Identificación microneurográfica de la actividad espontánea de los nociceptores C en los estados de dolor neuropático en humanos y ratas
Publicado en la Revista Pain 2012;153:42-55
DOI:
https://doi.org/10.47924/neurotarget2013271Palabras clave:
microneurografía, dolor neuropático, nociceptorResumen
Los nociceptores de las fibras de tipo C normalmente no disparan potenciales de acción a menos que sean estimulados por estímulos nocivos adecuados. Sin embargo, en estados patológicos, los nociceptores pueden volverse hiperexcitables y generan descargas ectópicas espontáneas. El objetivo de este estudio fue comparar modelos de dolor neuropático en ratas y evaluar su idoneidad para modelar la actividad espontánea de los nociceptores C que se encontró en pacientes con dolor neuropático. Los estudios fueron realizados en ratas normales (n=40), sujetos humanos sanos (n=15), pacientes con dolor neuropático periférico (n=20) y en cinco modelos de dolor neuropático en ratas: aplastamiento de nervio (n=24), sutura (n=14), lesión por compresión crónica (n = 12), neuropatía diabética inducida por estreptozotocina [STZ] (n=56) y neuropatía inducida por 2,3-dideoxicitidina [ddC] (n=15). Los registros microneurográficos fueron combinados con la estimulación eléctrica para monitorear la actividad en múltiples fibras de tipo C. La estimulación con 0,25 Hz permitió que los impulsos espontáneos puedan ser identificados por las fluctuaciones de la latencia basal. Las fluctuaciones anormales de la latencia podrían ser producidas por varios mecanismos. La actividad espontánea fue identificada de manera más fidedigna por la presencia de incrementos inexplicables de la latencia, correspondientes a dos o más potenciales de acción adicionales. La actividad espontánea estuvo presente en determinada proporción de nociceptores de tipo C insensibles a los estímulos mecánicos en los pacientes y en todos los modelos en ratas. Los tres modelos animales de lesión traumática focal en nervios presentaron la proporción más alta (59,5%), mientras que los dos modelos de polineuropatía tuvieron menos (18,6%), en tanto que los pacientes mostraron una proporción intermedia (33,3%). No se registraron nociceptores C sensibles a los estímulos mecánicos espontáneamente activos. Los registros microneurográficos de la actividad espontánea de los nociceptores C enfermos pueden ser de utilidad para el estudio de drogas a corto y largo plazo, tanto en animales como en humanos.
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Amir R, Michaelis M, Devor M. Burst discharge in primary sensory neurons: triggered by subthreshold oscillations, maintained by depolarizing afterpotentials. J Neurosci 2002;22:1187-98.
Attal N, Fermanian C, Fermanian J, Lanteri-Minet M, Alchaar H, Bouhassira D. Neuropathic pain: are there distinct subtypes depending on the aetiology or anatomical lesion? Pain 2008;138:343-53.
Baron R, Tölle TR, Gockel U, Brosz M, Freynhagen R. A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: differences in demographic data and sensory symptoms. Pain 2009;146:34-40.
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107.
Bostock H, Campero M, Serra J, Ochoa J. Velocity recovery cycles of C fibres innervating human skin. J Physiol 2003;553:649-63.
Bostock H, Campero M, Serra J, Ochoa JL. Temperature-dependent double spikes in C-nociceptors of neuropathic pain patients. Brain 2005;128:2154-63.
Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008;136:380-7.
Boyce S, Hill RG. Discrepant results from preclinical and clinical studies on the potential of substance P-receptor antagonist com- pounds as analgesics. En: Devor M, Rowbotham MC, Wiesenfeld- Hallin Z, editors. Proceedings of the 9th world congress on pain. Seattle: IASP Press; 2000. p. 313-24.
Campero M, Bostock H, Baumann TK, Ochoa JL. A search for activation of Cnociceptors by sympathetic fibers in complex regional pain syndrome. Clin Neurophysiol 2010;121:1072-9.
Campero M, Serra J, Marchettini P, Ochoa JL. Ectopic impulse generation andautoexcitation in single myelinated afferent fibers in patients with peripheral neuropathy and positive sensory symptoms. Muscle Nerve 1998;21:1661-7.
Campero M, Serra J, Bostock H, Ochoa JL. Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 2001;535:855-65.
Campero M, Serra J, Bostock H, Ochoa JL. Partial reversal of conduction slowing during repetitive stimulation of single sympathetic efferents in human skin. Acta Physiol Scand 2004;182:305-11.
Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing painand cold allodynia in a rat model of neuropathic pain. Pain 1994;59:369-76.
De Col R, Messlinger K, Carr RW. Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges. J Physiol 2008;586:1089-103.
Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci 2006;26:1281-92.
Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 2009;196:115-28.
