Microglia: Key innate immune cells of the brain, Toxicol. Pathol., 39, 103, 10.1177/0192623310387619

Tanga, 2005, The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy, Proc. Natl. Acad. Sci. USA, 102, 5856, 10.1073/pnas.0501634102

Ellis, 2014, Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain, J. Pain, 15, 407, 10.1016/j.jpain.2013.12.007

Sakurada, 2005, Mechanisms of Nociception Evoked by Intrathecal High-dose Morphine, NeuroToxicology, 26, 801, 10.1016/j.neuro.2004.12.011

Eidson, 2013, Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat, J. Pain Off. J. Am. Pain Soc., 14, 393, 10.1016/j.jpain.2012.12.010

Eidson, 2013, Blockade of Toll-Like Receptor 4 Attenuates Morphine Tolerance and Facilitates the Pain Relieving Properties of Morphine, J. Neurosci., 33, 15952, 10.1523/JNEUROSCI.1609-13.2013

Juni, 2007, Nociception increases during opioid infusion in opioid receptor triple knock-out mice, Neuroscience, 147, 439, 10.1016/j.neuroscience.2007.04.030

Liu, 2011, Naloxone-precipitated morphine withdrawal behavior and brain IL-1β expression: Comparison of different mouse strains, Brain Behav. Immun., 25, 1223, 10.1016/j.bbi.2011.03.016

Due, 2012, Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling, J. Neuroinflamm., 9, 725, 10.1186/1742-2094-9-200

Johnson, 2014, Codeine-induced hyperalgesia and allodynia: Investigating the role of glial activation, Transl. Psychiatry, 4, e482, 10.1038/tp.2014.121

Ferrini, 2013, Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl−homeostasis, Nat. Neurosci., 16, 183, 10.1038/nn.3295

Fukagawa, 2013, Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4, J. Anesth., 27, 93, 10.1007/s00540-012-1469-4

Mattioli, T.A., Leduc-Pessah, H., Skelhorne-Gross, G., Nicol, C.J.B., Milne, B., Trang, T., and Cahill, C.M. (2014). Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence. PLoS ONE, 9.

Cremonini, 2004, Opioids and the gut: Pharmacology and current clinical experience, Neurogastroenterol. Motil., 16, 383, 10.1111/j.1365-2982.2004.00513.x

Nee, 2018, Reduction in pain: Is it worth the gain? The effect of opioids on the GI tract, Neurogastroenterol. Motil., 30, e13367, 10.1111/nmo.13367

Testro, 2009, Toll-like receptors and their role in gastrointestinal disease, J. Gastroenterol. Hepatol., 24, 943, 10.1111/j.1440-1746.2009.05854.x

Guo, 2013, Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14, Am. J. Pathol., 182, 375, 10.1016/j.ajpath.2012.10.014

Guo, 2015, Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and MyD88, J. Immunol., 195, 4999, 10.4049/jimmunol.1402598

Camilleri, 2011, Opioid-Induced Constipation: Challenges and Therapeutic Opportunities, Am. J. Gastroenterol., 106, 835, 10.1038/ajg.2011.30

Baldini, 2012, A Review of Potential Adverse Effects of Long-Term Opioid Therapy: A Practitioner’s Guide, Prim. Care Companion CNS Disord., 14, PCC.11m01326

Kashani, 2021, The role of toll-like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?, J. Cell Physiol., 236, 4121, 10.1002/jcp.30166

Awasthi, 2014, Toll-Like Receptor-4 Modulation for Cancer Immunotherapy, Front. Immunol., 5, 328, 10.3389/fimmu.2014.00328

Sheikh, 2020, Opium use and subsequent incidence of cancer: Results from the Golestan Cohort Study, Lancet Glob. Health, 8, e649, 10.1016/S2214-109X(20)30059-0

Ramirez, 2021, Opioids and cancer prognosis: A summary of the clinical evidence, Neurosci. Lett., 746, 135661, 10.1016/j.neulet.2021.135661

Zheng, 2020, The impact of pain and opioids use on survival in cancer patients: Results from a population-based cohort study and a meta-analysis, Medicine, 99, e19306, 10.1097/MD.0000000000019306

Sekandarzad, 2019, Opiophobia in Cancer Biology- Justified?—The Role of Perioperative Use of Opioids in Cancer Recurrence, Curr. Pharm. Des., 25, 3020, 10.2174/1381612825666190703163329

Sessler, 2019, Recurrence of breast cancer after regional or general anaesthesia: A randomised controlled trial, Lancet, 394, 1807, 10.1016/S0140-6736(19)32313-X