Is the Neuroimmune System a Therapeutic Target for Opioid Use Disorder? A Systematic Review

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Katelyn Toloff, MS Eric A. Woodcock, PhD


Opioid use disorder (OUD) is an epidemic in the United States. In the past 12 months alone, there have been 75,000+ deaths attributed to opioid overdose: more than any other year in American history. Current pharmacotherapies for the treatment of OUD effectively suppress opioid withdrawal symptoms, but long-term relapse rates remain unacceptably high. Novel treatments for OUD are desperately needed to curb this epidemic. One target that has received considerable recent interest is the neuroimmune system. The neuroimmune system is anchored by glial cells, i.e., microglia and astrocytes, but neuroimmune signaling is known to influence neurons, including altering neurotransmission, synapse formation, and ultimately, brain function. Preclinical studies have shown that experimental attenuation of pro-inflammatory neuroimmune signaling modulates opioid addiction processes, including opioid reward, tolerance, and withdrawal symptoms, which suggests potential therapeutic benefit in patients. Whereas the peripheral immune system in OUD patients has been studied for decades and is well-understood, little is known about the neuroimmune system in OUD patients or its viability as a treatment target. Herein, we review the literature describing relationships between opioid administration and the neuroimmune system, the influence of neuroimmune signaling on opioid addiction processes, and the therapeutic potential for targeting the neuroimmune system in OUD subjects using glial modulator medications.  

Keywords: neuroinflammation, neuroimmune signaling, microglia, opioid use disorder, heroin, fentanyl

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TOLOFF, Katelyn; WOODCOCK, Eric A.. Is the Neuroimmune System a Therapeutic Target for Opioid Use Disorder? A Systematic Review. Medical Research Archives, [S.l.], v. 10, n. 8, aug. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 30 nov. 2023. doi:
Review Articles


1. Thompson BL, Oscar-Berman M, Kaplan GB. Opioid-induced structural and functional plasticity of medium-spiny neurons in the nucleus accumbens. Neuroscience & Biobehavioral Reviews. 2021;120:417-430.
2. Dydyk AM, Jain NK, Gupta M. Opioid use disorder. StatPearls [Internet]. StatPearls Publishing; 2021.
3. American Psychiatric Association. 4th ed. Diagnostic and Statistical Manual of Mental Disorders. 1994.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
5. Koob GF, Moal ML. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278(5335):52-58.
6. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35(1):217-238.
7. Drug Overdose Deaths in the U.S. Top 100,000 Annually. November 17, 2021, 2021.
8. Brown R, Kraus C, Fleming M, Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgraduate medical journal. 2004;80(949):654-659.
9. Marteau D, McDonald R, Patel K. The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales. BMJ open. 2015;5(5):e007629.
10. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain and Therapy. 2020;9(1):41-54.
11. Volpe DA, Tobin GAM, Mellon RD, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regulatory Toxicology and Pharmacology. 2011;59(3):385-390.
12. Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Current neuropharmacology. 2004;2(4):395-402.
13. Strain EC, Walsh SL, Bigelow GE. Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine. Psychopharmacology. 2002;159(2):161-166.
14. Singh D, Saadabadi A. Naltrexone. 2018;
15. Bell J, Strang J. Medication treatment of opioid use disorder. Biological psychiatry. 2020;87(1):82-88.
16. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane database of systematic reviews. 2014;(2)
17. Hser YI, Saxon AJ, Huang D, et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi‐site trial. Addiction. 2014;109(1):79-87.
18. Hser YI, Evans E, Huang D, et al. Long‐term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi‐site trial. Addiction. 2016;111(4):695-705.
19. Volkow N, Collins F. All scientific hands on deck” to end the opioid crisis. Web blog comment] Retrieved from: https://www drugabuse gov/about-nida/noras-blog/2017/05/all-scientific-hands-deck-to-end-opioid-crisis. 2017;
20. Volkow N, Czernin J. A Conversation Between Nora Volkow and Johannes Czernin. Journal of Nuclear Medicine. 2019;60(6):717-720.
