Evidence for brain glial activation in chronic pain patients

Marco L Loggia, Daniel B Chonde, Oluwaseun Akeju, Grae Arabasz, Ciprian Catana, Robert R Edwards, Elena Hill, Shirley Hsu, David Izquierdo-Garcia, Ru-Rong Ji, Misha Riley, Ajay D Wasan, Nicole R Zürcher, Daniel S Albrecht, Mark G Vangel, Bruce R Rosen, Vitaly Napadow, Jacob M Hooker, Marco L Loggia, Daniel B Chonde, Oluwaseun Akeju, Grae Arabasz, Ciprian Catana, Robert R Edwards, Elena Hill, Shirley Hsu, David Izquierdo-Garcia, Ru-Rong Ji, Misha Riley, Ajay D Wasan, Nicole R Zürcher, Daniel S Albrecht, Mark G Vangel, Bruce R Rosen, Vitaly Napadow, Jacob M Hooker

Abstract

Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.

Keywords: 11C-PBR28; TSPO; chronic pain; glia; neuroinflammation; translocator protein (18kDa).

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Figures

Figure 1
Figure 1
Evidence for glial activation in the thalamus of chronic LBP patients. (A) Boxplots are presented for the mean 11C-PBR28 SUVRs extracted for all 10 patients with chronic LBP and nine control subjects from the thalamic regions of interest (insert). The P-values refer to matched-pairs analyses (sign test) performed using nine chronic LBP-control matching pairs. The analyses were repeated twice, each time using one of the two patients matching the same control, with statistically significant results in both analyses. *P < 0.05, **P < 0.01. (B) Voxel-wise distribution of thalamic SUVRs, showing that patients with chronic LBP have a substantial number of voxels at values ≥ 1.4 (green arrows), whereas controls have a median voxel count of 0. (C) Individual thalamic SUVRs are presented as axial sections (left), and 3D rendering of values higher than the threshold of 1.4 (right). Each row displays SUVRs for each patient-control matched pair. TSPO polymorphism (Ala/Ala or Ala/Thr) is indicated.
Figure 2
Figure 2
Whole-brain voxel-wise analyses. (A) Median SUVR map from healthy controls (n = 9) and patients with chronic LBP (n = 10) are presented. Matched-pairs tests (nine versus nine) revealed significantly higher TSPO levels in patients, in thalamus, pre- and postcentral gyri, and paracentral lobule (P < 0.05 corrected for multiple comparisons; permutation testing, 10 000 permutations). As two patients were matching the same controls, the analyses were performed first using the patient best matching the control. A second analysis was performed using the other patient, limiting our search to significant clusters from the first analysis, with identical results. (B) Boxplots for each of the four regions demonstrating statistically higher SUVRs in patients are shown for illustrative purposes. postc. = postcentral; g. = gyrus; parac. lob. = postcentral lobule; prec. = precentral.
Figure 3
Figure 3
Anti-inflammatory and anti-nociceptive role of TSPO. SUVRs were negatively associated with pain outcomes (A–C) and blood levels of interleukin-6 (D). The scatterplots show the residuals adjusting for the effect of genotype. MPQ = McGill Pain Questionnaire.

