Lack of evidence for ectopic sprouting of genetically labeled Aβ touch afferents in inflammatory and neuropathic trigeminal pain

Molecular Pain

Fan Wang¹  Wolfgang Liedtke²  Yong Chen²  Yi Zhang¹ 

[1] Department of Neurobiology, Duke University Medical Center, Durham 27710, NC, USA;Department of Neurology, Center for Translational Neuroscience, Duke University Medical Center, Durham 27710, NC, USA

关键词: Neuropathic pain;    Inflammatory pain;    Sprouting;    Aβ fibers;    Mechanical allodynia;   

Others  :  1161759
DOI  :  10.1186/s12990-015-0017-2

 received in 2015-02-27, accepted in 2015-03-30,  发布年份 2015

【 摘 要 】

Background

Mechanical and in particular tactile allodynia is a hallmark of chronic pain in which innocuous touch becomes painful. Previous cholera toxin B (CTB)-based neural tracing experiments and electrophysiology studies had suggested that aberrant axon sprouting from touch sensory afferents into pain-processing laminae after injury is a possible anatomical substrate underlying mechanical allodynia. This hypothesis was later challenged by experiments using intra-axonal labeling of A-fiber neurons, as well as single-neuron labeling of electrophysiologically identified sensory neurons. However, no studies have used genetically labeled neurons to examine this issue, and most studies were performed on spinal but not trigeminal sensory neurons which are the relevant neurons for orofacial pain, where allodynia oftentimes plays a dominant clinical role.

Findings

We recently discovered that parvalbumin::Cre (Pv::Cre) labels two types of Aβ touch neurons in trigeminal ganglion. Using a Pv::CreER driver and a Cre-dependent reporter mouse, we specifically labeled these Aβ trigeminal touch afferents by timed taxomifen injection prior to inflammation or infraorbital nerve injury (ION transection). We then examined the peripheral and central projections of labeled axons into the brainstem caudalis nucleus after injuries vs controls. We found no evidence for ectopic sprouting of Pv::CreER labeled trigeminal Aβ axons into the superficial trigeminal noci-receptive laminae. Furthermore, there was also no evidence for peripheral sprouting.

Conclusions

CreER-based labeling prior to injury precluded the issue of phenotypic changes of neurons after injury. Our results suggest that touch allodynia in chronic orofacial pain is unlikely caused by ectopic sprouting of Aβ trigeminal afferents.