21. Jacobsen JHW, Watkins LR, Hutchinson MR. Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction. International review of neurobiology. 2014;118:129-163.
22. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nature Reviews Immunology. 2011;11(11):775-787.
23. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777-783.
24. Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Elsevier; 2019:112-120.
25. Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational neurodegeneration. 2020;9(1):1-12.
26. Hickman SE, Kingery ND, Ohsumi TK, et al. The microglial sensome revealed by direct RNA sequencing. Nature neuroscience. 2013;16(12):1896-1905.
27. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-934.
28. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nature neuroscience. 2018;21(10):1359-1369.
29. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. The Journal of clinical investigation. 2012;122(4):1164-1171.
30. Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. TheScientificWorldJournal. 2007;7:98-111.
31. Abdelhak A, Hottenrott T, Morenas-Rodríguez E, et al. Glial activation markers in CSF and serum from patients with primary progressive multiple sclerosis: potential of serum GFAP as disease severity marker? Frontiers in neurology. 2019;10:280.
32. Mika J. -Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacological reports. 2008;60(3):297.
33. Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron. 2009;64(1):93-109.
34. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61-78.
35. Frank MG, Watkins LR, Maier SF. Stress-and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse. Brain, behavior, and immunity. 2011;25:S21-S28.
36. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137-162.
37. Hueston CM, Deak T. The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic–pituitary–adrenal axis. Physiology & behavior. 2014;124:77-91.
38. Besedovsky H, Del Rey A. The cytokine-HPA axis feed-back circuit. Zeitschrift für Rheumatologie. 2000;59(2):II26-II30.
39. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, behavior, and immunity. 2011;25(2):181-213.
40. Kohman RA, Rhodes JS. Neurogenesis, inflammation and behavior. Brain, behavior, and immunity. 2013;27:22-32.
41. Cohen O, Reichenberg A, Perry C, et al. Endotoxin-induced changes in human working and declarative memory associate with cleavage of plasma “readthrough” acetylcholinesterase. Journal of Molecular Neuroscience. 2003;21(3):199-212.
42. Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Archives of general psychiatry. 2001;58(5):445-452.
43. Notter T, Coughlin JM, Sawa A, Meyer U. Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Molecular psychiatry. 2018;23(1):36-47.
44. Coller JK, Hutchinson MR. Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence. Pharmacology & therapeutics. 2012;134(2):219-245.
45. Linker K, Cross S, Leslie F. Glial mechanisms underlying substance use disorders. European Journal of Neuroscience. 2019;50(3):2574-2589.
46. Hutchinson MR, Lewis SS, Coats BD, et al. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain, behavior, and immunity. 2009;23(2):240-250.
47. Watkins LR, Hutchinson MR, Milligan ED, Maier SF. “Listening” and “talking” to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. Brain research reviews. 2007;56(1):148-169.
48. Qin L, He J, Hanes RN, Pluzarev O, Hong J-S, Crews FT. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. Journal of neuroinflammation. 2008;5(1):1-17.
49. Kane CJ, Phelan KD, Douglas JC, et al. Effects of ethanol on immune response in the brain: region-specific changes in aged mice. Journal of neuroinflammation. 2013;10(1):1-4.
50. Mansouri MT, Naghizadeh B, Ghorbanzadeh B, et al. Venlafaxine prevents morphine antinociceptive tolerance: the role of neuroinflammation and the l-arginine-nitric oxide pathway. Experimental neurology. 2018;303:134-141.
51. Raghavendra V, Tanga FY, DeLeo JA. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology. 2004;29(2):327-334.
52. Davis BM, Salinas-Navarro M, Cordeiro MF, Moons L, De Groef L. Characterizing microglia activation: a spatial statistics approach to maximize information extraction. Scientific reports. 2017;7(1):1-12.
53. Hutchinson MR, Watkins LR. Why is neuroimmunopharmacology crucial for the future of addiction research? Neuropharmacology. 2014;76:218-227.
