Download PDF
CC BY-NC-ND 4.0 · Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery 2018; 37(04): 317-325
DOI: 10.1002/lsm.22628
SBN Award | Prêmio SBN (Pre-Clinical Report)
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

The Mechanistic Basis for Photobiomodulation Therapy of Neuropathic Pain by Near Infrared Laser Light[1]

Vanessa Milanesi Holanda
1   Post Graduate Program in Biophotonics Applied to the Health Sciences, Universidade Nove de Julho-UNINOVE, São Paulo, SP, Brazil
2   Center of Neurology and Neurosurgery Associates (CENNA), Beneficência Portuguesa of São Paulo Hospital, São Paulo, SP, Brazil
,
Maria Cristina Chavantes
1   Post Graduate Program in Biophotonics Applied to the Health Sciences, Universidade Nove de Julho-UNINOVE, São Paulo, SP, Brazil
3   Post Graduate Program in Medicine, University Nove de Julho—UNINOVE, São Paulo, SP, Brazil
,
Xingjia Wu
4   Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
,
Juanita J. Anders
4   Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
12 December 2018 (online)

   Permissions and Reprints

Abstract

Background and Objective Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimental models, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance.

Study Design/Materials and Methods ln vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (L T) groups with different irradiation times (2, 5, 30, 60 or 120s). The laser parameters were: output power = 960 mW, irradiance = 300mW/cm2, 808 nm wavelength and spot size = 3cm diameter/ area = 7.07cm2, with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to β-Tubulin III. ln vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n = 5). 1) Control: SNI without LT, 2) Short term: SNI with LT on day 7 and euthanized on day 7, 3) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on Day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2, treatment time: 120s. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI.

Results ln vitro experiments: Mitochondrial metabolism was significantly lower compared with controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30µm or less. ln neurites of DRG neurons with a cell body diameter of greater than 30µm, varicosities formed only in the 120s group. ln vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared with the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared with the control group on day 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after L T. Sensitivity to these stimuli returned to the control levels after 5 days post-L T. No significant difference was found in mechanical allodynia between control and L T groups for all time points examined.

Conclusion These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 m W/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/fluence rates for prolonged pain relief by altering chronic inflammation.

Keywords

Dorsal Root Ganglion - Fluence Rate - Laser Irradiation - Photoneuromodulation - Transient Neuronal Injury

1 © 2017 Wiley Periodicals, Inc. Originally published as Holanda VM, Chavantes MC, Wu X, Anders JJ. The Mechanistic Basis for Photobiomodulation Therapy of Neuropathic Pain by Near Infrared Laser Light. Lasers Surg Med. 2017; doi https://doi.org/10.1002/lsm.22628.


 

