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Positron emission tomography (PET) is a noninvasive molecular imaging technique that utilizes biologically active radiolabeled compounds to image biochemical processes. As such, PET can provide important pathophysiological information associated with pain of different etiologies. Consequently, the information obtained using PET often combined with magnetic resonance imaging or computed tomography can provide useful information for diagnosing and monitoring changes associated with pain. This review covers the most important PET tracers that have been used to image pain including tracers for fundamental biological processes such as glucose metabolism and cerebral blood flow, to receptor‐specific tracers such as ion channels and neurotransmitters. For each tracer, we describe the structure and radiochemical synthesis of the tracer followed by a brief summary of the available preclinical and clinical studies. By providing a summary of the PET tracers that have been employed for PET imaging of pain, this review aims to serve as a reference for preclinical, translational, and clinical investigators interested in molecular imaging of pain. Finally, the review ends with an outlook of the needs and opportunities in this area.
Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–82. https://doi.org/10.1097/j.pain.0000000000001939
Rikard SM, Strahan AE, Schmit KM, Guy GP, Jr. Chronic pain among adults — United States, 2019–2021. MMWR Morb Mortal Wkly Rep. 2023;72(15):379–85. https://doi.org/10.15585/mmwr.mm7215a1
Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004;361(1):184–7. https://doi.org/10.1016/j.neulet.2003.12.007
Goodwin G, McMahon SB. The physiological function of different voltage‐gated sodium channels in pain. Nat Rev Neurosci. 2021;22(5):263–74. https://doi.org/10.1038/s41583-021-00444-w
Newton RA, Bingham S, Case PC, Sanger GJ, Lawson SN. Dorsal root ganglion neurons show increased expression of the calcium channel α2δ‐1 subunit following partial sciatic nerve injury. Mol Brain Res. 2001;95(1):1–8. https://doi.org/10.1016/S0169-328X(01)00188-7
Vučković S, Srebro D, Vujović KS, Vučetić Č, Prostran M. Cannabinoids and pain: new insights from old molecules. Front Pharmacol. 2018;9:1259. https://doi.org/10.3389/fphar.2018.01259
Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA‐receptor. J Pain Symptom Manage. 2000;19(1 Suppl):2–6. https://doi.org/10.1016/S0885-3924(99)00120-7
Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ Br Med J (Clin Res Ed). 2014;348:f7656. https://doi.org/10.1136/bmj.f7656
Stucky CL, Gold MS, Zhang X. Mechanisms of pain. Proc Natl Acad Sci USA. 2001;98(21):11845–6. https://doi.org/10.1073/pnas.211373398
Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D, Brenton A, et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol. 2020;16(7):381–400. https://doi.org/10.1038/s41582-020-0362-2
Vierck CJ, Hansson PT, Yezierski RP. Clinical and pre‐clinical pain assessment: are we measuring the same thing? Pain. 2008;135(1):7–10. https://doi.org/10.1016/j.pain.2007.12.008
Weissleder R, Mahmood U. Molecular imaging. Radiology. 2001;219(2):316–33. https://doi.org/10.1148/radiology.219.2.r01ma19316
Jaffer FA, Weissleder R. Molecular imaging in the clinical arena. JAMA. 2005;293(7):855–62. https://doi.org/10.1001/jama.293.7.855