54. Lucas K, Maes M. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Molecular neurobiology. 2013;48(1):190-204.
55. Lu Y-C, Yeh W-C, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42(2):145-151.
56. Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain, behavior, and immunity. 2010;24(1):83-95.
57. Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β. Neuroscience. 2010;165(2):569-583.
58. Eisenstein TK. The role of opioid receptors in immune system function. Frontiers in Immunology. 2019;10:2904.
59. Peng X, Mosser DM, Adler MW, Rogers TJ, Meissler Jr JJ, Eisenstein TK. Morphine enhances interleukin‐12 and the production of other pro‐inflammatory cytokines in mouse peritoneal macrophages. Journal of leukocyte biology. 2000;68(5):723-728.
60. Pacifici R, di Carlo S, Bacosi A, Pichini S, Zuccaro P. Pharmacokinetics and cytokine production in heroin and morphine-treated mice. International journal of immunopharmacology. 2000;22(8):603-614.
61. Seney ML, Kim S-M, Glausier JR, et al. Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder. Biological Psychiatry. 2021;90(8):550-562.
62. Moretti M, Belli G, Morini L, Monti MC, Osculati AMM, Visonà SD. Drug abuse-related neuroinflammation in human postmortem brains: an immunohistochemical approach. Journal of Neuropathology & Experimental Neurology. 2019;78(11):1059-1065.
63. Büttner A, Weis S. Neuropathological alterations in drug abusers. Forensic science, medicine, and pathology. 2006;2(2):115-126.
64. Woodcock EA, Schain M, Cosgrove KP, Hillmer AT. Quantification of [11C] PBR28 data after systemic lipopolysaccharide challenge. EJNMMI research. 2020;10(1):1-6.
65. Sandiego CM, Gallezot J-D, Pittman B, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proceedings of the National Academy of Sciences. 2015;112(40):12468-12473.
66. Hannestad J, Gallezot J-D, Schafbauer T, et al. Endotoxin-induced systemic inflammation activates microglia:[11C] PBR28 positron emission tomography in nonhuman primates. Neuroimage. 2012;63(1):232-239.
67. Hillmer AT, Holden D, Fowles K, et al. Microglial depletion and activation: A [11 C] PBR28 PET study in nonhuman primates. EJNMMI research. 2017;7(1):1-5.
68. Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders—a review. Current neurology and neuroscience reports. 2017;17(3):1-11.
69. Gouilly D, Saint‐Aubert L, Ribeiro MJ, et al. Neuroinflammation PET imaging of the translocator protein (TSPO) in Alzheimer's disease: An update. European Journal of Neuroscience. 2022;55(5):1322-1343.
70. Tournier BB, Tsartsalis S, Rigaud D, et al. TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer’s disease. Neurobiology of Disease. 2019;121:95-105.
71. Auvity S, Wadad S, Leroy C, et al. Susceptibility to morphine-induced glial activation assessed using TSPO PET imaging with 18F-DPA-714 in nonhuman primates. Soc Nuclear Med; 2017.
72. Woodcock E, Angarita-Africano G, Matuskey D, et al. A Translational Investigation of Morphine-Induced Neuroimmune Signaling: Implications for Opioid Use Disorder. SPRINGERNATURE CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND; 2021:391-392.
73. Brogden R, Speight T, Avery G. Minocycline: a review of its antibacterial and pharmacokinetic properties and therapeutic use. Drugs. 1975;9(4):251-291.
74. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. The Journal of Immunology. 2001;166(12):7527-7533.
75. Tikka T, Fiebich BL, Goldsteins G, Keinänen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. Journal of Neuroscience. 2001;21(8):2580-2588.
76. Familian A, Boshuizen RS, Eikelenboom P, Veerhuis R. Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation. Glia. 2006;53(3):233-240.
77. Garrido‐Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. British journal of pharmacology. 2013;169(2):337-352.
78. Si Q, Cosenza MA, Kim M-O, et al. A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. Journal of neurovirology. 2004;10(5):284-292.
79. Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert opinion on pharmacotherapy. 2009;10(17):2897-2904.