Endres W, Grafe P, Bostock H, ten Bruggencate G. Changes in extracellular pH during electrical stimulation of isolated rat vagus nerve. Neurosci Lett 1986;64:201-5.
England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis RA, Low PA, Fisher MA, Herrmann DN, Howard Jr JF, Lauria G, Miller RG, Polydefkis M, Sumner AJ, American Academy of Neurology. Practice parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Aca- demy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009;72:177-84.
FaisalAA, Laughlin SB. Stochastic simulations on the reliability of action potential propagation in thin axons. PLoS Comput Biol 2007;3:e79.
Jensen MP, Karoly P. Self-report scales and procedures for assessing pain in adults. In: Turk DC, Melzack R, editors. Handbook of pain assessment. New York: Guilford Press; 2001. pp. 135-51.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10:895- 926.
Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Solé J. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurologi- cal Societies and the Peripheral Nerve Society. Eur J Neurol 2010;17:e44-9
Lee DH, Chang L, Sorkin LS, Chaplan SR. Hyperpolarization-ac- tivated, cationnonselective, cyclic nucleotide-modulated channel blockade alleviates mechanical allodynia and suppresses ectopic discharge in spinal nerve ligated rats. J Pain 2005;6:417–24.
Lundberg LE, Jørum E, Holm E, Torebjörk HE. Intra-neural electrical stimulation of cutaneous nociceptive fibres in humans: effects of different pulse patterns on magnitude of pain. Acta Physiol Scand 1992;146:41-8.
McMahon SB, Wall PD. Physiological evidence for branching of peripheral unmyelinated sensory afferent fibers in the rat. J Comp Neurol 1987;261:130-6.
Ochoa JL, Campero M, Serra J, Bostock H. Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy. Muscle Nerve 2005;32:459-72.
Ørstavik K, Namer B, Schmidt R, Schmelz M, Hilliges M, Weidner C, Carr RW, Handwerker H, Jørum E, Torebjörk HE. Abnormal function of C-fibers in patients with diabetic neuropathy. J Neurosci 2006;26:11287-94.
Ørstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jørum E, Handwerker H, Torebjörk E. Pathological C-fibres in patients with a chronic painful condition. Brain 2003;126:567-78.
Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 2010;9:203–14.
Rang HP, Ritchie JM. The ionic content of mammalian nonmyelinated nerve fibres and its alteration as a result of electrical activity. J Physiol 1968;196:223-36.
Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix Fralish ML, Machin I, Preclinical Pain Consortium, Mogil JS, Stöhr T. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008;139:243-7.
Serra J. Microneurography: an opportunity for translational drug development in neuropathic pain. Neurosci Lett 2010;470:155-7.
Serra J, Campero M, Ochoa J, Bostock H. Activity dependent slowing of conduction differentiates functional types of C fibers innervating human skin. J Physiol 1999;515:799-811.
Serra J, Campero M, Bostock H, Ochoa J. Two types of C-nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia. J Neurophysiol 2004;91:2770-81.
Serra J, Solà R, Quiles C, Casanova-Molla J, Pascual V, Bostock H, Valls-Solé J. Cnociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia. Pain 2009;147:46-53.
Serra J, Bostock H, Navarro X. Microneurography in rats: a minimally invasive method to record single C-fiber action potentials from peripheral nerves in vivo. Neurosci Lett 2010;470:168-74.
Serra J, Solà R, Aleu J, Quiles C, Navarro X, Bostock H. Double and triple spikes in C-nociceptors in neuropathic pain states: an additional peripheral mechanism of hyperalgesia. Pain 2011;152:343-53.
Torebjörk HE, Hallin RG. Responses in human A and C fibres to repeated electrical intradermal stimulation. J Neurol Neurosurg Psychiatry 1974;37:653-64.
Vallbo A, Hagbarth KE. Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp Neurol 1968;21:270-89.
Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, RiceAS. Characterization of rodent models of HIV-gp120 and antiretroviralassociated neuropathic pain. Brain 2007;130:2688-702.
Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjörk HE. Functional attributes discriminating mechanoinsensitive and mechanoresponsive C-nociceptors in human skin. J Neurosci 1999;15:10184-90.
Weidner C, Schmidt R, Schmelz M, Torebjork HE, Handwerker HO. Action potential conduction in the terminal arborisation of nociceptive C-fiber afferents. J Physiol 2003;547:931-40.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2010;152:S2-S15.
Xie W, Strong JA, Meij JT, Zhang JM, Yu L. Neuropathic pain: early spontaneous afferent activity is the trigger. Pain 2005;116:243-56
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Derechos de autor 2013 Jordi Serra, Hugh Bostock, Romà Solà, Jordi Aleu, Elizabeth García, Barbara Cokic, Xavier Navarro, Cristina Quiles
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