Патофизиологическая основа и клиническая значимость нейропластических изменений спинного мозга в формировании фантомного болевого синдрома

Фантомный болевой синдром, возникающий у значительной части пациентов после ампутации конечности, представляет собой сложный по своей патофизиологической основе болевой феномен, существенно снижающий качество жизни пациентов. Накопленные в последнее время данные убедительно доказывают, что нейропластические изменения в спинном мозге являются критически важным ранним звеном в патогенезе развития данной патологии.

В настоящим обзоре дан анализ современных представлений о патофизиологической основе спинальной нейропластичности при фантомном болевом синдроме после травматической ампутации. Обсуждается вклад центральной сенситизации, структурной реорганизации и нейровоспаления в формирование специфических симптомов заболевания (спонтанной и стимулиндуцированной боли, соматотопической реорганизации и проч.). Особое внимание уделяется анализу клинической значимости обсуждаемых патофизиологических процессов: от объяснения эффективности существующих методов лечения до перспектив разработки новых таргетных стратегий, направленных на модуляцию спинальной нейропластичности для профилактики развития и терапии сформировавшегося фантомного болевого синдрома.

1. Flor H, Nikolajsen L, Staehelin JT. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. 2006;7(11):873–881. doi: 10.1038/nrn1991

2. Subedi B, Grossberg GT. Phantom limb pain: mechanisms and treatment approaches. Pain Res Treat. 2011;2011:864605. doi: 10.1155/2011/864605

3. Kooijman CM, Dijkstra PU, Geertzen JH, et al. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain. 2000;87(1):33–41. doi: 10.1016/S0304-3959(00)00264-5

4. Devor M. Neuropathic pain: pathophysiological response of nerves to injury. In: Wall and melzack’s textbook of pain. 6th ed. 2023. P. 861–888.

5. Kuner R, Flor H. Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci. 2016;18(1):20–30. doi: 10.1038/nrn.2016.162

6. Ortega-Márquez J, Garnier J, Mena L, et al. Clinical characteristics associated with the PLP-PLS index, a new potential metric to phenotype phantom limb pain. Biomedicines. 2024;12:2035. doi: 10.3390/biomedicines12092035

7. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Sci. 2000;288(5472):1765–1769. doi: 10.1126/science.288.5472.1765

8. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926. doi: 10.1016/j.jpain.2009.06.012

9. Makin TR, Flor H. Brain (re)organisation following amputation: implications for phantom limb pain. Neuroimag. 2020;218:116943. doi: 10.1016/j.neuroimage.2020.116943

10. Devor M. Response of nerves to injury in relation to neuropathic pain. In: Wall and melzack’s textbook of pain. 5th ed. 2006. P. 905–927. doi: 10.1016/B0-443-07287-6/50063-1

11. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Ann Rev Neurosci. 2006;29:507–538. doi: 10.1146/annurev.neuro.29.051605.112929

12. Merighi A, Salio C, Ghirri A, et al. BDNF as a pain modulator. Prog Neurobiol. 2008;85(3):297–317. doi: 10.1016/j.pneurobio.2008.04.004

13. Issa CJ, Svientek SR, Dehdashtian A, et al. Pathophysiological and neuroplastic changes in postamputation and neuropathic pain: review of the literature. Plast Reconstr Surg Glob Open. 2022;10(9):e4549. doi: 10.1097/gox.0000000000004549

14. Wu G, Ringkamp M, Murinson BB, et al. Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J Neurosci. 2002;22(17):7746–1753. doi: 10.1523/jneurosci.22-17-07746.200

15. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci. 2005;6(7):507–520. doi: 10.1038/nrn1701

16. Sparling T, Iyer L, Pasquina P, Petrus E. Cortical reorganization after limb loss: bridging the gap between basic science and clinical recovery. J Neurosci. 2024;44(1):e1051232024. doi: 10.1523/JNEUROSCI.1051-23.2023

17. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–S15. doi: 10.1016/j.pain.2010.09.030

18. Kinany N, Pirondini E, Micera S, van De Ville Dimitri. Spinal cord fMRI: a new window into the central nervous system. Neurosci. 2023;29(6):715–731. doi: 10.1177/10738584221101827

19. Sandkühler J. Understanding LTP in pain pathways. Mol Pain. 2007;3:9. doi: 10.1186/1744-8069-3-9

20. Krotov V, Kopach O. Targeting spinal dorsal horn sensitisation in chronic pain: mechanisms and translational strategies. Neurosci Bull. 2026 Jun 9. doi: 10.1007/s12264-026-01642-1

21. Wall JT, Xu J, Wang X. Human brain plasticity: an emerging view of the multiple substrates and mechanisms that cause cortical changes and related sensory dysfunctions after injuries of sensory inputs from the body. Brain Res Brain Res Rev. 2002;39(2-3):181–215. doi: 10.1016/s0165-0173(02)00192-3

22. Lenz FA, Dostrovsky JO, Tasker RR, et al. Single-unit analysis of the human ventral thalamic nuclear group: somatosensory responses. 1988;59(2):299–316. doi: 10.1152/jn.1988.59.2.299

23. Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. 2002;1(3):182–189. doi: 10.1016/s1474-4422(02)00074-1

24. Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature. 1992;355(6355):75–78. doi: 10.1038/355075a0

25. Hughes DI, Scott DT, Todd AJ, Riddell JS. Lack of evidence for sprouting of a afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J Neurosci. 2003;23(29):9491–9499. doi: 10.1523/JNEUROSCI.23-29-09491.2003

26. Lu Ya, Perl ER. Modular organization of excitatory circuits between. neurons of the spinal superficial dorsal horn (laminae I and II). J Neurosci. 2005;25(15):3900–3907. doi: 10.1523/JNEUROSCI.0102-05.2005

