BACKGROUND: There is a growing body of evidence that unilateral nerve injury induces bilateral response, the mechanism of which is not exactly known. Because cytokines act as crucial signaling molecules for response of peripheral nerves to injury, they may be induced to mediate the reaction in remote structures. METHODS: We studied levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) proteins using ELISA in the ipsilateral and contralateral lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) from naïve rats, rats operated on to create unilateral chronic constriction injury (CCI) of the sciatic nerve, and sham-operated rats. Withdrawal thresholds for mechanical allodynia and thermal hyperalgesia were measured in the ipsilateral and contralateral hind and forepaws. RESULTS: The ipsilateral hind paws of all rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and thermal hyperalgesia, while no significant behavioral changes were found in the contralateral hind paws and both forepaws. Significantly lower baseline levels of TNF-alpha and IL-10 protein were measured by ELISA in the lumbar than cervical DRG of naïve rats. Bilateral elevation of TNF-alpha was induced in both the lumbar and cervical DRG by unilateral CCI of the sciatic nerve for 7 and 14 days, while the level of IL-10 protein was increased bilaterally in the lumbar DRG 1 and 3 days after operation. IL-10 levels declined bilaterally even below baseline level in both cervical and lumbar DRG 7 days from CCI and normalized after 14 days. In contrast to no significant changes in TNF-alpha, level of IL-10 protein was significantly increased in the ipsilateral lumbar DRG after 3 days and bilaterally in the lumbar DRG after 14 days from sham operation. CONCLUSIONS: The results of our experiments show a bilateral elevation of TNF-alpha and IL-10 not only in the homonymous DRG but also in the heteronymous DRG unassociated with the injured nerve. This suggests that bilaterally increased levels of TNF-alpha and IL-10 in DRG following unilateral CCI are linked with general neuroinflammatory reaction of the nervous system to injury rather than only to development and maintenance of neuropathic pain.

Department of Anatomy Division of Neuroanatomy Medical Faculty Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959–1964. doi: 10.1016/S0140-6736(99)01307-0. PubMed DOI

Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of neuropathic pain. Eur J Pharmacol. 2001;429:1–11. doi: 10.1016/S0014-2999(01)01302-4. PubMed DOI

Suzuki R, Dickenson AH. Neuropathic pain: nerves bursting with excitement. Neuroreport. 2000;11:R17–21. doi: 10.1097/00001756-200011090-00001. PubMed DOI

Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. doi: 10.1126/science.288.5472.1765. PubMed DOI

Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol. 2001;429:23–37. doi: 10.1016/S0014-2999(01)01303-6. PubMed DOI

Koltzenburg M, Wall PD, McMahon SB. Does the right side know what the left is doing? Trends Neurosci. 1999;22:122–127. doi: 10.1016/S0166-2236(98)01302-2. PubMed DOI

Kleinschnitz C, Brinkhoff J, Sommer C, Stoll G. Contralateral cytokine gene induction after peripheral nerve lesions: dependence on the mode of injury and NMDA receptor signaling. Brain Res Mol Brain Res. 2005;136:23–28. doi: 10.1016/j.molbrainres.2004.12.015. PubMed DOI

Hopkins SJ, Rothwell NJ. Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci. 1995;18:83–88. doi: 10.1016/0166-2236(95)93881-W. PubMed DOI

Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: Actions and mechanisms of action. Trends Neurosci. 1995;18:130–136. doi: 10.1016/0166-2236(95)93890-A. PubMed DOI

Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–1040. PubMed PMC

Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004;361:184–187. doi: 10.1016/j.neulet.2003.12.007. PubMed DOI

Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–1368. doi: 10.1038/nn1992. PubMed DOI

Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J, O'Connor K, Martin D, Forsayeth JR, Maier SF, Johnson K. Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci. 2005;21:2136–2148. doi: 10.1111/j.1460-9568.2005.04057.x. PubMed DOI

Sweitzer S, Martin D, DeLeo JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience. 2001;103:529–539. doi: 10.1016/S0306-4522(00)00574-1. PubMed DOI

