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Semin Musculoskelet Radiol 2015; 19(02): 103-111
DOI: 10.1055/s-0035-1547371
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Neuropathic Pain Mechanisms and Imaging

Ka-Wah Tung
1   Department of Radiology, Stanford University School of Medicine, Stanford, California
,
Deepak Behera
1   Department of Radiology, Stanford University School of Medicine, Stanford, California
,
Sandip Biswal
2   Division of Musculoskeletal Radiology, Stanford University School of Medicine, Stanford, California
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Publikationsdatum:
12. März 2015 (online)

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Abstract

Molecular and cellular imaging of neuropathic pain, utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity, is a promising approach toward objectively identifying peripheral pain generators. Neuropathic conditions arise from injured and inflamed nerves, which have been shown to elaborate several molecular and cellular elements that give rise to the neuropathic phenotype and can be exploited for imaging purposes. As such, in vivo approaches to image neuropathic pain mechanisms include imaging voltage-gated sodium channels with radiolabeled saxitoxin, calcium signaling with manganese-enhanced magnetic resonance imaging, and inflammatory changes and nerve metabolism with 18F-fluorodeoxyglucose. Imaging approaches exploiting other mediators of nociceptive activity, such as substance P (neurokinin-1) receptor, sigma-1 receptor, and macrophages, have shown promising early advances in animal models. By combining the sensitivity and specificity of molecular imaging with the high anatomical, spatial and contrast resolution afforded by computed tomography and MRI, radiologists can potentially identify sites of nerve injury or neuroinflammation that are implicated as peripheral pain drivers with greater accuracy and confidence. In addition to guiding therapy, these approaches will aid in new drug designs for analgesia and more individualized treatment options.

Keywords

neuropathic pain - biological markers - musculoskeletal imaging - molecular imaging
 