27. Braz J., Solorzano C., Wang X., Basbaum AI. Transmitting pain and itch messages: A contemporary view of the spinal cord circuits that generate. Gate Control. Neuron. 2014; 82(3): 522–536. doi: 10.1016/j.neuron.2014.01.018

28. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PLoS One. 2007;2(11):e1116. doi: 10.1371/journal.pone.0001116

29. Martin WJ, Malmberg AB, Basbaum AI. PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. J Neurosci. 2001;21(14):5321–5327. doi: 10.1523/JNEUROSCI.21-14-05321.2001

30. Mendell LM. Constructing and deconstructing the gate theory of pain. Pain. 2014;155(2):210–216. doi: 10.1016/j.pain.2013.12.010

31. Beggs S, Salter MW. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun. 2007;21(5):624–633. doi: 10.1016/j.bbi.2006.10.017

32. Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13(7):533–548. doi: 10.1038/nrd4334

33. Fang XX, Zhai MN, Zhu M, et al. Inflammation in pathogenesis of chronic pain: foe and friend. Mol Pain. 2023;19:17448069231178176. doi: 10.1177/17448069231178

34. Vaso A, Adahan HM, Gjika A, et al. Peripheral nervous system origin of phantom limb pain. Pain. 2014;155(7):1384–1391. doi: 10.1016/j.pain.2014.04.018

35. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154(Suppl 1):S10–S28. doi: 10.1016/j.pain.2013.06.022

36. Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438(7070):1017–1021. doi: 10.1038/nature04223

37. Liu Y, Zhou LJ, Wang J, et al. TNF-alpha differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci. 2017;37(4):871–881. doi: 10.1523/jneurosci.2235-16.2016

38. Erlenweina J, Diersb M, Ernstc J, et al. Clinical updates on phantom limb pain. Pain Rep. 2021;6(1):e888. doi: 10.1097/PR9.0000000000000888

39. Robinson L, Czerniecki J, Ehde D, et al. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch Phys Med Rehab. 2004;85(1):1–6. doi: 10.1016/s0003-9993(03)00476-3

40. Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochr Datab Syst Rev. 2016;10:cd006380. doi: 10.1002/14651858.cd006380.pub

41. Huang Yu, Chen SR, Pan HL. α2δ-1: linked NMDA and AMPA receptors in neuropathic pain and gabapentinoid action. J Neurochem. 2025;169(4):e70064. doi: 10.1111/jnc.70064

42. Cliff R, Kulkarni J. A review of the management of phantom limb pain: challenges and solutions. J Pain Res. 2017;10:1861–1870. doi: 10.2147/jpr.s124664

43. Ferraro F, Jacopetti M, Spallnoe V, et al. Diagnosis and treatment of pain in plexopathy, radiculopathy, peripheral neuropathy and phantom limb pain evidence and recommendations from the italian consensus conference on pain on neurorehabilitation. Eur J Phys Rehab Med. 2016;52(6):855–866.

44. McCormick Z, Chang-Chien G, Marshall B, et al. Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain Med. 2014;15(2):292–305. doi: 10.1111/pme.12283

45. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. doi: 10.1016/S1474-4422(14)70251-0

46. Collins S, Sigtermans MJ, Dahan A, et al. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Med. 2010;11(11):1726–1742. doi: 10.1111/j.1526-4637.2010.00981.x

47. Cohen SP, Bhaskar A, Bhatia A, et al. Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group. Reg Anest Pain Med. 2020;46(6):424–467. doi: 10.1136/rapm-2020-102243

48. Krames ES, Foreman R. Spinal cord stimulation modulates visceral nociception and hyperalgesia via the spinothalamic tracts and the postsynaptic dorsal column pathways: a literature review and hypothesis. Neuromodulat. 2007;10(3):224–237. doi: 10.1111/j.1525-1403.2007.00112.x

49. Deer TR, Lamer TJ, Pope JE, et al. The Neurostimulation Appropriateness Consensus Committee (NACC) safety guidelines for the reduction of severe neurological injury. Neuromodulat. 2017;20(1):15–30. doi: 10.1111/ner.12564

50. Krause P, Foerderreuther S, Straube A. Effects of conditioning peripheral repetitive magnetic stimulation in patients with complex regional pain syndrome. Neurol Res. 2005;27(4):412–417. doi: 10.1179/016164105X17224

51. Akyuza G, Girayb E. Noninvasive neuromodulation techniques for the management of phantom limb pain: a systematic review of randomized controlled trials. Int J Rehab Res. 2019;42(1):1–10. doi: 10.1097/MRR.0000000000000317

52. Grigoreva OA, Samsonov TS, Dolgoarshinnaia A, et al. Peripheral magnetic stimulation of the upper-limb nerves: evoked sensations, phantom-pain relief, and cortical responses. medRxiv. 2025. doi: 10.64898/2025.12.05.25341696

53. Corbett M, South E, Harden M, et al. Brain and spinal stimulation therapies for phantom limb pain: a systematic review. Health Technol Assess. 2018;22(62):1–94. doi: 10.3310/hta22620

54. Chan BL, Witt R, Charrow AP, et al. Mirror therapy for phantom limb pain. N Engl J Med. 2007;357(21):2206–2207.

55. Ajzajy RO, Alharbi SJ, Aldhubaiban AS, Albassam MA. The use of mirror therapy for phantom limb pain and function in amputees: evaluating efficacy and clinical outcomes. Int J Innovat Res Eng Multidiscipl Phys Sci. 2022;10(3). doi: 10.5281/zenodo.13335589