  • References

  • 1 Tockarshewsky T. Public Comments by the Neuropathy Association at the FDA Anesthetic and Analgesic Drug Products Advisory Committee Meeting. Silver Spring, Maryland: The Neuropathy Association; 2012: 3
    Google Scholar
  • 2 O'Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009; 122 (10, Suppl) S22-S32
    PubMedGoogle Scholar
  • 3 Barbosa RI, da Silva Rodrigues EK, Tamanini G. , et al. Effectiveness of low-level laser therapy for patients with carpal tunnel syndrome: design of a randomized single-blinded controlled trial. BMC Musculoskelet Disord 2012; 13: 248
    CrossrefPubMedGoogle Scholar
  • 4 Chow RT, Barnsley L. Systematic review of the literature of low-level laser therapy (LLLT) in the management of neck pain. Lasers Surg Med 2005; 37 (01) 46-52
    CrossrefPubMedGoogle Scholar
  • 5 Chow RT, Johnson MI, Lopes-Martins RA, Bjordal JM. Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials. Lancet 2009; 374 (9705): 1897-1908
    CrossrefPubMedGoogle Scholar
  • 6 Alcântara CC, Gigo-Benato D, Salvini TF, Oliveira AL, Anders JJ, Russo TL. Effect of low-level laser therapy (LLLT) on acute neural recovery and inflammation-related gene expression after crush injury in rat sciatic nerve. Lasers Surg Med 2013; 45 (04) 246-252
    CrossrefPubMedGoogle Scholar
  • 7 Byrnes KR, Waynant RW, Ilev IK. , et al. Light promotes regeneration and functional recovery and alters the immune response after spinal cord injury. Lasers Surg Med 2005; 36 (03) 171-185
    CrossrefPubMedGoogle Scholar
  • 8 Fernandes KP, Alves AN, Nunes FD. , et al. Effect of photobiomodulation on expression of IL-1β in skeletal muscle following acute injury. Lasers Med Sci 2013; 28 (03) 1043-1046
    CrossrefPubMedGoogle Scholar
  • 9 Peplow PV, Chung TY, Ryan B, Baxter GD. Laser photobiomodulation of gene expression and release of growth factors and cytokines from cells in culture: a review of human and animal studies. Photomed Laser Surg 2011; 29 (05) 285-304
    CrossrefPubMedGoogle Scholar
  • 10 von Leden RE, Cooney SJ, Ferrara TM. , et al. 808 nm wavelength light induces a dose-dependent alteration in microglial polarization and resultant microglial induced neurite growth. Lasers Surg Med 2013; 45 (04) 253-263
    CrossrefPubMedGoogle Scholar
  • 11 Hsieh YL, Chou LW, Chang PL, Yang CC, Kao MJ, Hong CZ. Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1α (HIF-1α). J Comp Neurol 2012; 520 (13) 2903-2916
    CrossrefPubMedGoogle Scholar
  • 12 Cidral-Filho FJ, Martins DF, Moré AO. , et al. Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-α levels after sciatic nerve crush in mice. Eur J Pain 2013; 17 (08) 1193-1204
    CrossrefPubMedGoogle Scholar
  • 13 Kobiela Ketz A, Byrnes KR, Grunberg NE, Kasper CE, Osborne L, Pryor B, Tosini NL, Wu X, Anders JJ. Characterization of Macrophage/Microglial Activation and Effect of Photobiomodulation in the Spared Nerve Injury Model ofNeuropathic Pain. Pain medicine (Malden, Mass) 2016
    PubMedGoogle Scholar
  • 14 Chow RT, Heller GZ, Barnsley L. The effect of 300 mW, 830 nm laser on chronic neck pain: a double-blind, randomized, placebo-controlled study. Pain 2006; 124 (1-2): 201-210
    CrossrefPubMedGoogle Scholar
  • 15 Chow RT, David MA, Armati PJ. 830 nm laser irradiation induces varicosity formation, reduces mitochondrial membrane potential and blocks fast axonal flow in small and medium diameter rat dorsal root ganglion neurons: implications for the analgesic effects of 830 nm laser. J Peripher Nerv Syst 2007; 12 (01) 28-39
    CrossrefPubMedGoogle Scholar
  • 16 Chow R, Armati P, Laakso EL, Bjordal JM, Baxter GD. Inhibitory effects of laser irradiation on peripheral mammalian nerves and relevance to analgesic effects: a systematic review. Photomed Laser Surg 2011; 29 (06) 365-381
    CrossrefPubMedGoogle Scholar
  • 17 Holanda VM, Chavantes MC, Silva DF. , et al. Photobiomodulation of the dorsal root ganglion for the treatment of low back pain: A pilot study. Lasers Surg Med 2016; 48 (07) 653-659
    CrossrefPubMedGoogle Scholar
  • 18 Lanzafame RJ, Brandon P, Stadler I. Chapter XII: Wound healing: Experimental and clinical approaches to understanding photobiomodulation and its mechanisms, in Simunovic Z: Lasers ln Medicine And Dentistry. European Medical Laser Association; 2009. 4: 163-172
    Google Scholar
  • 19 Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87 (02) 149-158
    CrossrefPubMedGoogle Scholar