Tian M, He X, Jin C, He X, Wu S, Zhou R, et al. Transpathology: molecular imaging‐based pathology. EJNMMI. 2021;48(8):2338–50. https://doi.org/10.1007/s00259-021-05234-1
Piel M, Vernaleken I, Rösch F. Positron emission tomography in CNS drug discovery and drug monitoring. J Med Chem. 2014;57(22):9232–58. https://doi.org/10.1021/jm5001858
Ravert HT, Bencherif B, Madar I, Frost JJ. PET imaging of opioid receptors in pain: progress and new directions. Curr Pharmaceut Des. 2004;10(7):759–68. https://doi.org/10.2174/1381612043452992
May A. Neuroimaging: visualising the brain in pain. Neurol Sci. 2007;28(2):S101–7. https://doi.org/10.1007/s10072-007-0760-x
Moisset X, Bouhassira D. Brain imaging of neuropathic pain. Neuroimage. 2007;37:S80–8. https://doi.org/10.1016/j.neuroimage.2007.03.054
Min J‐J. Molecular pain imaging by nuclear medicine: where does it stand and where is it going? Nucl Med Mol Imaging. 2016;50(4):273–4. https://doi.org/10.1007/s13139-016-0457-2
Morton DL, Sandhu JS, Jones AKP. Brain imaging of pain: state of the art. J Pain Res. 2016;9:613–24. https://doi.org/10.2147/JPR.S60433
van der Heijden RA, Biswal S. Up‐and‐coming radiotracers for imaging pain generators. Semin Muscoskel Radiol. 2023;27(6):661–75. https://doi.org/10.1055/s-0043-1775745
Ido T, Wan CN, Casella V, Fowler JS, Wolf AP, Reivich M, et al. Labeled 2‐deoxy‐D‐glucose analogs. 18F‐labeled 2‐deoxy‐2‐fluoro‐D‐glucose, 2‐deoxy‐2‐fluoro‐D‐mannose and 14C‐2‐deoxy‐2‐fluoro‐D‐glucose. J Label Compd Radiopharm. 1978;14(2):175–83. https://doi.org/10.1002/jlcr.2580140204
Yu S. Review of 18F‐FDG synthesis and quality control. Biomed Imaging Interv J. 2006;2(4). https://doi.org/10.2349/biij.2.4.e57
Clark JC, Crouzel C, Meyer GJ, Strijckmans K. Current methodology for oxygen‐15 production for clinical use. Int J Rad Appl Instrum A. 1987;38(8):597–600. https://doi.org/10.1016/0883-2889(87)90122-5
Kabalka GW, Lambrecht RM, Sajjad M, Fowler JS, Kunda SA, McCollum GW, et al. Synthesis of 15O‐labeled butanol via organoborane chemistry. Int J Appl Radiat Isot. 1985;36(11):853–5. https://doi.org/10.1016/0020-708x(85)90017-1
Jacobson O, Kiesewetter DO, Chen X. Fluorine‐18 radiochemistry, labeling strategies and synthetic routes. Bioconjugate Chem. 2015;26(1):1–18. https://doi.org/10.1021/bc500475e
Graves SA, Hernandez R, Valdovinos HF, Ellison PA, Engle JW, Barnhart TE, et al. Preparation and in vivo characterization of 51MnCl2 as PET tracer of Ca2+ channel‐mediated transport. Sci Rep. 2017;7(1):3033. https://doi.org/10.1038/s41598-017-03202-0
Wester HJ, Willoch F, Tölle TR, Munz F, Herz M, Oye I, 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):1279–86.
Schoultz BW, Reed BJ, Marton J, Willoch F, Henriksen G. A fully automated radiosynthesis of [18F]fluoroethyl‐diprenorphine on a single module by use of SPE cartridges for preparation of high quality 2‐[18F]fluoroethyl tosylate. Molecules. 2013;18(6):7271–8. https://doi.org/10.3390/molecules18067271
Wey H‐Y, Catana C, Hooker JM, Dougherty DD, Knudsen GM, Wang DJJ, et al. Simultaneous fMRI–PET of the opioidergic pain system in human brain. Neuroimage. 2014;102:275–82. https://doi.org/10.1016/j.neuroimage.2014.07.058
Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA, et al. Multicompartmental analysis of [C]‐Carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cerebr Blood Flow Metabol. 1989;9(3):398–409. https://doi.org/10.1038/jcbfm.1989.59
Frost JJ, Wagner HN, Jr, Dannals RF, Ravert HT, Links JM, Wilson AA, et al. Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr. 1985;9(2):231–6. https://doi.org/10.1097/00004728-198503000-00001
Farde L, Ehrin E, Eriksson L, Greitz T, Hall H, Hedström CG, et al. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA. 1985;82(11):3863–7. https://doi.org/10.1073/pnas.82.11.3863
Pretze M, Wängler C, Wängler B. 6‐[18F]Fluoro‐L‐DOPA: a well‐established neurotracer with expanding application spectrum and strongly improved radiosyntheses. BioMed Res Int. 2014;2014:674063. https://doi.org/10.1155/2014/674063
Neves ÂCB, Hrynchak I, Fonseca I, Alves VHP, Pereira MM, Falcão A, et al. Advances in the automated synthesis of 6‐[18F]Fluoro‐L‐DOPA. EJNMMI Radiopha Chem. 2021;6(1):11. https://doi.org/10.1186/s41181-021-00126-z
Hoehne A, Behera D, Parsons WH, James ML, Shen B, Borgohain P, 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):18012–5. https://doi.org/10.1021/ja408300e
Hooker JM, Strebl MG, Schroeder FA, Wey H‐Y, Ambardekar AV, McKinsey TA, et al. Imaging cardiac SCN5A using the novel F‐18 radiotracer radiocaine. Sci Rep. 2017;7(1):42136. https://doi.org/10.1038/srep42136
Zhou Y‐P, Sun Y, Takahashi K, Belov V, Andrews N, Woolf CJ, et al. Development of a PET radioligand for α2δ‐1 subunit of calcium channels for imaging neuropathic pain. Eur J Med Chem. 2022;242, 114688. https://doi.org/10.1016/j.ejmech.2022.114688
Tan PZ, Baldwin RM, Van Dyck CH, Al‐Tikriti M, Roth B, Khan N, et al. Characterization of radioactive metabolites of 5‐HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol. 1999;26(6):601–8. https://doi.org/10.1016/S0969-8051(99)00022-0
Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S. Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of 11C‐labeled 2‐(phenylthio)araalkylamines. J Med Chem. 2000;43(16):3103–10. https://doi.org/10.1021/jm000079i
James ML, Shen B, Nielsen CH, Behera D, Buckmaster CL, Mesangeau C, et al. Evaluation of σ‐1 receptor radioligand 18F‐FTC‐146 in rats and squirrel monkeys using PET. J Nucl Med. 2014;55(1):147–53. https://doi.org/10.2967/jnumed.113.120261
Shen B, James ML, Andrews L, Lau C, Chen S, Palner M, et al. Further validation to support clinical translation of [18F]FTC‐146 for imaging sigma‐1 receptors. EJNMMI Res. 2015;5(1):49. https://doi.org/10.1186/s13550-015-0122-2
Villarinho JG, Pinheiro KdV, Pinheiro FdV, Oliveira SM, Machado P, Martins MAP, et al. The antinociceptive effect of reversible monoamine oxidase ‐ a inhibitors in a mouse neuropathic pain model. Prog Neuropsychopharmacol Biol Physc. 2013;44:136–42. https://doi.org/10.1016/j.pnpbp.2013.02.005
Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S, et al. Radiosynthesis and preclinical evaluation of 11C‐ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med. 2006;47(4):698–705.
Camsonne R, Crouzel C, Comar D, Mazière M, Prenant C, Sastre J, et al. Synthesis of N‐(11C) methyl, N‐(methyl‐1 propyl), (chloro‐2 phenyl)‐1 isoquinoleine carboxamide‐3 (PK 11195): a new ligand for peripheral benzodiazepine receptors. J Label Compd Radiopharm. 1984;21(10):985–91.
