Brazilian Journal of Pain
https://brjp.org.br/article/doi/10.5935/2595-0118.20220049-en
Brazilian Journal of Pain
Original Article

Electrical stimulation of the posterior insular cortex induces opioid and cannabinoid-dependent antinociception and regulates glial cells in the spinal cord

A estimulação elétrica do córtex insular posterior induz antinocicepção opioide e canabinoide dependente e regula células da glia na medula espinal

Elizamara Santos Gonçalves; Heloísa Alonso Matielo; Manoel Jacobsen Teixeira; Daniel Ciampi de Andrade; Clement Hamani; Camila Squarzoni Dale

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Abstract

BACKGROUND AND OBJECTIVES: Half of neuropathic pain patients still end up failing clinical treatments. Electrical stimulation of the posterior insular cortex (ESI) modulates sensory and nociceptive circuits. This study evaluated the effects of a range of frequencies of ESI proposed to improve neuropathic pain.

METHODS: Male Sprague Dawley rats, 280-340 g, submitted to the chronic constriction of the right sciatic nerve were tested for mechanical sensitivity using the paw pressure and von Frey flaments tests, and for thermal sensitivity using the hot plate test. The rats were submitted to ESI 10, 60 or 100 Hz (one, five or seven ESI, 15 min, 210 µs, 1V), applied to the posterior insular cortex, and were evaluated in the tests before and after ESI, or in follow-up of 48, 72 and 168h. The open field evaluated general activity after ESI 5. The involvment of opioid and cannabinoid testes were evaluated through treatment with naloxone and SR1416A - antagonist and inverse agonist/antagonist of the receptors, respectively, after ESI 5, while activation of astrocytes, marked by glial fibrillary acid protein (GFAP), and of microglia, marked by IBA-1 (glial marker), in the spinal cord evaluated by immunohistochemistry.

RESULTS: Data demonstrate that 10, 60, and 100 Hz ESIs modulate mechanical and thermal sensitivity. ESI 5 increased immunoreactivity of GFAP in the spinal cord, without altering IBA-1 (glial marker). Naloxone and SR141716A reversed the antinociception of 60 Hz ESI 5. 60 Hz ESI 7 induced antinociception up to 72h.

CONCLUSION: 60 Hz ESI induces opioid and cannabinoid-dependent antinociception and regulates glia.

HIGHLIGHTS

  • 60 Hz-delivered ESI was the best analgesic protocol for the insular stimulation.
  • Data showed a prolonged analgesic effect up to 72h after repetitive ESI.
  • ESI regulates glia activation in pain modulatory system.

Keywords

Chronic pain, Electric stimulation, Neuroglia

Resumo

JUSTIFICATIVA E OBJETIVOS: Metade dos pacientes com dor neuropática são refratários aos tratamentos. A estimulação elétrica do córtex insular (EECI) posterior modula circuitos sensoriais e nociceptivos. Assim, este estudo avaliou os efeitos de uma faixa de frequências de EECI como tratamento em modelo animal de dor neuropática.

MÉTODOS: Ratos machos, Sprague Dawley, 280-340 g, submetidos a cirurgia para indução de constrição crônica (ICC) do nervo isquiático direito, foram avaliados em relação à sensibilidade mecânica com a utilização do teste de pressão de pata e de flamentos de von Frey, e sensibilidade térmica usando o teste de placa quente. Os ratos foram submetidos a EECI de 10, 60 ou 100 Hz (uma, cinco ou sete EECI, 15 min, 210 µs, 1V), aplicada ao córtex insular posterior esquerdo, e avaliados nos testes antes e após EECI, ou em follow up de 48, 72 e 168 horas. Por meio do teste de campo aberto, avaliou-se a atividade geral após a EECI5. O envolvimento de receptores opioides e canabinoides foi avaliado por meio da administração de naloxona e SR141716A - antagonista e agonista/antagonista inverso dos receptores, respectivamente - após a EECI 5, enquanto a ativação de astrócitos - marcada por proteína ácida fibrilar glial (GFAP), e de micróglia - marcada por IBA-1 - na medula espinal foi avaliada por imuno-histoquímica.