  • References

  • 1 Institute of Medicine of the National Academies. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Available at: www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx . Accessed April 15, 2013
    PubMedGoogle Scholar
  • 2 Englund M, Guermazi A, Gale D , et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 2008; 359 (11) 1108-1115
    CrossrefPubMedGoogle Scholar
  • 3 Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331 (2) 69-73
    CrossrefPubMedGoogle Scholar
  • 4 Sher JS, Uribe JW, Posada A, Murphy BJ, Zlatkin MB. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am 1995; 77 (1) 10-15
    CrossrefPubMedGoogle Scholar
  • 5 Chou R, Fu R, Carrino JA, Deyo RA. Imaging strategies for low-back pain: systematic review and meta-analysis. Lancet 2009; 373 (9662) 463-472
    CrossrefPubMedGoogle Scholar
  • 6 Jarvik JG, Hollingworth W, Martin B , et al. Rapid magnetic resonance imaging vs radiographs for patients with low back pain: a randomized controlled trial. JAMA 2003; 289 (21) 2810-2818
    CrossrefPubMedGoogle Scholar
  • 7 Lurie JD, Birkmeyer NJ, Weinstein JN. Rates of advanced spinal imaging and spine surgery. Spine 2003; 28 (6) 616-620
    PubMedGoogle Scholar
  • 8 Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331 (2) 69-73
    CrossrefPubMedGoogle Scholar
  • 9 Matsumoto M, Fujimura Y, Suzuki N , et al. MRI of cervical intervertebral discs in asymptomatic subjects. J Bone Joint Surg Br 1998; 80 (1) 19-24
    CrossrefPubMedGoogle Scholar
  • 10 Needell SD, Zlatkin MB, Sher JS, Murphy BJ, Uribe JW. MR imaging of the rotator cuff: peritendinous and bone abnormalities in an asymptomatic population. AJR Am J Roentgenol 1996; 166 (4) 863-867
    CrossrefPubMedGoogle Scholar
  • 11 Pope Jr TL. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am 1996; 78 (4) 633-635
    PubMedGoogle Scholar
  • 12 Sher JS, Uribe JW, Posada A, Murphy BJ, Zlatkin MB. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am 1995; 77 (1) 10-15
    CrossrefPubMedGoogle Scholar
  • 13 Moisset X, Bouhassira D. Brain imaging of neuropathic pain. Neuroimage 2007; 37 (Suppl. 01) S80-S88
    CrossrefPubMedGoogle Scholar
  • 14 Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 2000; 30 (5) 263-288
    CrossrefPubMedGoogle Scholar
  • 15 Kuner R. Central mechanisms of pathological pain. Nat Med 2010; 16 (11) 1258-1266
    CrossrefPubMedGoogle Scholar
  • 16 Loeser JD, Treede RD. The Kyoto protocol of IASP Basic Pain Terminology. Pain 2008; 137 (3) 473-477
    CrossrefPubMedGoogle Scholar
  • 17 Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007; 10 (11) 1361-1368
    CrossrefPubMedGoogle Scholar
  • 18 Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32: 1-32
    CrossrefPubMedGoogle Scholar
  • 19 Sweitzer SM, Hickey WF, Rutkowski MD, Pahl JL, DeLeo JA. Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 2002; 100 (1-2) 163-170
    CrossrefPubMedGoogle Scholar
  • 20 Hu P, McLachlan EM. Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat. Exp Neurol 2003; 184 (2) 590-605
    CrossrefPubMedGoogle Scholar
  • 21 Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2 (12) 973-985
    CrossrefPubMedGoogle Scholar
  • 22 Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 2007; 21 (5) 599-616
    CrossrefPubMedGoogle Scholar
  • 23 Papadopoulos V, Baraldi M, Guilarte TR , 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 (8) 402-409
    CrossrefPubMedGoogle Scholar
  • 24 Papadopoulos V, Lecanu L. Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Exp Neurol 2009; 219 (1) 53-57
    CrossrefPubMedGoogle Scholar
  • 25 Garvey LJ, Pavese N, Politis M , et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS 2014; 28 (1) 67-72
    CrossrefPubMedGoogle Scholar
  • 26 Golla S, Boellaard R, Oikonen V , et al. Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients. J Cereb Blood Flow Metab 2015; ; February 4 (Epub ahead of print)
    PubMedGoogle Scholar
  • 27 Brody AL, Okita K, Shieh J , et al. Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers. Nucl Med Biol 2014; 41 (10) 871-875
    CrossrefPubMedGoogle Scholar
  • 28 Owen DR, Guo Q, Kalk NJ , et al. Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study. J Cereb Blood Flow Metab 2014; 34 (6) 989-994
    CrossrefPubMedGoogle Scholar
  • 29 Imamoto N, Momosaki S, Fujita M , et al. [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats. Neuroimage 2013; 79: 121-128
    CrossrefPubMedGoogle Scholar
  • 30 Díaz JL, Zamanillo D, Corbera J , et al. Selective sigma-1 (sigma1) receptor antagonists: emerging target for the treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem 2009; 9 (3) 172-183
    CrossrefPubMedGoogle Scholar
  • 31 Gannon CJ, Malone DL, Napolitano LM. Reduction of IL-10 and nitric oxide synthesis by SR31747A (sigma ligand) in RAW murine macrophages. Surg Infect (Larchmt) 2001; 2 (4) 267-272 ; discussion 273
    CrossrefPubMedGoogle Scholar
