The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury

Molecular Pain

Maria Fitzgerald³  Gareth Hathway²  Rebecca McKelvey³  David Vega-Avelaira¹ 

[1] Current address: Dpto. Fisiología, Edificio Medicina, Universidad Alcalá, Madrid, 28871, Spain;Current address: School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham, NG7 2UH, UK;UCL Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E6BT, UK

关键词: Neonatal;    Dorsal root ganglia;    Spinal cord;    Astrocytes;    Microglia;    Neuropathic pain;   

Others  :  863865
DOI  :  10.1186/1744-8069-8-30

 received in 2011-12-23, accepted in 2012-04-24,  发布年份 2012

【 摘 要 】

Background

Peripheral nerve injuries can trigger neuropathic pain in adults but cause little or no pain when they are sustained in infancy or early childhood. This is confirmed in rodent models where neonatal nerve injury causes no pain behaviour. However, delayed pain can arise in man some considerable time after nerve damage and to examine this following early life nerve injury we have carried out a longer term follow up of rat pain behaviour into adolescence and adulthood.

Results

Spared nerve injury (SNI) or sham surgery was performed on 10 day old (P10) rat pups and mechanical nociceptive reflex thresholds were analysed 3, 7, 14, 21, 28, 38 and 44 days post surgery. While mechanical thresholds on the ipsilateral side are not significantly different from controls for the first 2–3 weeks post P10 surgery, after that time period, beginning at 21 days post surgery (P31), the SNI group developed following early life nerve injury significant hypersensitivity compared to the other groups. Ipsilateral mechanical nociceptive threshold was 2-fold below that of the contralateral and sham thresholds at 21 days post surgery (SNI-ipsilateral 28 (±5) g control groups 69 (±9) g, p < 0.001, 3-way ANOVA, n = 6 per group). Importantly, no effect was observed on thermal thresholds. This hypersensivity was accompanied by macrophage, microglial and astrocyte activation in the DRG and dorsal horn, but no significant change in dorsal horn p38 or JNK expression. Preemptive minocycline (daily 40 mg/kg, s.c) did not prevent the effect. Ketamine (20 mg/kg, s.c), on the other hand, produced a dose-dependent reversal of mechanical nociceptive thresholds ipsilateral to the nerve injury such that thresholds return to control levels at the highest doses of 20 mg/Kg.

Conclusions

We report a novel consequence of early life nerve injury whereby mechanical hypersensitivity only emerges later in life. This delayed adolescent onset in mechanical pain thresholds is accompanied by neuroimmune activation and NMDA dependent central sensitization of spinal nociceptive circuits. This delayed onset in mechanical pain sensitivity may provide clues to understand the long term effects of early injury such as late onset phantom pain and the emergence of complex adolescent chronic pain syndromes.

