Acta Neurochirurgica

, Volume 157, Issue 6, pp 1051–1057 | Cite as

Longitudinal FDG microPET imaging of neuropathic pain: does cerebellar activity correlate with neuropathic pain development in a rat model?

  • Jinhyung Kim
  • Jaewoo Shin
  • Jin-Hwan Oh
  • Hyun Ho Jung
  • Young-Bo Kim
  • Zang-Hee Cho
  • Jin Woo ChangEmail author
Experimental Research - Functional



We used [F-18] FDG microPET imaging as part of a longitudinal study to investigate changes in the brain.


Glucose metabolism during the development of neuropathic pain after tibial and sural nerve transection (TST) model rats. MicroPET images were obtained 1 week before operation and then weekly for 8 weeks post-operation.


The behavioral test was performed immediately after the every FDG administration. After TST modeling, neuropathic pain rats showed increased mechanical sensitivity of the injured hind paw. The withdrawal response to mechanical pain stimulation by von Frey filaments was observed within the first week (3.8 ± 0.73), and it rapidly increased in the third week (7.13 ± 0.82). This response reached a peak in the fourth week after surgery (9.0 ± 0.53), which persisted until the eighth week. In microPET scan imaging, cerebellum, which initially started from the ansiform lobule, was activated gradually to all part from the third week in all image acquisitions through the eighth week.


The longitudinal microPET scan study of brains from neuropathic pain rat models showed sequential cerebellar activity that was in accordance with results from behavioral test responses, thus supporting a role for the cerebellum in the development of neuropathic pain.


Neuropathic pain microPET FDG Cerebellum Neuromodulation 



This study was financially supported by a grant from the Industrial Source Technology Development Program (no.10033812) of the Ministry of Knowledge Economy (MKE).