80. Goodman AD, Gyang T, Smith III AD. Ibudilast for the treatment of multiple sclerosis. Expert Opinion on Investigational Drugs. 2016;25(10):1231-1237.
81. Lee J-Y, Cho E, Ko YE, et al. Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, protects against ischemic brain injury in rats. Brain research. 2012;1431:97-106.
82. Wu N-C, Wang J-J. Ibudilast, a phosphodiesterase inhibitor and Toll-like receptor-4 antagonist, improves hemorrhagic shock and reperfusion-induced left ventricular dysfunction by reducing myocardial tumor necrosis factor α. Elsevier; 2020:1869-1874.
83. Belforte N, Cueva-Vargas JL, Di Polo A. The phosphodiesterase inhibitor Ibudilast attenuates glial cell reactivity, production of proinflammatory cytokines and neuronal loss in experimental glaucoma. Investigative Ophthalmology & Visual Science. 2014;55(13):2665-2665.
84. Zhaleh M, Panahi M, Broujerdnia MG, Ghorbani R, Angali KA, Saki G. Role of phosphodiesterase inhibitor Ibudilast in morphine-induced hippocampal injury. Journal of Injury and Violence Research. 2014;6(2):72.
85. Arezoomandan R, Haghparast A. Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior. Canadian journal of physiology and pharmacology. 2016;94(3):257-264.
86. Hutchinson MR, Coats BD, Lewis SS, et al. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain, behavior, and immunity. 2008;22(8):1178-1189.
87. Self DW. Regulation of drug-taking and-seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology. 2004;47:242-255.
88. Bland ST, Hutchinson MR, Maier SF, Watkins LR, Johnson KW. The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release. Brain, behavior, and immunity. 2009;23(4):492-497.
89. Cui Y, Liao X-X, Liu W, et al. A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain, behavior, and immunity. 2008;22(1):114-123.
90. Zhang X-Q, Cui Y, Cui Y, et al. Activation of p38 signaling in the microglia in the nucleus accumbens contributes to the acquisition and maintenance of morphine-induced conditioned place preference. Brain, behavior, and immunity. 2012;26(2):318-325.
91. Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia: novel counter-regulators of opioid analgesia. Trends in neurosciences. 2005;28(12):661-669.
92. Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. Journal of Neuroscience. 2004;24(33):7353-7365.
93. Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411) a new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert opinion on investigational drugs. 2007;16(7):935-950.
94. Lewis S, Hutchinson M, Coats B, et al. AV411, a blood brain barrier permeable glial activation inhibitor, reduces morphine withdrawal behaviors in rats. 2006:762.
95. Lilius TO, Rauhala PV, Kambur O, Kalso EA. Modulation of morphine-induced antinociception in acute and chronic opioid treatment by ibudilast. The Journal of the American Society of Anesthesiologists. 2009;111(6):1356-1364.
96. Cooper ZD, Johnson KW, Pavlicova M, et al. The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid‐dependent volunteers. Addiction biology. 2016;21(4):895-903.
97. Cooper Z, Johnson K, Vosburg S, et al. Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers. Drug and alcohol dependence. 2017;178:340-347.
98. Metz VE, Jones JD, Manubay J, et al. Effects of ibudilast on the subjective, reinforcing, and analgesic effects of oxycodone in recently detoxified adults with opioid dependence. Neuropsychopharmacology. 2017;42(9):1825.
99. Arout CA, Waters AJ, MacLean RR, Compton P, Sofuoglu M. Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients. Psychopharmacology. 2019;236(10):2857-2866.
100. Mogali S, Askalsky P, Madera G, Jones J, Comer S. Minocycline attenuates oxycodone-induced positive subjective responses in non-dependent, recreational opioid users. Pharmacology Biochemistry and Behavior. 2021;209:173241.
101. Nettis MA, Lombardo G, Hastings C, et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology. 2021;46(5):939-948.
102. Sofuoglu M, Mooney M, Kosten T, Waters A, Hashimoto K. Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology. 2011;213(1):61-68.