【 授权许可】

   
2012 Vega-Avelaira et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Anand P, Birch R: Restoration of sensory function and lack of long-term chronic pain syndromes after brachial plexus injury in human neonates. Brain 2002, 125:113-122.
• [2]Walco GA, Dworkin RH, Krane EJ, LeBel AA, Treede RD: Neuropathic pain in children: Special considerations. Mayo Clin Proc 2010, 85:S33-S41.
• [3]Ririe D, Eisenach J: Age-dependent responses to nerve injury-induced mechanical allodynia. Anesthesiology 2006, 104:344-350.
• [4]Lee DH, Chung JM: Neuropathic pain in neonatal rats. Neurosci Lett 1996, 209:140-142.
• [5]Howard R, Walker S, Mota P, Fitzgerald M: The ontogeny of neuropathic pain: postnatal onset of mechanical allodynia in rat spared nerve injury (SNI) and chronic constriction injury (CCI) models. Pain 2005, 115:382-389.
• [6]Hermann C, Hohmeister J, Demirakca S, Zohsel K, Flor H: Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain 2006, 125:278-285.
• [7]Walker SM, Franck LS, Fitzgerald M, Myles J, Stocks J, Marlow N: Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm. Pain 2009, 141:79-87.
• [8]Grunau RE, Holsti L, Peters JW: Long-term consequences of pain in human neonates. Semin Fetal Neonatal Med 2006, 11:268-275.
• [9]Melzack R, Israel R, Lacroix R, Schultz G: Phantom limbs in people with congenital limb deficiency or amputation in early childhood. Brain 1997, 120(Pt 9):1603-1620.
• [10]Sethna NF, Meier PM, Zurakowski D, Berde CB: Cutaneous sensory abnormalities in children and adolescents with complex regional pain syndromes. Pain 2007, 131:153-161.
• [11]Decosterd I, Woolf C: Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000, 87:149-158.
• [12]Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32:77-88.
• [13]Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003, 306:624-630.
• [14]Suzuki R, Matthews EA, Dickenson AH: Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 2001, 91:101-109.
• [15]Plenderleith MB, Wright LL, Snow PJ: Expression of lectin binding in the superficial dorsal horn of the rat spinal cord during pre- and postnatal development. Brain Res Dev Brain Res 1992, 68:103-109.
• [16]Narita M, Yoshida T, Nakajima M, Miyatake M, Takagi T, Yajima Y, Suzuki T: Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice. J Neurochem 2006, 97:1337-1348.
• [17]Eng LF, Ghirnikar RS: GFAP and astrogliosis. Brain Pathol 1994, 4:229-237.
• [18]Molander C, Wang H, Rivero-Melian C, Grant G: Early decline and late restoration of spinal cord binding and transganglionic transport of isolectin B4 from Griffonia simplicifolia I after peripheral nerve transection and crush. Restor Neurol Neuros 1996, 10:123-133.
• [19]Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S: A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 1996, 224:855-862.
• [20]Dahl D, Labkovsky B, Bignami A: Neurofilament phosphorylation in axons and perikarya: immunofluorescence study of the rat spinal cord and dorsal root ganglia with monoclonal antibodies. J Comp Neurol 1988, 271:445-450.
• [21]Vega-Avelaira D, Geranton SM, Fitzgerald M: Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Mol Pain 2009, 5:70. BioMed Central Full Text
• [22]Falcon M, Guendellman D, Stolberg A, Frenk H, Urca G: Development of thermal nociception in rats. Pain 1996, 67:203-208.
• [23]Huang HW, Wang WC, Lin CC: Influence of age on thermal thresholds, thermal pain thresholds, and reaction time. J Clin Neurosci 2010, 17:722-726.
• [24]De Leo J, Tawfik V, LaCroix-Fralish M: The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 2006, 122:17-21.
• [25]DeLeo J, Sorkin L, Watkins L: Immune and glial regulation of pain. 2007, 67-106.
• [26]DeLeo J, Yezierski R: The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 2001, 90:1-6.
• [27]Hu P, McLachlan E: Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience 2002, 112:23-38.
• [28]Ji R, Suter M: p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 2007, 3:33. BioMed Central Full Text
• [29]Scholz J, Woolf C: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10:1361-1368.
• [30]Moss A, Beggs S, Vega-Avelaira D, Costigan M, Hathway GJ, Salter MW, Fitzgerald M: Spinal microglia and neuropathic pain in young rats. Pain 2007, 128:215-224.
• [31]Vega-Avelaira D, Moss A, Fitzgerald M: Age-related changes in the spinal cord microglial and astrocytic response profile to nerve injury. Brain Behav Immun 2007, 21:617-623.