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(1):17–30. https://doi.org/10.1021/jm0707370
Keller T, Krzyczmonik A, Forsback S, Picón FRL, Kirjavainen AK, Takkinen J, et al. Radiosynthesis and preclinical evaluation of [(18)F]F‐DPA, A novel pyrazolo[1,5a]pyrimidine acetamide TSPO radioligand, in healthy sprague dawley rats. Mol Imag Biol. 2017;19(5):736–45. https://doi.org/10.1007/s11307-016-1040-z
Behera D, Jacobs KE, Behera S, Rosenberg J, Biswal S. 18F‐FDG PET/MRI can be used to identify injured peripheral nerves in a model of neuropathic pain. J Nucl Med. 2011;52(8):1308–12. https://doi.org/10.2967/jnumed.110.084731
Kim C‐E, Kim YK, Chung G, Im HJ, Lee DS, Kim J, et al. Identifying neuropathic pain using 18F‐FDG micro‐PET: a multivariate pattern analysis. Neuroimage. 2014;86, 311–6. https://doi.org/10.1016/j.neuroimage.2013.10.001
Cui Y, Neyama H, Hu D, Huang T, Hayashinaka E, Wada Y, et al. FDG PET imaging of the pain matrix in neuropathic pain model rats. Biomedicines. 2023;11(1):63. https://doi.org/10.3390/biomedicines11010063
Biswal S, Behera D, Yoon DH, Holley D, Ith MAM, Carroll I, et al. [18F]FDG PET/MRI of patients with chronic pain alters management: early experience. EJNMMI Physics. 2015;2(1):84. https://doi.org/10.1186/2197-7364-2-S1-A84
Yoon D, Xu Y, Cipriano PW, Alam IS, Mari Aparici C, Tawfik VL, et al. Neurovascular, muscle, and skin changes on [18F]FDG PET/MRI in complex regional pain syndrome of the foot: a prospective clinical study. Pain Med. 2021;23(2):339–46. https://doi.org/10.1093/pm/pnab315
Lassen NA, Ingvar DH, Skinhøj E. Brain function and blood flow. Sci Am. 1978;239(4):62–71.
Nagamachi S, Fujita S, Nishii R, Futami S, Wakamatsu H, Takanori Y, et al. Alteration of regional cerebral blood flow in patients with chronic pain — evaluation before and after epidural spinal cord stimulation. Ann Nucl Med. 2006;20(4):303–10. https://doi.org/10.1007/BF02984647
Katherine H, Taber PD, Kevin J, Black MD, Robin A, Hurley MD. Blood flow imaging of the brain: 50 years experience. J Neuropsychiatry Clin Neurosci. 2005;17(4):441–6. https://doi.org/10.1176/jnp.17.4.441
Feng C‐M, Narayana S, Lancaster JL, Jerabek PA, Arnow TL, Zhu F, et al. CBF changes during brain activation: fMRI vs. PET. Neuroimage. 2004;22(1):443–6. https://doi.org/10.1016/j.neuroimage.2004.01.017
Ter‐Pogossian MM, Eichling JO, Davis DO, Welch MJ, Metzger JM. The determination of regional cerebral blood flow by means of water labeled with radioactive oxygen 15. Radiology. 1969;93(1):31–40. https://doi.org/10.1148/93.1.31
Berridge MS, Adler LP, Nelson AD, Cassidy EH, Muzic RF, Bednarczyk EM, et al. Measurement of human cerebral blood flow with [15O]butanol and positron emission tomography. J Cerebr Blood Flow Metabol. 1991;11(5):707–15. https://doi.org/10.1038/jcbfm.1991.127
Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci USA. 1999;96(14):7668–74. https://doi.org/10.1073/pnas.96.14.7668
Craig AD, Reiman EM, Evans A, Bushnell MC. Functional imaging of an illusion of pain. Nature. 1996;384(6606):258–60. https://doi.org/10.1038/384258a0
Vogt BA, Derbyshire S, Jones AKP. Pain processing in four regions of human cingulate cortex localized with co‐registered PET and MR imaging. Eur J Neurosci. 1996;8(7):1461–73. https://doi.org/10.1111/j.1460-9568.1996.tb01608.x
May A, Kaube H, Büchel C, Eichten C, Rijntjes M, Jüptner M, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain. 1998;74(1):61–6. https://doi.org/10.1016/S0304-3959(97)00144-9
Hsieh J‐C, Hannerz J, Ingvar M. Right‐lateralised central processing for pain of nitroglycer‐induced cluster headache. Pain. 1996;67(1):59–68. https://doi.org/10.1016/0304-3959(96)03066-7
Peyron R, García‐Larrea L, Grégoire MC, Convers P, Richard A, Lavenne F, et al. Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case. Pain. 2000;84(1):77–87. https://doi.org/10.1016/S0304-3959(99)00190-6
Blau M, Nagler W, Bender MA. Fluorine‐18: a new isotope for bone scanning. J Nucl Med. 1962;3:332–4.