RESULTADOS: Os dados mostraram que EECI em 10, 60 e 100 Hz modulam a sensibilidade mecânica e térmica dos animais. A EECI 5 aumentou a imunorreatividade de GFAP na medula espinhal, sem alterar IBA-1 (marcador glial). Naloxona e SR141716A reverteram a antinocicepção produzida por EECI 5 de 60 Hz. EECI 7 de 60 Hz induziu antinocicepção por até 72 horas.

CONCLUSÃO: A EECI 60 Hz produz antinocicepção dependente de opioides e canabinoides e regula a glia.

DESTAQUES

  • A EECI de 60 Hz foi o melhor protocolo analgésico para nossa estimulação insular.
  • Os dados mostram um efeito analgésico prolongado de até 72h após repetidas EECI.
  • A EECI regula a ativação da glia no sistema modulatório da dor.

Palavras-chave

Dor crônica, Estimulação elétrica, Neuroglia

References

Garcia-Larrea L, Peyron R. Pain matrices and neuropathic pain matrices: A review. Pain. 2013;154(^sSuppl 1):S29-43.

Lu C, Yang T, Zhao H, Zhang M, Meng F, Fu H, Xie Y, Xu H. Insular cortex is critical for the perception, modulation, and chronification of pain. Neurosci Bull. 2016;32(2):191-201.

Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287-333.

Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ. 2014;348:f7656.

Ciampi de Andrade D, Galhardoni R, Pinto LF, Lancelotti R, Rosi Jr J, Marcolin MA, Teixeira MJ. Into the island: a new technique of non-invasive cortical stimulation of the insula. Neurophysiol Clin. 2012;42(6):363-8.

Galhardoni R, Aparecida da Silva V, García-Larrea L, Dale C, Baptista AF, Barbosa LM, Menezes LMB, de Siqueira SRDT, Valério F, Rosi Jr J, de Lima Rodrigues AL, Reis Mendes Fernandes DT, Lorencini Selingardi PM, Marcolin MA, Duran FLS, Ono CR, Lucato LT, Fernandes AMBL, da Silva FEF, Yeng LT, Brunoni AR, Buchpiguel CA, Teixeira MJ, Ciampi de Andrade D. Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: disassembling the percept of pain. Neurology. 2019;92(18).

Dimov LF, Toniolo EF, Alonso-Matielo H, de Andrade DC, Garcia-Larrea L, Ballester G, Teixeira MJ, Dale CS. Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents. Behav Brain Res. 2018;346:86-95.

Alonso-Matielo H, Gonçalves ES, Campos M, Oliveira VRS, Toniolo EF, Alves AS, Lebrun I, de Andrade DC, Teixeira MJ, Britto LRG, Hamani C, Dale CS. Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry. Brain Res. 2021;1754:147237.

Comoli E, Ribeiro-Barbosa ER, Canteras NS. Predatory hunting and exposure to a live predator induce opposite patterns of Fos immunoreactivity in the PAG. Behav Brain Res. 2003;138(1):17-28.

Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage. 2012;60(1):505-22.

Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355-474.

Ni HD, Yao M, Huang B, Xu LS, Zheng Y, Chu YX, Wang HQ, Liu MJ, Xu SJ, Li HB. Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway. J Neurosci Res. 2016;94(1):50-61.

Tsuda M. Microglia in the spinal cord and neuropathic pain. J Diabetes Investig. 2016;7(1):17-26.

Eto K, Ishibashi H, Yoshimura T, Watanabe M, Miyamoto A, Ikenaka K, Moorhouse AJ, Nabekura J. Enhanced GABAergic activity in the mouse primary somatosensory cortex is insuficient to alleviate chronic pain behavior with reduced expression of neuronal potassium-chloride cotransporter. J Neurosci. 2012;32(47):16552-9.

Ren K. Emerging role of astroglia in pain hypersensitivity. Jpn Dent Sci Rev. 2010;46(1):86-92.

Wieseler-Frank J, Maier SF, Watkins LR. Glial activation and pathological pain. Neurochem Int. 2004;45(2-3):389-95.

Gosselin RD, Suter MR, Ji RR, Decosterd I. Glial cells and chronic pain. Neuroscientist. 2010;16(5):519-31.

Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ. Studying sex and gender diferences in pain and analgesia: a consensus report. Pain. 2007;132(^sSuppl 1):S26-45.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6).

Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K. Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J Vis Exp. 2014;29(91):51785.

Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87-107.