• [32]Bailey AL, Ribeiro-da-Silva A: Transient loss of terminals from non-peptidergic nociceptive fibers in the substantia gelatinosa of spinal cord following chronic constriction injury of the sciatic nerve. Neuroscience 2006, 138:675-690.
• [33]Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN: Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 2001, 108:143-155.
• [34]Beggs S, Salter MW: Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun 2007, 21:624-633.
• [35]Chang YW, Waxman SG: Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. J Pain 2010, 11:1146-1154.
• [36]Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB: Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 2006, 121:219-231.
• [37]Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009, 29:4096-4108.
• [38]Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I: Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2006, 2:259-269.
• [39]Gao X, Kim HK, Chung JM, Chung K: Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain 2005, 116:62-72.
• [40]Bourquin AF, Suveges M, Pertin M, Gilliard N, Sardy S, Davison AC, Spahn DR, Decosterd I: Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse. Pain 2006, 122(14):e11-e14.
• [41]Fitzgerald M: The development of nociceptive circuits. Nat Rev Neurosci 2005, 6:507-520.
• [42]Baccei ML: Development of pain: maturation of spinal inhibitory networks. Int Anesthesiol Clin 2007, 45:1-11.
• [43]McCutcheon JE, Marinelli M: Age matters. Eur J Neurosci 2009, 29:997-1014.
• [44]Atherton DD, Taherzadeh O, Elliot D, Anand P: Age-dependent development of chronic neuropathic pain, allodynia and sensory recovery after upper limb nerve injury in children. J Hand Surg Eur Vol 2008, 33:186-191.
• [45]McCann ME, Waters P, Goumnerova LC, Berde C: Self-mutilation in young children following brachial plexus birth injury. Pain 2004, 110:123-129.
• [46]Saadah ES, Melzack R: Phantom limb experiences in congenital limb-deficient adults. Cortex 1994, 30:479-485.
• [47]Clinch J, Eccleston C: Chronic musculoskeletal pain in children: assessment and management. Rheumatology (Oxford) 2009, 48:466-474.
• [48]Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M: T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 2009, 29:14415-14422.
• [49]Fadel S, Sarzotti M: Cellular immune responses in neonates. Int Rev Immunol 2000, 19:173-193.
• [50]Adkins B: Development of neonatal Th1/Th2 function. Int Rev Immunol 2000, 19:157-171.
• [51]Zhuang ZY, Gerner P, Woolf CJ, Ji RR: ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005, 114:149-159.
• [52]Zhang J, De Koninck Y: Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006, 97:772-783.
• [53]Colton CA: Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 2009, 4:399-418.
• [54]Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308:1314-1318.
• [55]Ji R, Strichartz G: Cell signaling and the genesis of neuropathic pain. Sci STKE 2004, 2004:reE14.
• [56]Wieseler-Frank J, Maier SF, Watkins LR: Central proinflammatory cytokines and pain enhancement. Neurosignals 2005, 14:166-174.
• [57]Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010, 468:253-262.
• [58]Woolf CJ: Evidence for a central component of post-injury pain hypersensitivity. Nature 1983, 306:686-688.
• [59]Latremoliere A, Woolf CJ: Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009, 10:895-926.
• [60]Ma QP, Woolf CJ: Noxious stimuli induce an N-methyl-D-aspartate receptor-dependent hypersensitivity of the flexion withdrawal reflex to touch: implications for the treatment of mechanical allodynia. Pain 1995, 61:383-390.
• [61]Qian J, Brown SD, Carlton SM: Systemic ketamine attenuates nociceptive behaviors in a rat model of peripheral neuropathy. Brain Res 1996, 715:51-62.
• [62]Li J, Walker SM, Fitzgerald M, Baccei ML: Activity-dependent modulation of glutamatergic signaling in the developing rat dorsal horn by early tissue injury. J Neurophysiol 2009, 102:2208-2219.
• [63]Hathway GJ, Koch S, Low L, Fitzgerald M: The changing balance of brainstem-spinal cord modulation of pain processing over the first weeks of rat postnatal life. J Physiol 2009, 587:2927-2935.
• [64]Beggs S, Currie G, Salter MW, Fitzgerald M: Walker SM: Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain 2011, 135(Pt2):404-417.