References

    1. Abourbeh G, Theze B, Maroy R, Dubois A, Brulon V, Fontyn Y, et al. Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [(1)(8)F]DPA-714. J Neurosci. 2012 25; 32: 5728–36.
    1. Bae KR, Shim HJ, Balu D, Kim SR, Yu SW. Translocator protein 18 kDa negatively regulates inflammation in microglia. J Neuroimmune Pharmacol. 2014;9:424–37.
    1. Banati RB, Myers R, Kreutzberg GW. PK (‘peripheral benzodiazepine')—binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol. 1997;26:77–82.
    1. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123(Pt 11):2321–37.
    1. Banati RB. Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Br Med Bull. 2003;65:121–31.
    1. Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol. 2010;327:1–12.
    1. Beggs S, Salter MW. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun. 2007;21:624–33.
    1. Beggs S, Trang T, Salter MW. P2X4R+ microglia drive neuropathic pain. Nat Neurosci. 2012;15:1068–73.
    1. Boendermaker B, Meier ML, Luechinger R, Humphreys BK, Hotz-Boendermaker S. The cortical and cerebellar representation of the lumbar spine. Hum Brain Mapp. 2014;35:3962–71.
    1. Brisby H, Olmarker K, Rosengren L, Cederlund CG, Rydevik B. Markers of nerve tissue injury in the cerebrospinal fluid in patients with lumbar disc herniation and sciatica. Spine (Phila Pa 1976) 1999;24:742–6.
    1. Briard E, Zoghbi SS, Imaizumi M, Gourley JP, Shetty HU, Hong J, et al. Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. J Med Chem. 2008;51:17–30.
    1. Bromander S, Anckarsater R, Kristiansson M, Blennow K, Zetterberg H, Anckarsater H, et al. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J Neuroinflammation. 2012;9:242.
    1. Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH, et al. Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med. 2007;48:2072–9.
    1. Cagnin A, Kassiou M, Meikle SR, Banati RB. Positron emission tomography imaging of neuroinflammation. Neurotherapeutics. 2007;4:443–52.
    1. Calvo M, Bennett DL. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol. 2012;234:271–82.
    1. Calvo M, Dawes JM, Bennett DL. The role of the immune system in the generation of neuropathic pain. Lancet Neurol. 2012;11:629–42.
    1. Catana C, Procissi D, Wu Y, Judenhofer MS, Qi J, Pichler BJ, et al. Simultaneous in vivo positron emission tomography and magnetic resonance imaging. Proc Natl Acad Sci USA. 2008;105:3705–10.
    1. Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 2009;35:306–28.
    1. Chen MK, Baidoo K, Verina T, Guilarte TR. Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain. 2004;127(Pt 6):1379–92.
    1. Chen G, Park CK, Xie RG, Berta T, Nedergaard M, Ji RR. Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain. 2014;137(Pt 8):2193–209.
    1. Chen MK, Guilarte TR. Imaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination. Toxicol Sci. 2006;91:532–9.
    1. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017–21.
    1. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179–94.
    1. Del Valle L, Schwartzman RJ, Alexander G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun. 2009;23:85–91.
    1. Echeverry S, Shi XQ, Zhang J. Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain. 2008;135:37–47.
    1. Eidson LN, Murphy AZ. Blockade of Toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine. J Neurosci. 2013;33:15952–63.
    1. Ferrini F, Trang T, Mattioli TA, Laffray S, Del'Guidice T, Lorenzo LE, et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci. 2013;16:183–92.
    1. Friston K. Introduction: experimental design and statistical parametric mapping. In: Frackowiak RSJ, Ashburner JT, Penny WD, Zeki S, Friston K, Frith CD, et al., editors. Human brain function. London, UK: Academic Press; 2003.
    1. Fujita M, Mahanty S, Zoghbi SS, Ferraris Araneta MD, Hong J, Pike VW, et al. PET reveals inflammation around calcified Taenia solium granulomas with perilesional edema. PLoS One. 2013;8:e74052.
    1. Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995;20:269–87.
    1. Geisser ME, Roth RS, Robinson ME. Assessing depression among persons with chronic pain using the Center for Epidemiological Studies-Depression Scale and the Beck Depression Inventory: a comparative analysis. Clin J Pain. 1997;13:163–70.
    1. Gomez-Mancilla B, Marrer E, Kehren J, Kinnunen A, Imbert G, Hillebrand R, et al. Central nervous system drug development: an integrative biomarker approach toward individualized medicine. NeuroRx. 2005;2:683–95.
    1. Gulyas B, Makkai B, Kasa P, Gulya K, Bakota L, Varszegi S, et al. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. Neurochem Int. 2009;54:28–36.
    1. Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007;27:6006–18.
    1. Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26:4308–17.
    1. Hernstadt H, Wang S, Lim G, Mao J. Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis. Brain Res. 2009;1286:42–52.
    1. Hirvonen J, Kreisl WC, Fujita M, Dustin I, Khan O, Appel S, et al. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J Nuclear Med. 2012;53:234–40.
    1. Imaizumi M, Kim HJ, Zoghbi SS, Briard E, Hong J, Musachio JL, et al. PET imaging with 11C-PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007;411:200–5.
    1. Izquierdo-Garcia D, Hansen AE, Förster S, Benoit D, Schachoff S, Fürst S, et al. An SPM8-based approach for attenuation correction combining segmentation and non-rigid template formation: application to simultaneous PET/MR brain imaging. J Nucl Med. 2014;55:1825–30.
    1. Ji RR, Berta T, Nedergaard M. Glia and pain: Is chronic pain a gliopathy? Pain. 2013;154(Suppl 1):S10–28.
    1. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006;2:259–69.
    1. Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies. J Neurosci. 2008;28:12255–67.
    1. Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain. 2007;3:33.