Austin PJ, Wu A, Moalem-Taylor G. Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. J Vis Exp. 2012;13(61):3393.

Paxinos GW. The rat brain in stereotaxic coordiates. 2005.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55-63.

Deuis JR, Dvorakova LS, Vetter I. Methods Used to Evaluate Pain Behaviors in Rodents. Front Mol Neurosci. 2017;10:284.

Rachidi I, Minotti L, Martin G, Hoffmann D, Bastin J, David O, Kahane P. The insula: a stimulating Island of the brain. Brain Sci. 2021;11(11):1533.

Klooster DC, de Louw AJ, Aldenkamp AP, Besseling RM, Mestrom RM, Carrette S, Zinger S, Bergmans JW, Mess WH, Vonck K, Carrette E, Breuer LE, Bernas A, Tijhuis AG, Boon P. Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols. Neurosci Biobehav Rev. 2016;65:113-41.

Moisset X, Lefaucheur JP. Non pharmacological treatment for neuropathic pain: Invasive and non-invasive cortical stimulation. Rev Neurol (Paris). 2019;175(1-2):51-8.

Tan LL, Kuner R. Neocortical circuits in pain and pain relief. Nat Rev Neurosci. 2021;22(8):458-71.

Zhou H, Zhang Q, Martinez E, Dale J, Robinson E, Huang D, Wang J. A novel neuromodulation strategy to enhance the prefrontal control to treat pain. Mol Pain. 2019;15:1744806919845739.

Hamani C, Nóbrega JN. Deep brain stimulation in clinical trials and animal models of depression. Eur J Neurosci. 2010;32(7):1109-17.

Hamani C, Nobrega JN. Preclinical studies modeling deep brain stimulation for depression. Biol Psychiatry. 2012;72(11):916-23.

Ostrowsky K, Magnin M, Ryvlin P, Isnard J, Guenot M, Mauguière F. Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb Cortex. 2002;12(4):376-85.

Aff A, Hoffmann D, Minotti L, Benabid AL, Kahane P. Middle short gyrus of the insula implicated in pain processing. Pain. 2008;138(3):546-55.

Mazzola L, Isnard J, Peyron R, Guénot M, Mauguière F. Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex. Pain. 2009;146(1-2):99-104.

Denis DJ, Marouf R, Rainville P, Bouthillier A, Nguyen DK. Efects of insular stimulation on thermal nociception. Eur J Pain. 2016;20(5):800-10.

Pagano RL, Assis DV, Clara JA, Alves AS, Dale CS, Teixeira MJ, Fonof ET, Britto LR. Transdural motor cortex stimulation reverses neuropathic pain in rats: a profile of neuronal activation. Eur J Pain. 2011;15(3):268.

Challa SR. Surgical animal models of neuropathic pain: Pros and Cons. Int J Neurosci. 2015;125(3):170-4.

Pol O, Murtra P, Caracuel L, Valverde O, Puig MM, Maldonado R. Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain. Neuropharmacology. 2006;50(1):123-32.

Komboz F, Mehsein Z, Kobaïter-Maarrawi S, Chehade HD, Maarrawi J. Epidural posterior insular stimulation alleviates neuropathic pain manifestations in rats with spared nerve injury through endogenous opioid system. Neuromodulation. 2022;23(22^sS1094-7159):00022-8.

Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci. 2001;2(3):185-93.

Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol. 1994;129(2):237-43.

Kim SK, Hayashi H, Ishikawa T, Shibata K, Shigetomi E, Shinozaki Y, Inada H, Roh SE, Kim SJ, Lee G, Bae H, Moorhouse AJ, Mikoshiba K, Fukazawa Y, Koizumi S, Nabekura J. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. J Clin Invest. 2016;126(5):1983-97.

Tanaka Y, Tozuka Y, Takata T, Shimazu N, Matsumura N, Ohta A, Hisatsune T. Excitatory GABAergic activation of cortical dividing glial cells. Cereb Cortex. 2009;19(9):2181-95.

Yoon BE, Woo J, Lee CJ. Astrocytes as GABA-ergic and GABA-ceptive cells. Neurochem Res. 2012;37(11):2474-9.

Zhuo M. Contribution of synaptic plasticity in the insular cortex to chronic pain. Neuroscience. 2016;338:220-9.


Submitted date:
07/14/2022

Accepted date:
09/13/2022

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