Peripheral Glial Cell Line–Derived Neurotrophic Factor Facilitates the Functional Recovery of Mechanical Nociception Following Inferior Alveolar Nerve Transection in Rats

Aims: To identify endogenous sources of glial cell line–derived neurotrophic factor (GDNF) at the injury site following inferior alveolar nerve transection (IANX) and to determine whether GDNF signaling promotes the recovery of orofacial pain sensation. Methods: Nociceptive mechanical sensitivity of the facial skin was assessed following IANX (n = 10) or sham operation (n = 7). GDNF-positive cells were identified and the amount of GDNF measured in the injured region of IANX rats (n = 10) and in sham rats (n = 10). The number of trigeminal ganglion neurons with regenerated axons and the nociceptive mechanical sensitivity after continuous GDNF administration at the injury site were also assessed in IANX (n = 28) and sham (n = 12) rats. The effect of GDNF neutralization on nociceptive mechanical sensitivity at the injury site was evaluated using a neutralizing antibody (GFRα1 Nab) in four groups: IANX + phosphate-buffered saline (PBS) (n = 6); sham (n = 12); IANX + GDNF (n = 12); and IANX + GDNF + GFRα1 Nab (n = 12). Statistical analyses included one-way and two-way repeated measures analysis of variance followed by post hoc tests or unpaired t tests. The threshold for statistical significance was set at P < .05. Results: Nociceptive mechanical sensitivity was lost over the 5 days following IANX and was recovered by day 13. GDNF was expressed in infiltrating inflammatory cells and had enhanced expression. GDNF administration enhanced axonal regeneration and recovery of nociceptive mechanical sensitivity. GDNF neutralization inhibited the recovery of nociceptive mechanical sensitivity after IANX. Conclusion: GDNF signaling at the injury site facilitates the functional recovery of mechanical nociception following IANX and is an attractive therapeutic target for the functional disturbance of pain sensation.

GDNF family receptor alpha;glial cell line–derived neurotrophic factor;inferior alveolar nerve injury;mechanical nociception nerve regeneration

1.Tay AB, Lai JB, Lye KW, et al. Inferior alveolar nerve injury in trau-ma-induced mandible fractures. J Oral Maxillofac Surg 2015; 73:1328–1340.

2.Veitz-Keenan A, Keenan JR. Trials needed to identify best management of iatrogenic inferior alveolar and lingual nerve injuries. Evid Based Dent 2015;16:29.

3.Deppe H, Mücke T, Wagenpfeil S, Kesting M, Linsenmeyer E, Tölle T. Trigeminal nerve injuries after mandibular oral surgery in a university outpatient setting—A retrospective analysis of 1,559 cases. Clin Oral Investig 2015;19:149–157.

4.Altun I, Kurutas¸ EB. Vitamin B complex and vitamin B12 lev-els after peripheral nerve injury. Neural Regen Res 2016;11: 842–845.

5.Anders JJ, Moges H, Wu X, et al. In vitro and in vivo optimi-zation of infrared laser treatment for injured peripheral nerves. Lasers Surg Med 2014;46:34–45.

6.Airaksinen MS, Saarma M. The GDNF family: Signalling, biolog-ical functions and therapeutic value. Nat Rev Neurosci 2002; 3:383–394.

7.Ibáñez CF, Andressoo JO. Biology of GDNF and its receptors—Relevance for disorders of the central nervous system. Neuro-biol Dis 2017;97:80–89.

8.Ibáñez CF. Structure and physiology of the RET receptor ty-rosine kinase. Cold Spring Harb Perspect Biol 2013;5. pii: a009134.

9.Mirsky R, Jessen KR. The neurobiology of Schwann cells. Brain Pathol 1999;9:293–311.

10.Widenfalk J, Lundströmer K, Jubran M, Brene S, Olson L. Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci 2001;21:3457–3475.