【 授权许可】

   
2015 Zhang et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Campbell JN, Raja SN, Meyer RA, Mackinnon SE: Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 1988, 32(1):89-94.
• [2]Kohama I, Ishikawa K, Kocsis JD: Synaptic reorganization in the substantia gelatinosa after peripheral nerve neuroma formation: aberrant innervation of lamina II neurons by Abeta afferents. J Neurosci 2000, 20(4):1538-49.
• [3]Shortland P, Woolf CJ: Chronic peripheral nerve section results in a rearrangement of the central axonal arborizations of axotomized A beta primary afferent neurons in the rat spinal cord. J Comp Neurol 1993, 330(1):65-82.
• [4]Woolf CJ, Shortland P, Coggeshall RE: Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992, 355(6355):75-8.
• [5]Koerber HR, Mirnics K, Brown PB, Mendell LM: Central sprouting and functional plasticity of regenerated primary afferents. J Neurosci 1994, 14(6):3655-71.
• [6]Koerber HR, Mirnics K, Kavookjian AM, Light AR: Ultrastructural analysis of ectopic synaptic boutons arising from peripherally regenerated primary afferent fibers. J Neurophysiol 1999, 81(4):1636-44.
• [7]Shehab SAS, Spike RC, Todd AJ: Evidence against cholera toxin B subunit as a reliable tracer for sprouting of primary afferents following peripheral nerve injury. Brain Res 2003, 964(2):218-27.
• [8]Tong YG, Wang HF, Ju G, Grant G, Hokfelt T, Zhang X: Increased uptake and transport of cholera toxin B-subunit in dorsal root ganglion neurons after peripheral axotomy: possible implications for sensory sprouting. J Comp Neurol 1999, 404(2):143-58.
• [9]Bao L, Wang HF, Cai HJ, Tong YG, Jin SX, Lu YJ, Grant G, Hokfelt T, Zhang X: Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Eur J Neurosci 2002, 16(2):175-85.
• [10]Santha P, Jancso G: Transganglionic transport of choleragenoid by capsaicin-sensitive C-fibre afferents to the substantia gelatinosa of the spinal dorsal horn after peripheral nerve section. Neuroscience 2003, 116(3):621-7.
• [11]Hughes DI, Scott DT, Todd AJ, Riddell JS: Lack of evidence for sprouting of A beta afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J Neurosci 2003, 23(29):9491-9.
• [12]Hughes DI, Polgar E, Shehab SA, Todd AJ: Peripheral axotomy induces depletion of the vesicular glutamate transporter VGLUT1 in central terminals of myelinated afferent fibres in the rat spinal cord. Brain Res 2004, 1017(1–2):69-76.
• [13]Woodbury CJ, Kullmann FA, McIlwrath SL, Koerber HR: Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J Comp Neurol 2008, 508(3):500-9.
• [14]Benemei S, De Cesaris F, Fusi C, Rossi E, Lupi C, Geppetti P: TRPA1 and other TRP channels in migraine. J Headache Pain 2013, 14:71. BioMed Central Full Text
• [15]Oaklander AL: Mechanisms of pain and itch caused by herpes zoster (shingles). J Pain 2008, 9(1 Suppl 1):S10-8.
• [16]Noseda R, Burstein R: Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain 2013, 154(Suppl 1):S44-53.
• [17]Ashkenazi A: Allodynia in cluster headache. Curr Pain Headache Rep 2010, 14(2):140-4.
• [18]Schurks M, Diener HC: Migraine, allodynia, and implications for treatment. Eur J Neurol 2008, 15(12):1279-85.
• [19]Oshinsky ML: Insights from experimental studies into allodynia and its treatment. Curr Pain Headache Rep 2006, 10(3):225-30.
• [20]Moskowitz MA: Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993, 43(6 Suppl 3):S16-20.
• [21]Rosenthal P, Borsook D: The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf 2012, 10(1):2-14.
• [22]Fried K, Bongenhielm U, Boissonade FM, Robinson PP: Nerve injury-induced pain in the trigeminal system. Neuroscientist 2001, 7(2):155-65.
• [23]Rhoades RW, Chiaia NL, Macdonald GJ, Jacquin MF: Effect of fetal infraorbital nerve transection upon trigeminal primary afferent-projections in the Rat. J Comp Neurol 1989, 287(1):82-97.
• [24]Waite PME, dePermentier PJ: Effect of neonatal capsaicin and infraorbital nerve section on whisker-related patterns in the rat trigeminal nucleus. J Comp Neurol 1997, 385(4):599-615.
• [25]Bae YC, Oh JM, Hwang SJ, Shigenaga Y, Valtschanoff JG: Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei. J Comp Neurol 2004, 478(1):62-71.
• [26]Sakurai K, Akiyama M, Cai B, Scott A, Han BX, Takatoh J, Sigrist M, Arber S, Wang F: The organization of submodality-specific touch afferent inputs in the vibrissa column. Cell Rep 2013, 5(1):87-98.
• [27]Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, et al.: A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 2010, 13(1):133-40.
• [28]Bennett-Clarke CA, Chiaia NL, Jacquin MF, Rhoades RW: Parvalbumin and calbindin immunocytochemistry reveal functionally distinct cell groups and vibrissa-related patterns in the trigeminal brainstem complex of the adult rat. J Comp Neurol 1992, 320(3):323-38.
• [29]Krzyzanowska A, Pittolo S, Cabrerizo M, Sanchez-Lopez J, Krishnasamy S, Venero C, Avendano C: Assessing nociceptive sensitivity in mouse models of inflammatory and neuropathic trigeminal pain. J Neurosci Methods 2011, 201(1):46-54.
• [30]Benoliel R, Wilensky A, Tal M, Eliav E: Application of a pro-inflammatory agent to the orbital portion of the rat infraorbital nerve induces changes indicative of ongoing trigeminal pain. Pain 2002, 99(3):567-78.
• [31]Chen Y, Williams SH, McNulty AL, Hong JH, Lee SH, Rothfusz NE, Parekh PK, Moore C, Gereau RW, Taylor AB, et al.: Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. Pain 2013, 154(8):1295-304.
• [32]Morgan JR, Gebhart GF: Characterization of a model of chronic orofacial hyperalgesia in the rat: contribution of NA(V) 1.8. J Pain 2008, 9(6):522-31.
• [33]Okumura M, Iwata K, Yasuda K, Inoue K, Shinoda M, Honda K, Shibuta K, Yasuda M, Kondo E: Alternation of gene expression in trigeminal ganglion neurons following complete Freund’s adjuvant or capsaicin injection into the Rat face. J Mol Neurosci 2010, 42(2):200-9.
• [34]Garrett FG, Hawkins JL, Overmyer AE, Hayden JB, Durham PL: Validation of a novel Rat-holding device for studying heat- and mechanical-evoked trigeminal nocifensive behavioral responses. J Orofac Pain 2012, 26(4):337-44.
• [35]Simonic-Kocijan S, Zhao XH, Liu W, Wu YW, Uhac I, Wang KW. TRPV1 channel-mediated bilateral allodynia induced by unilateral masseter muscle inflammation in rats. Mol Pain. 2013;9. doi:10.1186/1744-8069-9-68.
• [36]Wang H, Rivero-Melian C, Robertson B, Grant G: Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons. Neuroscience 1994, 62(2):539-51.
• [37]Kernisant M, Gear RW, Jasmin L, Vit JP, Ohara PT: Chronic constriction injury of the infraorbital nerve in the rat using modified syringe needle. J Neurosci Methods 2008, 172(1):43-7.
• [38]Alvarez P, Dieb W, Hafidi A, Voisin DL, Dallel R: Insular cortex representation of dynamic mechanical allodynia in trigeminal neuropathic rats. Neurobiol Dis 2009, 33(1):89-95.
• [39]Lim EJ, Jeon HJ, Yang GY, Lee MK, Ju JS, Han SR, Ahn DK: Intracisternal administration of mitogen-activated protein kinase inhibitors reduced mechanical allodynia following chronic constriction injury of infraorbital nerve in rats. Prog Neuro-Psychoph 2007, 31(6):1322-9.
• [40]Woolf CJ: Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011, 152(3 Suppl):S2-15.
• [41]Kuner R: Central mechanisms of pathological pain. Nat Med 2010, 16(11):1258-66.
• [42]Que J, Wilm B, Hasegawa H, Wang F, Bader D, Hogan BL: Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development. Proc Natl Acad Sci U S A 2008, 105(43):16626-30.