  • 32 Palacios G, Muro A, Verdú E, Pumarola M, Vela JM. Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve. Brain Res 2004; 1007 (1–2) 65-70
    CrossrefPubMedGoogle Scholar
  • 33 Woolf CJ ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140 (6) 441-451
    CrossrefPubMedGoogle Scholar
  • 34 Behera D, Shen B, James ML , et al. Radiolabeled sigma-1 receptor ligand detects peripheral neuroinflammation in a neuropathic pain model using PET/MRI. In: Pichler B, , ed. 2012 World Molecular Imaging Congress. Dublin, Ireland: World Molecular Imaging Society; 2012: SS123
    Google Scholar
  • 35 James ML, Shen B, Zavaleta CL , et al. New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects. J Med Chem 2012; 55 (19) 8272-8282
    CrossrefPubMedGoogle Scholar
  • 36 Ghanouni P, Behera D, Xie J, Chen X, Moseley M, Biswal S. In vivo USPIO magnetic resonance imaging shows that minocycline mitigates macrophage recruitment to a peripheral nerve injury. Mol Pain 2012; 8: 49
    CrossrefPubMedGoogle Scholar
  • 37 Woolf CJ ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140 (6) 441-451
    CrossrefPubMedGoogle Scholar
  • 38 Dirig DM, Yaksh TL. Thermal hyperalgesia in rat evoked by intrathecal substance P at multiple stimulus intensities reflects an increase in the gain of nociceptive processing. Neurosci Lett 1996; 220 (2) 93-96
    CrossrefPubMedGoogle Scholar
  • 39 Honor P, Menning PM, Rogers SD , et al. Spinal substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states. J Neurosci 1999; 19 (17) 7670-7678
    PubMedGoogle Scholar
  • 40 Ji RR, Befort K, Brenner GJ, Woolf CJ. ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 2002; 22 (2) 478-485
    PubMedGoogle Scholar
  • 41 Breeman WA, VanHagen MP, Visser-Wisselaar HA , et al. In vitro and in vivo studies of substance P receptor expression in rats with the new analog [indium-111-DTPA-Arg1]substance P. J Nucl Med 1996; 37 (1) 108-117
    PubMedGoogle Scholar
  • 42 Chin FT, Morse CL, Shetty HU, Pike VW. Automated radiosynthesis of [18F]SPA-RQ for imaging human brain NK1 receptors with PET. J Labelled Comp Radiopharm 2006; 49: 17-31
    CrossrefPubMedGoogle Scholar
  • 43 Bergström M, Hargreaves RJ, Burns HD , et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry 2004; 55 (10) 1007-1012
    CrossrefPubMedGoogle Scholar
  • 44 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288 (5472) 1765-1769
    CrossrefPubMedGoogle Scholar
  • 45 Willoch F, Schindler F, Wester HJ , et al. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 2004; 108 (3) 213-220
    CrossrefPubMedGoogle Scholar
  • 46 Wester HJ, Willoch F, Tölle TR , et al. 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]DPN): synthesis, biologic evaluation, and comparison with [11C]DPN in humans. J Nucl Med 2000; 41 (7) 1279-1286
    PubMedGoogle Scholar
  • 47 Galynker I, Schlyer DJ, Dewey SL , et al. Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain. Nucl Med Biol 1996; 23 (3) 325-331
    CrossrefPubMedGoogle Scholar
  • 48 Yang DJ, Bryant J, Chang JY , et al. Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex. Anticancer Drugs 2004; 15 (3) 255-263
    CrossrefPubMedGoogle Scholar
  • 49 McCarthy TJ, Sheriff AU, Graneto MJ, Talley JJ, Welch MJ. Radiosynthesis, in vitro validation, and in vivo evaluation of 18F-labeled COX-1 and COX-2 inhibitors. J Nucl Med 2002; 43 (1) 117-124
    PubMedGoogle Scholar
  • 50 de Vries EF, van Waarde A, Buursma AR, Vaalburg W. Synthesis and in vivo evaluation of 18F-desbromo-DuP-697 as a PET tracer for cyclooxygenase-2 expression. J Nucl Med 2003; 44 (10) 1700-1706
    PubMedGoogle Scholar
  • 51 Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 2008; 64 (6) 644-653
    CrossrefPubMedGoogle Scholar
  • 52 Pertin M, Ji RR, Berta T , et al. Upregulation of the voltage-gated sodium channel β2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons. J Neurosci 2005; 25 (47) 10970-10980
    CrossrefPubMedGoogle Scholar
  • 53 Hoehne A, Behera D, Parsons WH , et al. A 18F-labeled saxitoxin derivative for in vivo PET-MR imaging of voltage-gated sodium channel expression following nerve injury. J Am Chem Soc 2013; 135 (48) 18012-18015
    CrossrefPubMedGoogle Scholar
  • 54 Jacobs KE, Behera D, Rosenberg J , et al. Oral manganese as an MRI contrast agent for the detection of nociceptive activity. NMR Biomed 2012; 25 (4) 563-569
    CrossrefPubMedGoogle Scholar
  • 55 Behera D, Behera S, Jacobs KE, Biswal S. Bilateral peripheral neural activity observed in vivo following unilateral nerve injury. Am J Nucl Med Mol Imaging 2013; 3 (3) 282-290
    PubMedGoogle Scholar
  • 56 Behera D, Jacobs KE, Behera S, Rosenberg J, Biswal S. (18)F-FDG PET/MRI can be used to identify injured peripheral nerves in a model of neuropathic pain. J Nucl Med 2011; 52 (8) 1308-1312
    CrossrefPubMedGoogle Scholar
  • 57 Cheng G, Chamroonrat W, Bing Z, Huang S, Zhuang H. Elevated FDG activity in the spinal cord and the sciatic nerves due to neuropathy. Clin Nucl Med 2009; 34 (12) 950-951
    CrossrefPubMedGoogle Scholar