11.Satake K, Matsuyama Y, Kamiya M, et al. Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following trau-matic spinal cord injury. Neuroreport 2000;11:3877–3881.

12.Fontana X, Hristova M, Da Costa C, et al. c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. J Cell Biol 2012;198:127–141.

13.Zhang L, Ma Z, Smith GM, et al. GDNF-enhanced axonal re-generation and myelination following spinal cord injury is medi-ated by primary effects on neurons. Glia 2009;57:1178–1191.

14.Liu H, Lv P, Zhu Y, et al. Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy us-ing Schwann cells and PLGA: In vitro and in vivo. Sci Rep 2017;7:39869.

15.Santos D, Giudetti G, Micera S, Navarro X, del Valle J. Fo-cal release of neurotrophic factors by biodegradable micro-spheres enhance motor and sensory axonal regeneration in vitro and in vivo. Brain Res 2016;1636:93–106.

16.Tajdaran K, Gordon T, Wood MD, Shoichet MS, Borschel GH. A glial cell line-derived neurotrophic factor delivery system en-hances nerve regeneration across acellular nerve allografts. Acta Biomater 2016;29:62–70.

17.Zimmermann M. Ethical guidelines for investigations of experi-mental pain in conscious animals. Pain 1983;16:109–110.

18.Tamagawa T, Shinoda M, Honda K, et al. Involvement of mi-croglial P2Y12 signaling in tongue cancer pain. J Dent Res 2016;95:1176–1182.

19.Urata K, Shinoda M, Honda K, et al. Involvement of TRPV1 and TRPA1 in incisional intraoral and extraoral pain. J Dent Res 2015;94:446–454.

20.Nagashima H, Shinoda M, Honda K, et al. CXCR4 signaling in macrophages contributes to periodontal mechanical hyper-sensitivity in Porphyromonas gingivalis-induced periodontitis in mice. Mol Pain 2017;13:1744806916689269.

21.Wood MD, Gordon T, Kemp SW, et al. Functional motor re-covery is improved due to local placement of GDNF mi-crospheres after delayed nerve repair. Biotechnol Bioeng 2013;110:1272–1281.

22.Tsuboi Y, Honda K, Bae YC, et al. Morphological and func-tional changes in regenerated primary afferent fibres follow-ing mental and inferior alveolar nerve transection. Eur J Pain 2015;19:1258–1266.

23.Bianchi B, Ferri A, Varazzani A, Bergonzani M, Sesenna E. Microsurgical decompression of inferior alveolar nerve af-ter endodontic treatment complications. J Craniofac Surg 2017;28:1365–1368.

24.Biglioli F, Allevi F, Lozza A. Surgical treatment of painful le-sions of the inferior alveolar nerve. J Craniomaxillofac Surg 2015;43:1541–1545.

25.Rood JP. Permanent damage to inferior alveolar and lingual nerves during the removal of impacted mandibular third mo-lars. Comparison of two methods of bone removal. Br Dent J 1992;172:108–110.

26.Ozen T, Orhan K, Gorur I, Ozturk A. Efficacy of low level laser therapy on neurosensory recovery after injury to the inferior al-veolar nerve. Head Face Med 2006;2:3.

27.Chernov AV, Dolkas J, Hoang K, et al. The calcium-binding proteins S100A8 and S100A9 initiate the early inflam-matory program in injured peripheral nerves. J Biol Chem 2015;290:11771–11784.

28.Segond von Banchet G, Boettger MK, Fischer N, Gajda M, Bräuer R, Schaible HG. Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. Pain 2009;145:151–159.

29.Gómez-Nicola D, Valle-Argos B, Suardíaz M, Taylor JS, Nie-to-Sampedro M. Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: Regulation of macrophage and T-cell infiltration. J Neurochem 2008;107:1741–1752.

30.Vora AR, Bodell SM, Loescher AR, Smith KG, Robinson PP, Boissonade FM. Inflammatory cell accumulation in traumatic neuromas of the human lingual nerve. Arch Oral Biol 2007; 52:74–82.

31.Chen YM, Shen RW, Zhang B, Zhang WN. Regional tissue immune responses after sciatic nerve injury in rats. Int J Clin Exp Med 2015;8:13408–13412.

32.Batchelor PE, Liberatore GT, Wong JY, et al. Activated mac-rophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic fac-tor and glial cell line-derived neurotrophic factor. J Neurosci 1999;19:1708–1716.

33.Ahn M, Jin JK, Moon C, Matsumoto Y, Koh CS, Shin T. Glial cell line-derived neurotrophic factor is expressed by inflammatory cells in the sciatic nerves of Lewis rats with experimental auto-immune neuritis. J Peripher Nerv Syst 2010;15:104–112.

34.Lindwall C, Kanje M. Retrograde axonal transport of JNK sig-naling molecules influence injury induced nuclear changes in p- c-Jun and ATF3 in adult rat sensory neurons. Mol Cell Neu-rosci 2005;29:269–282.

35.Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene 2007;26:3100–3112.

36.Napoli I, Noon LA, Ribeiro S, et al. A central role for the ERK-signaling pathway in controlling Schwann cell plastici-ty and peripheral nerve regeneration in vivo. Neuron 2012; 73:729–742.

37.Mòdol L, Santos D, Cobianchi S, González-Pérez F, López-Al-varez V, Navarro X. NKCC1 activation is required for myelin-ated sensory neurons regeneration through JNK-dependent pathway. J Neurosci 2015;35:7414–7427.

38.Morooka T, Nishida E. Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem 1998;273:24285–24288.

39.Wiklund P, Ekström PA, Edström A. Mitogen-activated protein kinase inhibition reveals differences in signalling pathways ac-tivated by neurotrophin-3 and other growth-stimulating condi-tions of adult mouse dorsal root ganglia neurons. J Neurosci Res 2002;67:62–68.

40.Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL. Sema-phorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 2003;424:398–405.

41.Forcet C, Stein E, Pays L, et al. Netrin-1-mediated axon out-growth requires deleted in colorectal cancer-dependent MAPK activation. Nature 2002;417:443–447.

42.Jesuraj NJ, Marquardt LM, Kwasa JA, Sakiyama-Elbert SE. Glial cell line-derived neurotrophic factor promotes increased pheno-typic marker expression in femoral sensory and motor-derived Schwann cell cultures. Exp Neurol 2014;257:10–18.

43.Naveilhan P, ElShamy WM, Ernfors P. Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR al-pha after sciatic nerve lesion in the mouse. Eur J Neurosci 1997;9:1450–1460.

44.Abraira VE, Ginty DD. The sensory neurons of touch. Neuron 2013;79:618–639.

45.Lawson SN, Perry MJ, Prabhakar E, McCarthy PW. Primary sensory neurones: Neurofilament, neuropeptides, and con-duction velocity. Brain Res Bull 1993;30:239–243.

46.Honda K, Shinoda M, Kondo M, et al. Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contrib-utes to thermal and mechanical hypersensitivity. Pain 2017; 158:1754–1764.

47.Mueller-Tribbensee SM, Karna M, Khalil M, Neurath MF, Reeh PW, Engel MA. Differential contribution of TRPA1, TRPV4 and TRPM8 to colonic nociception in mice. PLoS One 2015; 10:e0128242.

48.Ivanova T, Karolczak M, Beyer C. Estradiol stimulates GDNF expression in developing hypothalamic neurons. Endocrinolo-gy 2002;143:3175–3178.

49.Talavera K, Nilius B, Voets T. Neuronal TRP channels: Ther-mometers, pathfinders and life-savers. Trends Neurosci 2008; 31:287–295.

50.Walsh CM, Bautista DM, Lumpkin EA. Mammalian touch catches up. Curr Opin Neurobiol 2015;34:133–139.