  • 20 Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32 (01) 77-88
    CrossrefPubMedGoogle Scholar
  • 21 Cobianchi S, Casals-Diaz L, Jaramillo J, Navarro X. Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury. Exp Neurol 2013; 240: 157-167
    CrossrefPubMedGoogle Scholar
  • 22 Zengin-Toktas Y, Ferrier J, Durif F, Llorca PM, Authier N. Bilateral lesions of the nigrostriatal pathways are associated with chronic mechanical pain hypersensitivity in rats. Neurosci Res 2013; 76 (04) 261-264
    CrossrefPubMedGoogle Scholar
  • 23 Tang-Schomer MD, Johnson VE, Baas PW, Stewart W, Smith DH. Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Exp Neurol 2012; 233 (01) 364-372
    CrossrefPubMedGoogle Scholar
  • 24 Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurgical focus 2004; 16 (05) El
    PubMedGoogle Scholar
  • 25 Kakulas BA. A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 1999; 22 (02) 119-124
    CrossrefPubMedGoogle Scholar
  • 26 Saxena S, Caroni P. Mechanisms of axon degeneration: from development to disease. Prog Neurobiol 2007; 83 (03) 174-191
    CrossrefPubMedGoogle Scholar
  • 27 Haines JD, Inglese M, Casaccia P. Axonal damage in multiple sclerosis. Mt Sinai J Med 2011; 78 (02) 231-243
    CrossrefPubMedGoogle Scholar
  • 28 Tseng CY, Firestein BL. The role of PSD-95 and cypin in morphological changes in dendrites following sublethal NMDA exposure. J Neurosci 2011; 31 (43) 15468-15480
    CrossrefPubMedGoogle Scholar
  • 29 Liebert AD, Chow RT, Bicknell BT, Varigos E. Neuroprotective Effects Against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton. J Exp Neurosci 2016; 10: 1-19
    PubMedGoogle Scholar
  • 30 Tanelian DL, Markin VS. Biophysical and functional consequences of receptor-mediated nerve fiber transformation. Biophys J 1997; 72 (03) 1092-1108
    CrossrefPubMedGoogle Scholar
  • 31 Nicolson GL, Smith JR, Poste G. Effects of local anesthetics on cell morphology and membrane-associated cytoskeletal organization in BALB/3T3 cells. J Cell Biol 1976; 68 (02) 395-402
    CrossrefPubMedGoogle Scholar
  • 32 Miyamoto Y, Muto E, Mashimo T, Iwane AH, Yoshiya I, Yanagida T. Direct inhibition of microtubule-based kinesin motility by local anesthetics. Biophys J 2000; 78 (02) 940-949
    CrossrefPubMedGoogle Scholar
  • 33 Yan W, Chow R, Armati PJ. Inhibitory effects of visible 650-nm and infrared 808-nm laser irradiation on somatosensory and compound muscle action potentials in rat sciatic nerve: implications for laser-induced analgesia. J Peripher Nerv Syst 2011; 16 (02) 130-135
    CrossrefPubMedGoogle Scholar
  • 34 Ibáñez CF. Message in a bottle: long-range retrograde signaling in the nervous system. Trends Cell Biol 2007; 17 (11) 519-528
    CrossrefPubMedGoogle Scholar
  • 35 Magdesian MH, Sanchez FS, Lopez M. , et al. Atomic force microscopy reveals important differences in axonal resistance to injury. Biophys J 2012; 103 (03) 405-414
    CrossrefPubMedGoogle Scholar
  • 36 Oblinger MM, Brady ST, McQuarrie IG, Lasek RJ. Cytotypic differences in the protein composition of the axonally transported cytoskeleton in mammalian neurons. J Neurosci 1987; 7 (02) 453-462
    CrossrefPubMedGoogle Scholar
  • 37 Maxwell WL. Frontiers in Neuroengineering Development of Concepts in the Pathology ofTraumatic Axonal and Traumatic Brain Injury. ln: Kobeissy FH. , ed. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis (e); 2015. by Taylor & Francis Group, LLC. 2015.
    Google Scholar
  • 38 Lingor P, Koch JC, Tönges L, Bähr M. Axonal degeneration as a therapeutic target in the CNS. Cell Tissue Res 2012; 349 (01) 289-311
    CrossrefPubMedGoogle Scholar
  • 39 Masoumipoor M, Jameie SB, Janzadeh A, Nasirinezhad F, Soleimani M, Kerdary M. Effects of 660- and 980-nm low-level laser therapy on neuropathic pain relief following chronic constriction injury in rat sciatic nerve. Lasers Med Sci 2014; 29 (05) 1593-1598
    CrossrefPubMedGoogle Scholar
  • 40 Saidu E, Wu X, Alberico S, Pryor B, Smith J, Anders JJ. 980 nm Wavelength Light Decreases Mechanical Allodynia ln A Rat Neuropathic Pain Model. Lasers Surg Med 2013; 45 (25) 51
    PubMedGoogle Scholar
  • 41 Karu TI. Mitochondrial signaling in mammalian cells activated by red and near-IR radiation. Photochem Photobiol 2008; 84 (05) 1091-1099
    CrossrefPubMedGoogle Scholar
  • 42 Wu S, Cing D. lntracellular signaling cascades following light irradiation. Laser Photonics Rev 2014; 8 (01) 115-130
    CrossrefPubMedGoogle Scholar