    1. Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol. 2012;242:33–8.
    1. Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008;28:5189–94.
    1. Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P, et al. Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. Neuroimage. 2010;49:2924–32.
    1. Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab. 2013;33:53–8.
    1. Kuhlmann AC, Guilarte TR. Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem. 2000;74:1694–704.
    1. Landry RP, Jacobs VL, Romero-Sandoval EA, DeLeo JA. Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp Neurol. 2012;234:340–50.
    1. Leblanc BW, Zerah ML, Kadasi LM, Chai N, Saab CY. Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy. Neurosci Lett. 2011;498:138–42.
    1. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005;115:71–83.
    1. Liu L, Rudin M, Kozlova EN. Glial cell proliferation in the spinal cord after dorsal rhizotomy or sciatic nerve transection in the adult rat. Exp Brain Res. 2000;131:64–73.
    1. Liu X, Li W, Dai L, Zhang T, Xia W, Liu H, et al. Early repeated administration of progesterone improves the recovery of neuropathic pain and modulates spinal 18kDa-translocator protein (TSPO) expression. J Steroid Biochem Mol Biol. 2014;143:130–40.
    1. Loggia ML, Edwards RR, Kim J, Vangel MG, Wasan AD, Gollub RL, et al. Disentangling linear and nonlinear brain responses to evoked deep tissue pain. Pain. 2012;153:2140–51.
    1. Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, et al. Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100–11.
    1. Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, et al. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:230–41.
    1. Martinez V, Szekely B, Lemarie J, Martin F, Gentili M, Ben Ammar S, et al. The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain. 2013;154:1197–203.
    1. Mattioli TA, Milne B, Cahill CM. Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats. Mol Pain. 2010;6:22.
    1. Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology. 1994;33:1471–8.
    1. Melzack R. The short-form McGill Pain questionnaire. Pain. 1987;30:191–7.
    1. Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60:297–307.
    1. Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp. 2002;15:1–25.
    1. Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY, Salter MW, Dostrovsky JO, et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci. 2009;29:11161–71.
    1. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.
    1. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.
    1. Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev. 2014;94:1077–98.
    1. Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. 2014;565:30–8.
    1. Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003;306:624–30.
    1. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16:1267–76.
    1. Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, et al. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab. 2007;27:1975–86.
    1. Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nat Rev Neurosci. 2009;10:235–41.
    1. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010;9:971–88.
    1. Rupprecht R, Rammes G, Eser D, Baghai TC, Schule C, Nothdurfter C, et al. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science. 2009;325:490–3.
    1. Shao X, Wang X, English SJ, Desmond T, Sherman PS, Quesada CA, et al. Imaging of carrageenan-induced local inflammation and adjuvant-induced systemic arthritis with [(11)C]PBR28 PET. Nucleic Med Biol. 2013;40:906–11.
    1. Shi Y, Gelman BB, Lisinicchia JG, Tang SJ. Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J Neurosci. 2012;32:10833–40.
    1. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23(Suppl 1):S208–19.
    1. Smith SM, Nichols TE. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage. 2009;44:83–98.
    1. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res. 1997;50:345–53.
    1. de Vries EF, Dierckx RA, Klein HC. Nuclear imaging of inflammation in neurologic and psychiatric disorders. Curr Clin Pharmacol. 2006;1:229–42.
    1. Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain. 2009;10:1113–20.
    1. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778–83.
    1. Turner JA, Romano JM. Self-report screening measures for depression in chronic pain patients. J Clin Psychol. 1984;40:909–13.
    1. Uceyler N, Sommer C. Cytokine-related and histological biomarkers for neuropathic pain assessment. Pain Manag. 2012;2:391–8.
    1. Venneti S, Wang G, Wiley CA. Activated macrophages in HIV encephalitis and a macaque model show increased [3H](R)-PK11195 binding in a PI3-kinase-dependent manner. Neurosci Lett. 2007;426:117–22.
    1. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci. 2004;20:1150–60.
    1. Wang M, Wang X, Zhao L, Ma W, Rodriguez IR, Fariss RN, et al. Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci. 2014;34:3793–806.
    1. Watkins LR, Hutchinson MR, Johnson KW. Commentary on Landry et al.: “Propentofylline, a CNS glial modulator, does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages". Exp Neurol. 2012;234:351–3.
    1. Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun. 2007;21:131–46.
    1. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009;30:581–91.
    1. Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain. 1997;71:225–35.
    1. Wei XH, Wei X, Chen FY, Zang Y, Xin WJ, Pang RP, et al. The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. J Neurosci. 2013;33:1540–51.
    1. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10:663–72.
    1. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65:529–38.
    1. Yoder KK, Nho K, Risacher SL, Kim S, Shen L, Saykin AJ. Influence of TSPO genotype on 11C-PBR28 standardized uptake values. J Nuclear Med. 2013;54:1320–2.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.

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