Ahuja K, Sotoudeh H, Galgano SJ, Singh R, Gupta N, Gaddamanugu S, et al. F‐sodium fluoride PET: history, technical feasibility, mechanism of action, normal biodistribution, and diagnostic performance in bone metastasis detection compared with other imaging modalities. J Nucl Med Technol. 2020;48(1):9–16. https://doi.org/10.2967/jnmt.119.234336
Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST. Skeletal PET with 18F‐fluoride: applying new technology to an old tracer. J Nucl Med. 2008;49(1):68–78. https://doi.org/10.2967/jnumed.106.037200
Draper CE, Fredericson M, Gold GE, Besier TF, Delp SL, Beaupre GS, et al. Patients with patellofemoral pain exhibit elevated bone metabolic activity at the patellofemoral joint. J Orthop Res. 2012;30(2):209–13. https://doi.org/10.1002/jor.21523
Draper CE, Quon A, Fredericson M, Besier TF, Delp SL, Beaupre GS, et al. Comparison of MRI and 18F‐NaF PET/CT in patients with patellofemoral pain. J Magn Reson Imag. 2012;36(4):928–32. https://doi.org/10.1002/jmri.23682
Kobayashi N, Inaba Y, Tateishi U, Yukizawa Y, Ike H, Inoue T, et al. New application of 18F‐fluoride PET for the detection of bone remodeling in early‐stage osteoarthritis of the hip. Clin Nucl Med. 2013;38(10):e379–83. https://doi.org/10.1097/RLU.0b013e31828d30c0
Kobayashi N, Inaba Y, Tateishi U, Ike H, Kubota S, Inoue T, et al. Comparison of 18F‐fluoride positron emission tomography and magnetic resonance imaging in evaluating early‐stage osteoarthritis of the hip. Nucl Med Commun. 2015;36(1):84–9. https://doi.org/10.1097/mnm.0000000000000214
Daube ME, Nickles RJ. Development of myocardial perfusion tracers for positron emission tomography. Int J Nucl Med Biol. 1985;12(4):303–14. https://doi.org/10.1016/0047-0740(85)90185-8
Cha M, Choi S, Kim K, Lee BH. Manganese‐enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats. Mol Brain. 2020;13(1):158. https://doi.org/10.1186/s13041-020-00687-1
Barrett K, Biswal S, Lennertz R, Jeffery J, Becker K, Aluicio‐Sarduy E, et al. Cyclotron produced radio‐manganese as a potential radiotracer for identifying neuroinflammation in inflammatory pain. J Nucl Med. 2022;63(Suppl 2):2555.
Al‐Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor‐dependent signaling and behavior. Anesthesiology. 2011;115(6):1363–81. https://doi.org/10.1097/ALN.0b013e318238bba6
Lever JR, Dannals RF, Wilson AA, Ravert HT, Wagner HN. Synthesis of carbon‐11 labeled diprenorphine: a radioligand for positron emission tomographic studies of opiate receptors. Tetrahedron Lett. 1987;28(35):4015–8. https://doi.org/10.1016/S0040-4039(01)83849-1
Luthra SK, Pike VW, Brady F. The preparation of carbon‐11 labelled diprenorphine: a new radioligand for the study of the opiate receptor system in vivo. J Chem Soc, Chem Commun. 1985;20:1423–5. https://doi.org/10.1039/C39850001423
Goud NS, Bhattacharya A, Joshi RK, Nagaraj C, Bharath RD, Kumar P. Carbon‐11: radiochemistry and target‐based PET molecular imaging applications in oncology, cardiology, and neurology. J Med Chem. 2021;64(3):1223–59. https://doi.org/10.1021/acs.jmedchem.0c01053
Baumgärtner U, Buchholz H‐G, Bellosevich A, Magerl W, Siessmeier T, Rolke R, et al. High opiate receptor binding potential in the human lateral pain system. Neuroimage. 2006;30(3):692–9. https://doi.org/10.1016/j.neuroimage.2005.10.033
Sprenger T, Valet M, Boecker H, Henriksen G, Spilker ME, Willoch F, et al. Opioidergic activation in the medial pain system after heat pain. PAIN®. 2006;122(1):63–7. https://doi.org/10.1016/j.pain.2006.01.003
Jones AKP, Watabe H, Cunningham VJ, Jones T. Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET. Eur J Pain. 2004;8(5):479–85. https://doi.org/10.1016/j.ejpain.2003.11.017
Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, et al. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain. 2004;108(3):213–20. https://doi.org/10.1016/j.pain.2003.08.014
Dougherty DD, Kong J, Webb M, Bonab AA, Fischman AJ, Gollub RL. A combined [11C]diprenorphine PET study and fMRI study of acupuncture analgesia. Behav Brain Res. 2008;193(1):63–8. https://doi.org/10.1016/j.bbr.2008.04.020
Dannals RF, Ravert HT, James Frost J, Wilson AA, Donald Burns H, Wagner HN. Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil. Int J Appl Radiat Isot. 1985;36(4):303–6. https://doi.org/10.1016/0020-708X(85)90089-4
Jewett DM. A simple synthesis of [11C]carfentanil using an extraction disk instead of HPLC. Nucl Med Biol. 2001;28(6):733–4. https://doi.org/10.1016/s0969-8051(01)00226-8
Bencherif B, Fuchs PN, Sheth R, Dannals RF, Campbell JN, Frost JJ. Pain activation of human supraspinal opioid pathways as demonstrated by [11C]‐carfentanil and positron emission tomography (PET). Pain. 2002;99(3):589–98. https://doi.org/10.1016/S0304-3959(02)00266-X
Karjalainen T, Karlsson HK, Lahnakoski JM, Glerean E, Nuutila P, Jääskeläinen IP, et al. Dissociable roles of cerebral μ‐opioid and type 2 dopamine receptors in vicarious pain: a combined PET–fMRI study. Cerebr Cortex. 2017;27(8):4257–66. https://doi.org/10.1093/cercor/bhx129
DosSantos M, Love T, Martikainen I, Nascimento T, Fregni F, Cummiford C, et al. Immediate effects of tDCS on the μ‐opioid system of a chronic pain patient. Front Psychiatr. 2012;3. https://doi.org/10.3389/fpsyt.2012.00093
Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, et al. Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. Pain. 2016;157(10):2217–25. https://doi.org/10.1097/j.pain.0000000000000633
Ly HG, Dupont P, Geeraerts B, Bormans G, Van Laere K, Tack J, et al. Lack of endogenous opioid release during sustained visceral pain: a [11C]carfentanil PET study. PAIN®. 2013;154(10):2072–7. https://doi.org/10.1016/j.pain.2013.06.026