Zahn PK, Subieta A, Park SS, Brennan TJ. Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision. J Pain. 2004;5:157–163. doi: 10.1016/j.jpain.2004.02.538. PubMed DOI

Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV. Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res. 2001;913:86–89. doi: 10.1016/S0006-8993(01)02743-3. PubMed DOI

Shamash S, Reichert F, Rotshenker S. The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci. 2002;22:3052–3060. PubMed PMC

Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol. 2002;513:87–113. PubMed

Wagner R, Myers RR. Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves. Neuroscience. 1996;73:625–629. doi: 10.1016/0306-4522(96)00127-3. PubMed DOI

Sommer C, Schafers M. Painful mononeuropathy in C57BL/Wld mice with delayed wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res. 1998;784:154–162. doi: 10.1016/S0006-8993(97)01327-9. PubMed DOI

Woolf CJ, Allchorne A, Safieh-Garabedian B, Poole S. Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol. 1997;121:417–424. doi: 10.1038/sj.bjp.0701148. PubMed DOI PMC

Sorkin LS, Doom CM. Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J Peripher Nerv Syst. 2000;5:96–100. doi: 10.1046/j.1529-8027.2000.00012.x. PubMed DOI

Schafers M, Geis C, Brors D, Yaksh TL, Sommer C. Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. J Neurosci. 2002;22:536–545. PubMed PMC

Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci. 2003;23:2517–2521. PubMed PMC

Dubovy P, Tuckova L, Jancalek R, Svizenska I, Klusakova I. Increased invasion of ED-1 positive macrophages in both ipsi- and contralateral dorsal root ganglia following unilateral nerve injuries. Neurosci Lett. 2007;427:88–93. doi: 10.1016/j.neulet.2007.09.012. PubMed DOI

Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765. doi: 10.1146/annurev.immunol.19.1.683. PubMed DOI

Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995;154:5492–5499. PubMed

Conti P, Kempuraj D, Kandere K, Di Gioacchino M, Barbacane RC, Castellani ML, Felaco M, Boucher W, Letourneau R, Theoharides TC. IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett. 2003;86:123–129. doi: 10.1016/S0165-2478(03)00002-6. PubMed DOI

Sawada M, Suzumura A, Hosoya H, Marunouchi T, Nagatsu T. Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J Neurochem. 1999;72:1466–1471. doi: 10.1046/j.1471-4159.1999.721466.x. PubMed DOI

Wagner R, Janjigian M, Myers RR. Anti-inflammatory interleukin-10 therapy in CCI neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alpha expression. Pain. 1998;74:35–42. doi: 10.1016/S0304-3959(97)00148-6. PubMed DOI

Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, Martin D, Maier SF, Johnson KW, Leinwand LA. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun. 2007;21:686–698. doi: 10.1016/j.bbi.2006.10.012. PubMed DOI PMC

Wagner R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport. 1996;7:2897–2901. doi: 10.1097/00001756-199611250-00018. PubMed DOI

Sommer C, Schmidt C, George A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp Neurol. 1998;151:138–142. doi: 10.1006/exnr.1998.6797. PubMed DOI

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. doi: 10.1016/0304-3959(88)90209-6. PubMed DOI

Maves TJ, Pechman PS, Gebhart GF, Meller ST. Possible chemical contribution from chromic gut sutures produces disorders of pain sensation like those seen in man. Pain. 1993;54:57–69. doi: 10.1016/0304-3959(93)90100-4. PubMed DOI

Sorkin LS, Xiao WH, Wagner R, Myers RR. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience. 1997;81:255–262. doi: 10.1016/S0306-4522(97)00147-4. PubMed DOI

Zhang JM, Li H, Liu B, Brull SJ. Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons. J Neurophysiol. 2002;88:1387–1392. doi: 10.1152/jn.01025.2001. PubMed DOI

Schafers M, Geis C, Svensson CI, Luo ZD, Sommer C. Selective increase of tumour necrosis factor-alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. Eur J Neurosci. 2003;17:791–804. doi: 10.1046/j.1460-9568.2003.02504.x. PubMed DOI