Conflict of interest



  1. 1.
    Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9:463–484CrossRefPubMedGoogle Scholar
  2. 2.
    Baron R (2006) Mechanisms of disease: neuropathic pain–a clinical perspective. Nat Clin Pract Neurol 2:95–106CrossRefPubMedGoogle Scholar
  3. 3.
    Becerra L, Morris S, Bazes S, Gostic R, Sherman S, Gostic J, Pendse G, Moulton E, Scrivani S, Keith D, Chizh B, Borsook D (2006) Trigeminal neuropathic pain alters responses in CNS circuits to mechanical (brush) and thermal (cold and heat) stimuli. J Neurosci 26:10646–10657CrossRefPubMedGoogle Scholar
  4. 4.
    Bentley DE, Derbyshire SW, Youell PD, Jones AK (2003) Caudal cingulate cortex involvement in pain processing: an inter-individual laser evoked potential source localisation study using realistic head models. Pain 102:265–271CrossRefPubMedGoogle Scholar
  5. 5.
    Bingel U, Quante M, Knab R, Bromm B, Weiller C, Buchel C (2002) Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 99:313–321CrossRefPubMedGoogle Scholar
  6. 6.
    Bingel U, Tracey I (2008) Imaging CNS modulation of pain in humans. Physiology (Bethesda) 23:371–380CrossRefGoogle Scholar
  7. 7.
    Borsook D, Moulton EA, Tully S, Schmahmann JD, Becerra L (2008) Human cerebellar responses to brush and heat stimuli in healthy and neuropathic pain subjects. Cerebellum 7:252–272CrossRefPubMedGoogle Scholar
  8. 8.
    Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F (2004) Development and validation of the Neuropathic Pain Symptom Inventory. Pain 108:248–257CrossRefPubMedGoogle Scholar
  9. 9.
    Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30CrossRefPubMedGoogle Scholar
  10. 10.
    Davis KD (2000) The neural circuitry of pain as explored with functional MRI. Neurol Res 22:313–317PubMedGoogle Scholar
  11. 11.
    Dimitrova A, Kolb FP, Elles HG, Maschke M, Forsting M, Diener HC, Timmann D (2003) Cerebellar responses evoked by nociceptive leg withdrawal reflex as revealed by event-related FMRI. J Neurophysiol 90:1877–1886CrossRefPubMedGoogle Scholar
  12. 12.
    Dowdall T, Robinson I, Meert TF (2005) Comparison of five different rat models of peripheral nerve injury. Pharmacol Biochem Behav 80:93–108CrossRefPubMedGoogle Scholar
  13. 13.
    Dum RP, Levinthal DJ, Strick PL (2009) The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. J Neurosci 29:14223–14235CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Ekerot CF, Garwicz M, Schouenborg J (1991) The postsynaptic dorsal column pathway mediates cutaneous nociceptive information to cerebellar climbing fibres in the cat. J Physiol 441:275–284CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH (2005) Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118:289–305CrossRefPubMedGoogle Scholar
  16. 16.
    Grodd W, Hulsmann E, Ackermann H (2005) Functional MRI localizing in the cerebellum. Neurosurg Clin N Am 16:77–99, vCrossRefPubMedGoogle Scholar
  17. 17.
    Iadarola MJ, Max MB, Berman KF, Byas-Smith MG, Coghill RC, Gracely RH, Bennett GJ (1995) Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain. Pain 63:55–64CrossRefPubMedGoogle Scholar
  18. 18.
    Ingvar M (1999) Pain and functional imaging. Philos Trans R Soc Lond B Biol Sci 354:1347–1358CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Jie W, Pei-Xi C (1992) Discharge response of cerebellar Purkinje cells to stimulation of C-fiber in cat saphenous nerve. Brain Res 581:269–272CrossRefPubMedGoogle Scholar
  20. 20.
    Kelly RM, Strick PL (2003) Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci 23:8432–8444PubMedGoogle Scholar
  21. 21.
    Keltner JR, Furst A, Fan C, Redfern R, Inglis B, Fields HL (2006) Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J Neurosci 26:4437–4443CrossRefPubMedGoogle Scholar
  22. 22.
    Lee BH, Won R, Baik EJ, Lee SH, Moon CH (2000) An animal model of neuropathic pain employing injury to the sciatic nerve branches. Neuroreport 11:657–661CrossRefPubMedGoogle Scholar
  23. 23.
    Lenz FA, Rios M, Zirh A, Chau D, Krauss G, Lesser RP (1998) Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J Neurophysiol 79:2231–2234PubMedGoogle Scholar
  24. 24.
    Maschke M, Erichsen M, Drepper J, Jentzen W, Muller SP, Kolb FP, Diener HC, Timmann D (2002) Limb flexion reflex-related areas in human cerebellum. Neuroreport 13:2325–2330CrossRefPubMedGoogle Scholar
  25. 25.
    Mason P (2005) Ventromedial medulla: pain modulation and beyond. J Comp Neurol 493:2–8CrossRefPubMedGoogle Scholar
  26. 26.
    Meyer ME, Cottrell GA, Van Hartesveldt C (1993) Intracerebral haloperidol potentiates the dorsal immobility response in the rat. Pharmacol Biochem Behav 44:157–160CrossRefPubMedGoogle Scholar
  27. 27.
    Moisset X, Bouhassira D (2007) Brain imaging of neuropathic pain. Neuroimage 37(Suppl 1):S80–S88CrossRefPubMedGoogle Scholar