Megat S, Shiers S, Moy JK, Barragan‐Iglesias P, Pradhan G, Seal RP, et al. A critical role for dopamine D5 receptors in pain chronicity in male mice. J Neurosci. 2018;38(2):379–97. https://doi.org/10.1523/jneurosci.2110-17.2017
Ledermann K, Jenewein J, Sprott H, Hasler G, Schnyder U, Warnock G, et al. Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression – a [11C] raclopride PET‐study. Eur Neuropsychopharmacol. 2016;26(2):320–30. https://doi.org/10.1016/j.euroneuro.2015.12.007
Wood PB, Patterson JC, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain. 2007;8(1):51–8. https://doi.org/10.1016/j.jpain.2006.05.014
Rogers M, Tang L, Madge DJ, Stevens EB. The role of sodium channels in neuropathic pain. Semin Cell Dev Biol. 2006;17(5):571–81. https://doi.org/10.1016/j.semcdb.2006.10.009
Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, et al. Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve‐injured rats. J Neurosci. 2001;21(6):1868–75. https://doi.org/10.1523/jneurosci.21-06-01868.2001
Melrose HL, Kinloch RA, Cox PJ, Field MJ, Collins D, Williams D. [3H] pregabalin binding is increased in ipsilateral dorsal horn following chronic constriction injury. Neurosci Lett. 2007;417(2):187–92. https://doi.org/10.1016/j.neulet.2007.02.068
Bartolo ND, Reid SE, Krishnan HS, Haseki A, Renganathan M, Largent‐Milnes TM, et al. Radiocaine: an imaging marker of neuropathic injury. ACS Chem Neurosci. 2022;13(24):3661–7. https://doi.org/10.1021/acschemneuro.2c00717
Zhou Y‐P, Normandin MD, Belov V, Macdonald‐Soccorso MT, Moon S‐H, Sun Y, et al. Evaluation of trans‐ and cis‐4‐[18F]fluorogabapentin for brain PET imaging. ACS Chem Neurosci. 2023;14(23):4208–15. https://doi.org/10.1021/acschemneuro.3c00593
Liu QQ, Yao XX, Gao SH, Li R, Li BJ, Yang W, et al. Role of 5‐HT receptors in neuropathic pain: potential therapeutic implications. Pharmacol Res. 2020;159, 104949. https://doi.org/10.1016/j.phrs.2020.104949
Huang C, van Wijnen AJ, Im H‐J. Serotonin transporter (5‐hydroxytryptamine transporter, SERT, SLC6A4) and sodium‐dependent reuptake inhibitors as modulators of pain behaviors and analgesic responses. J Pain. 2024;25(3):618–31. https://doi.org/10.1016/j.jpain.2023.10.008
Haleem JD. Targeting Serotonin1A receptors for treating chronic pain and depression. Curr Neuropharmacol. 2019;17(12):1098–108. https://doi.org/10.2174/1570159X17666190811161807
Martin SL, Power A, Boyle Y, Anderson IM, Silverdale MA, Jones AKP. 5‐HT modulation of pain perception in humans. Psychopharmacology. 2017;234(19):2929–39. https://doi.org/10.1007/s00213-017-4686-6
Bazzichi L, Giannaccini G, Betti L, Mascia G, Fabbrini L, Italiani P, et al. Alteration of serotonin transporter density and activity in fibromyalgia. Arthritis Res Ther. 2006;8(4):R99. https://doi.org/10.1186/ar1982
Kupers R, Frokjaer VG, Naert A, Christensen R, Budtz‐Joergensen E, Kehlet H, et al. A PET [18F]altanserin study of 5‐HT2A receptor binding in the human brain and responses to painful heat stimulation. Neuroimage. 2009;44(3):1001–7. https://doi.org/10.1016/j.neuroimage.2008.10.011
Kupers R, Frokjaer VG, Erritzoe D, Naert A, Budtz‐Joergensen E, Nielsen FA, et al. Serotonin transporter binding in the hypothalamus correlates negatively with tonic heat pain ratings in healthy subjects: a [11C]DASB PET study. Neuroimage. 2011;54(2):1336–43. https://doi.org/10.1016/j.neuroimage.2010.09.010
Shen B, Behera D, James ML, Reyes ST, Andrews L, Cipriano PW, et al. Visualizing nerve injury in a neuropathic pain model with [18F]FTC‐146 PET/MRI. Theranostics. 2017;7(11):2794–805. https://doi.org/10.7150/thno.19378
James ML, Shen B, Zavaleta CL, Nielsen CH, Mesangeau C, Vuppala PK, et al. New positron emission tomography (PET) radioligand for imaging σ‐1 receptors in living subjects. J Med Chem. 2012;55(19):8272–82. https://doi.org/10.1021/jm300371c
Yous S, Wallez V, Belloir M, Caignard DH, McCurdy CR, Poupaert JH. Novel 2(3H)‐Benzothiazolones as highly potent and selective sigma‐1 receptor ligands. Med Chem Res. 2005;14(3):158–68. https://doi.org/10.1007/s00044-005-0131-1
Cipriano PW, Lee S‐W, Yoon D, Shen B, Tawfik VL, Curtin CM, et al. Successful treatment of chronic knee pain following localization by a sigma‐1 receptor radioligand and PET/MRI: a case report. J Pain Res. 2018;11:2353–7. https://doi.org/10.2147/JPR.S167839
Yoon D, Fast AM, Cipriano P, Shen B, Castillo JB, McCurdy CR, et al. Sigma‐1 receptor changes observed in chronic pelvic pain patients: a pilot PET/MRI study. Front. Pain Res. 2021;2. https://doi.org/10.3389/fpain.2021.711748
Buccino P, Kreimerman I, Zirbesegger K, Porcal W, Savio E, Engler H. Automated radiosynthesis of [11C]L‐deprenyl‐D2 and [11C]D‐deprenyl using a commercial platform. Appl Radiat Isot. 2016;110, 47–52. https://doi.org/10.1016/j.apradiso.2015.12.051
Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, et al. Mapping human brain monoamine oxidase A and B with 11C‐labeled suicide inactivators and PET. Science. 1987;235(4787):481–5. https://doi.org/10.1126/science.3099392
Aarnio M, Appel L, Fredrikson M, Gordh T, Wolf O, Sörensen J, et al. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [11C]‐D‐deprenyl PET/CT. Scandinavian J Pain. 2017;17(1):418–24. https://doi.org/10.1016/j.sjpain.2017.10.008
Vincent K, Cornea VM, Jong Y‐JI, Laferrière A, Kumar N, Mickeviciute A, et al. Intracellular mGluR5 plays a critical role in neuropathic pain. Nat Commun. 2016;7(1):10604. https://doi.org/10.1038/ncomms10604
Chung G, Kim CY, Yun Y‐C, Yoon SH, Kim M‐H, Kim YK, et al. Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats. Sci Rep. 2017;7(1):9743. https://doi.org/10.1038/s41598-017-09991-8
Werry EL, Bright FM, Piguet O, Ittner LM, Halliday GM, Hodges JR, et al. Recent developments in TSPO PET imaging as A biomarker of neuroinflammation in neurodegenerative disorders. Int J Mol Sci. 2019;20(13):3161. https://doi.org/10.3390/ijms20133161
Wang L, Cheng R, Fujinaga M, Yang J, Zhang Y, Hatori A, et al. A facile radiolabeling of [18F]FDPA via spirocyclic iodonium ylides: preliminary PET imaging studies in preclinical models of neuroinflammation. J Med Chem. 2017;60(12):5222–7. https://doi.org/10.1021/acs.jmedchem.7b00432
Imamoto N, Momosaki S, Fujita M, Omachi S, Yamato H, Kimura M, et al. [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats. Neuroimage. 2013;79:121–8. https://doi.org/10.1016/j.neuroimage.2013.04.039
Shimochi S, Keller T, Kujala E, Khabbal J, Rajander J, Löyttyniemi E, et al. Evaluation of [18F]F‐DPA PET for detecting microglial activation in the spinal cord of a rat model of neuropathic pain. Mol Imag Biol. 2022;24(4):641–50. https://doi.org/10.1007/s11307-022-01713-5
Albrecht DS, Forsberg A, Sandström A, Bergan C, Kadetoff D, Protsenko E, et al. Brain glial activation in fibromyalgia – a multi‐site positron emission tomography investigation. Brain Behav Immun. 2019;75:72–83. https://doi.org/10.1016/j.bbi.2018.09.018
Albrecht DS, Mainero C, Ichijo E, Ward N, Granziera C, Zürcher NR, et al. Imaging of neuroinflammation in migraine with aura. A [11C]PBR28 PET/MRI Study. 2019;92(17):e2038–50. https://doi.org/10.1212/wnl.0000000000007371
Housman H, Brusaferri L, Datko M, Tohyama S, Round K, Gomez RGG, et al. In Vivo Molecular Imaging of Neuroinflammation in Patients with Migraine. J Pain. 2022;23(5 Supplement):44. https://doi.org/10.1016/j.jpain.2022.03.169
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