Dubovy P, Jancalek R, Klusakova I, Svizenska I, Pejchalova K. Intra- and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol. 2006;26:1205–1217. doi: 10.1007/s10571-006-9006-3. PubMed DOI

Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. PubMed DOI

Mosmann TR. Properties and functions of interleukin-10. Adv Immunol. 1994;56:1–26. full_text. PubMed

Cunha JM, Cunha FQ, Poole S, Ferreira SH. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br J Pharmacol. 2000;130:1418–1424. doi: 10.1038/sj.bjp.0703434. PubMed DOI PMC

Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL. Cytokine involvement in dynorphin-induced allodynia. Pain. 2000;84:159–167. doi: 10.1016/S0304-3959(99)00195-5. PubMed DOI

de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27:537–541. doi: 10.3109/07853899509002465. PubMed DOI

Kanaan SA, Poole S, Saade NE, Jabbur S, Safieh-Garabedian B. Interleukin-10 reduces the endotoxin-induced hyperalgesia in mice. J Neuroimmunol. 1998;86:142–150. doi: 10.1016/S0165-5728(98)00027-7. PubMed DOI

Tu H, Juelich T, Smith EM, Tyring SK, Rady PL, Hughes TK Jr. Evidence for endogenous interleukin-10 during nociception. J Neuroimmunol. 2003;139:145–149. doi: 10.1016/S0165-5728(03)00126-7. PubMed DOI

Giuffrida R, Rustioni A. Dorsal root ganglion neurons projecting to the dorsal column nuclei of rats. J Comp Neurol. 1992;316:206–220. doi: 10.1002/cne.903160206. PubMed DOI

Crawford PM, Lloyd KG, Chadwick DW. CSF gradients for amino acid neurotransmitters. J Neurol Neurosurg Psychiatry. 1988;51:1193–1200. doi: 10.1136/jnnp.51.9.1193. PubMed DOI PMC

Peranteau WH, Zhang L, Muvarak N, Badillo AT, Radu A, Zoltick PW, Liechty KW. IL-10 overexpression decreases inflammatory mediators and promotes regenerative healing in an adult model of scar formation. J Invest Dermatol. 2008;128:1852–1860. doi: 10.1038/sj.jid.5701232. PubMed DOI

George A, Marziniak M, Schafers M, Toyka KV, Sommer C. Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain. 2000;88:267–275. doi: 10.1016/S0304-3959(00)00333-X. PubMed DOI

Turrin NP, Plata-Salaman CR. Cytokine-cytokine interactions and the brain. Brain Res Bull. 2000;51:3–9. doi: 10.1016/S0361-9230(99)00203-8. PubMed DOI

Stoll G, Jander S, Myers RR. Degeneration and regeneration of the peripheral nervous system: from Augustus Waller's observations to neuroinflammation. J Peripher Nerv Syst. 2002;7:13–27. doi: 10.1046/j.1529-8027.2002.02002.x. PubMed DOI

Makwana M, Raivich G. Molecular mechanisms in successful peripheral regeneration. FEBS J. 2005;272:2628–2638. doi: 10.1111/j.1742-4658.2005.04699.x. PubMed DOI

Uceyler N, Schafers M, Sommer C. Mode of action of cytokines on nociceptive neurons. Exp Brain Res. 2009;196:67–78. doi: 10.1007/s00221-009-1755-z. PubMed DOI

Ruohonen S, Jagodi M, Khademi M, Taskinen HS, Ojala P, Olsson T, Roytta M. Contralateral non-operated nerve to transected rat sciatic nerve shows increased expression of IL-1beta, TGF-beta1, TNF-alpha, and IL-10. J Neuroimmunol. 2002;132:11–17. doi: 10.1016/S0165-5728(02)00281-3. PubMed DOI

Paulson PE, Morrow TJ, Casey KL. Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat. Pain. 2000;84:233–245. doi: 10.1016/S0304-3959(99)00216-X. PubMed DOI PMC