  28. 28.
    Moulton EA, Schmahmann JD, Becerra L, Borsook D (2010) The cerebellum and pain: passive integrator or active participator? Brain Res Rev 65:14–27CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Ohyama T, Nores WL, Murphy M, Mauk MD (2003) What the cerebellum computes. Trends Neurosci 26:222–227CrossRefPubMedGoogle Scholar
  30. 30.
    Petrovic P, Ingvar M, Stone-Elander S, Petersson KM, Hansson P (1999) A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 83:459–470CrossRefPubMedGoogle Scholar
  31. 31.
    Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, Froment JC, Mauguiere F, Michel D, Laurent B (1998) Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. Brain 121(Pt 2):345–356CrossRefPubMedGoogle Scholar
  32. 32.
    Peyron R, Laurent B, Garcia-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30:263–288CrossRefPubMedGoogle Scholar
  33. 33.
    Peyron R, Schneider F, Faillenot I, Convers P, Barral FG, Garcia-Larrea L, Laurent B (2004) An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. Neurology 63:1838–1846CrossRefPubMedGoogle Scholar
  34. 34.
    Restuccia D, Della Marca G, Valeriani M, Leggio MG, Molinari M (2007) Cerebellar damage impairs detection of somatosensory input changes. A somatosensory mismatch-negativity study. Brain 130:276–287CrossRefPubMedGoogle Scholar
  35. 35.
    Romero A, Rojas S, Cabanero D, Gispert JD, Herance JR, Campillo A, Puig MM (2011) A (1)(8)F-fluorodeoxyglucose MicroPET imaging study to assess changes in brain glucose metabolism in a rat model of surgery-induced latent pain sensitization. Anesthesiology 115:1072–1083CrossRefPubMedGoogle Scholar
  36. 36.
    Saab CY, Willis WD (2001) Nociceptive visceral stimulation modulates the activity of cerebellar Purkinje cells. Exp Brain Res 140:122–126CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt BL, Tambeli CH, Barletta J, Luo L, Green P, Levine JD, Gear RW (2002) Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats. J Neurosci 22:6773–6780PubMedGoogle Scholar
  38. 38.
    Schmidt BL, Tambeli CH, Gear RW, Levine JD (2001) Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens. Neuroscience 106:129–136CrossRefPubMedGoogle Scholar
  39. 39.
    Schmidt BL, Tambeli CH, Levine JD, Gear RW (2002) mu/delta cooperativity and opposing kappa-opioid effects in nucleus accumbens-mediated antinociception in the rat. Eur J Neurosci 15:861–868CrossRefPubMedGoogle Scholar
  40. 40.
    Schweinhardt P, Fransson P, Olson L, Spenger C, Andersson JL (2003) A template for spatial normalisation of MR images of the rat brain. J Neurosci Methods 129:105–113CrossRefPubMedGoogle Scholar
  41. 41.
    Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I, Bountra C, Tracey I (2006) An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32:256–265CrossRefPubMedGoogle Scholar
  42. 42.
    Seminowicz DA, Laferriere AL, Millecamps M, Yu JS, Coderre TJ, Bushnell MC (2009) MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage 47:1007–1014CrossRefPubMedGoogle Scholar
  43. 43.
    Stoodley CJ, Schmahmann JD (2010) Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 46:831–844CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Tambeli CH, Fischer L, Monaliza SL, Menescal-de-Oliveira L, Parada CA (2012) The functional role of ascending nociceptive control in defensive behavior. Brain Res 1464:24–29CrossRefPubMedGoogle Scholar
  45. 45.
    Tesche CD, Karhu JJ (2000) Anticipatory cerebellar responses during somatosensory omission in man. Hum Brain Mapp 9:119–142CrossRefPubMedGoogle Scholar
  46. 46.
    Tracey I (2005) Nociceptive processing in the human brain. Curr Opin Neurobiol 15:478–487CrossRefPubMedGoogle Scholar
  47. 47.
    Witting N, Kupers RC, Svensson P, Jensen TS (2006) A PET activation study of brush-evoked allodynia in patients with nerve injury pain. Pain 120:145–154CrossRefPubMedGoogle Scholar
  48. 48.
    Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964CrossRefPubMedGoogle Scholar
  49. 49.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Jinhyung Kim
    • 1
    • 2
    • 4
  • Jaewoo Shin
    • 1
    • 2
  • Jin-Hwan Oh
    • 3
  • Hyun Ho Jung
    • 2
  • Young-Bo Kim
    • 3
  • Zang-Hee Cho
    • 3
  • Jin Woo Chang
    • 1
    • 2
    Email author
  1. 1.Brain Korea 21 Project for Medical Science and Brain Research InstituteYonsei University College of MedicineSeoulKorea
  2. 2.Department of NeurosurgeryYonsei University College of MedicineSeoulKorea
  3. 3.Neuroscience Research InstituteGachon UniversityIncheonKorea
  4. 4.Department of Biological ScienceKorea Advanced Institute of Science and Technology (KAIST)DaejeonKorea

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