Sotgiu ML, Biella G. Contralateral inhibitory control of spinal nociceptive transmission in rats with chronic peripheral nerve injury. Neurosci Lett. 1998;253:21–24. doi: 10.1016/S0304-3940(98)00589-8. PubMed DOI

Suzuki R, Dickenson A. Spinal and supraspinal contributions to central sensitization in peripheral neuropathy. Neurosignals. 2005;14:175–181. doi: 10.1159/000087656. PubMed DOI

English AW, Tigges J, Lennard PR. Anatomical Organization of Long Ascending Propriospinal Neurons in the Cat Spinal-Cord. Journal of Comparative Neurology. 1985;240:349–358. doi: 10.1002/cne.902400403. PubMed DOI

Jankowska E, Lundberg A. Interneurones in the Spinal-Cord. Trends in Neurosciences. 1981;4:230–233. doi: 10.1016/0166-2236(81)90072-2. DOI

Mellick RS, Cavanagh JB. Changes in Blood Vessel Permeability during Degeneration and Regeneration in Peripheral Nerves. Brain. 1968;91:141–60. doi: 10.1093/brain/91.1.141. PubMed DOI

Olsson Y. Studies on vascular permeability in peripheral nerves. I. Distribution of circulating fluorescent serum albumin in normal, crushed and sectioned rat sciatic nerve. Acta Neuropathol. 1966;7:1–15. doi: 10.1007/BF00686605. PubMed DOI

Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6:521–532. doi: 10.1038/nrn1700. PubMed DOI

Ruohonen S, Khademi M, Jagodic M, Taskinen HS, Olsson T, Roytta M. Cytokine responses during chronic denervation. J Neuroinflammation. 2005;2:26. doi: 10.1186/1742-2094-2-26. PubMed DOI PMC

Arvidson B. A study of the perineurial diffusion barrier of a peripheral ganglion. Acta Neuropathol. 1979;46:139–144. doi: 10.1007/BF00684815. PubMed DOI

Arvidson B. Distribution of intravenously injected protein tracers in peripheral ganglia of adult mice. Exp Neurol. 1979;63:388–410. doi: 10.1016/0014-4886(79)90134-1. PubMed DOI

Jacobs JM, Macfarlane RM, Cavanagh JB. Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase. J Neurol Sci. 1976;29:95–107. doi: 10.1016/0022-510X(76)90083-6. PubMed DOI

Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y. Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem. 2000;75:965–972. doi: 10.1046/j.1471-4159.2000.0750965.x. PubMed DOI

Kim M, Chiego DJ Jr, Bradley RM. Ionotropic glutamate receptor expression in preganglionic neurons of the rat inferior salivatory nucleus. Auton Neurosci. 2008;138:83–90. PubMed PMC

Karanth S, Yang G, Yeh J, Richardson PM. Nature of signals that initiate the immune response during Wallerian degeneration of peripheral nerves. Exp Neurol. 2006;202:161–166. doi: 10.1016/j.expneurol.2006.05.024. PubMed DOI

Levin ME, Jin JG, Ji RR, Tong J, Pomonis JD, Lavery DJ, Miller SW, Chiang LW. Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain. Pain. 2008;137:182–201. doi: 10.1016/j.pain.2007.11.005. PubMed DOI

Alexander JK, DeVries AC, Kigerl KA, Dahlman JM, Popovich PG. Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation. Brain Behavior and Immunity. 2009;23:851–860. doi: 10.1016/j.bbi.2009.04.001. PubMed DOI PMC

Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci. 2009;14:5291–5338. PubMed

Woolf CJ. Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci. 2004;74:2605–2610. doi: 10.1016/j.lfs.2004.01.003. PubMed DOI

Dynamic response to peripheral nerve injury detected by in situ hybridization of IL-6 and its receptor mRNAs in the dorsal root ganglia is not strictly correlated with signs of neuropathic pain

Bilateral changes of cannabinoid receptor type 2 protein and mRNA in the dorsal root ganglia of a rat neuropathic pain model

Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve

Modulation of spinal cord synaptic activity by tumor necrosis factor α in a model of peripheral neuropathy

Tumor necrosis factor alpha sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine