Neurotrophin receptor expression is induced in a subpopulation of trigeminal neurons that label by retrograde transport of NGF or Fluoro-gold following tooth injury

Recent research has shown that peripheral mechanisms of pain are much more complex than previously thought, and they differ for acutely injured normal tissues compared with chronic inflammation or neuropathic (nerve injury) pain. The purpose of the present review is to describe uses of dental injury models as experimental tools for understanding the normal functions of polymodal nociceptive nerves in healthy tissues, their neuroinflammatory interactions, and their roles in healing. A brief review of normal dental innervation and its interactions with healthy pulp tissue will be presented first, as a framework for understanding the changes that occur after injury. Then, the different types of dental injury that allow gradation of the extent of tissue damage will be described, along with the degree and duration of inflammation, the types of reactions in the trigeminal ganglion and brainstem, and the type of healing. The dental injury models have some unique features compared with neuroinflammation paradigms that affect other peripheral tissues such as skin, viscera, and joints. Peripheral inflammation models can all be contrasted to nerve injury studies that produce a different kind of neuroplasticity and neuropathic pain. Each of these models provides different insights about the normal and pathologic functions of peripheral nerve fibers and their effects on tissue homeostasis, inflammation, and wound healing. The physical confinement of dental pulp and its innervation within the tooth, the high incidence of polymodal A-delta and C-fibers in pulp and dentin, and the somatotopic organization of the trigeminal ganglion provide some special advantages for experimental design when dental injury models are used for the study of neuroinflammatory interactions.

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“…Similar results have now been found for trigeminal neurons after mild Type-I dental injury in rats (Wheeler et al., 1998) (Fig. 1 1).…”

Section: (A) Trigeminal Nerve and Ganglion Reactionssupporting

confidence: 88%

Dental Injury Models: Experimental Tools for Understanding Neuroinflammatory Interactions and Polymodal Nociceptor Functions

Byers

Närhi

1999

Critical Reviews in Oral Biology & Medicine

277

222

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“…12,[16][17][18][19][20] Neurotrophins also participate in the robust neuronal plasticity seen in the dental pulp after dental injury due to infection (caries) or trauma. 25,27 In particular, NGF has been shown to mediate nociceptive axonal targeting of the injured site, as well as upregulation and sensitization of pain receptors such as the ionotropic channel transient receptor potential vanilloid type-1 (TRPV1) and transient receptor potential ankyrin type-1 (TRPA1). [64][65][66] Interestingly, similar detectable levels of NGF, GDNF, and BDNF were measured from media from SCAP cultured in the absence of TG neurons.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 Among these neurotrophins, NGF has been identified as a key molecular signal for axonal targeting during dental development, 24 and later in response to injury such as caries and trauma. [24][25][26] Importantly, both the putative NGF high-affinity receptor tyrosine kinase A (TrkA) and its low-affinity receptor p75 are expressed by a major subpopulation of dental nociceptors. 25,26 Interestingly, although BDNF and its high-affinity receptor, TrkB, have been detected in the developing tooth, 27 mice carrying the genetic deletion of TrkB do not display deficiency in dental pulp innervation.…”

mentioning

confidence: 99%

“…[24][25][26] Importantly, both the putative NGF high-affinity receptor tyrosine kinase A (TrkA) and its low-affinity receptor p75 are expressed by a major subpopulation of dental nociceptors. 25,26 Interestingly, although BDNF and its high-affinity receptor, TrkB, have been detected in the developing tooth, 27 mice carrying the genetic deletion of TrkB do not display deficiency in dental pulp innervation. 28 Conversely, BDNF mediates neuronal plasticity in the developed dental pulp with a significant percentage of trigeminal neurons expressing TrkB after injury.…”

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confidence: 99%

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Stem Cells of the Apical Papilla Regulate Trigeminal Neurite Outgrowth and Targeting through a BDNF-Dependent Mechanism

Almeida

Chen

Henry

et al. 2014

Tissue Engineering Part A

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Regenerative endodontic procedures have become a valuable alternative for the treatment of immature teeth with pulp necrosis. In addition to resolution of periradicular pathosis and promotion of continued root development, positive vitality testing has been observed in some regenerative clinical cases. Importantly, the positive response to electric stimulation of the regenerated tissue requires targeting of periradicular axons into the previously empty root canal space. However, the mechanism by which this process occurs is largely unknown. Since stem cells of the apical papilla (SCAP) have been proposed to populate the root canal following regenerative endodontic procedures, we hypothesized that SCAP regulate neurite outgrowth and axonal targeting. To test this hypothesis, we established primary co-cultures of human SCAP and rat trigeminal neurons, and performed neurite outgrowth assays using ELISA and confocal microscopy to determine the effect of increasing concentration of SCAP on the total neurite outgrowth and axonal targeting. In addition, we evaluated whether SCAP evoked axonal targeting in vivo using a matrigel subcutaneous implant assay. Data were analyzed by ANOVA with Bonferroni's post hoc test, and significance was set at p < 0.05. The results demonstrated that SCAP release a soluble factor that regulates neurite outgrowth from cultured trigeminal neurons. Next, we demonstrated that this effect is completely abolished by pretreatment with a neutralizing antibody to brain-derived neurotrophic factor (BDNF), but not by antibodies to other neurotrophins. Further, SCAP release BDNF in a concentration-dependent manner as detected by ELISA, and trigger directed axonal targeting both in vitro and in vivo as demonstrated by microfluidic and matrigel implant experiments, respectively. Collectively, these results suggest that SCAP may be responsible for the chemical signal driving axons to target regenerated tissue via a BDNF-dependent mechanism.

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“…Florogold (FG) applied to exposed dentin diffuses into the pulp and labels pulpal afferents without (39,40). Injection of DiI (DiIC 18; 1,1¢-dioctadecyl-3,3,3¢,3¢-tetramethylindocarbocyanine perchlorate) into orofacial structures (such as the masseter or the dental pulp) is yet another way to retrogradely label neurons (41-44).…”

Section: Dental Injury Modelmentioning

confidence: 99%

Animal Models of Orofacial Pain

Khan

Hargreaves

2010

Methods in Molecular Biology

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Pain is one of the most common reasons for which patients seek dental and medical care. Orofacial pain conditions consist of a wide range of disorders including odontalgia (toothache), temporomandibular disorders, trigeminal neuralgia and others. Most of these conditions are either inflammatory or neuropathic in nature. This chapter provides an overview of the commonly used models to study inflammatory and neuropathic orofacial pain.

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Neurotrophin receptor expression is induced in a subpopulation of trigeminal neurons that label by retrograde transport of NGF or Fluoro-gold following tooth injury

Cited by 42 publications

References 60 publications

Dental Injury Models: Experimental Tools for Understanding Neuroinflammatory Interactions and Polymodal Nociceptor Functions

Dental Injury Models: Experimental Tools for Understanding Neuroinflammatory Interactions and Polymodal Nociceptor Functions

Stem Cells of the Apical Papilla Regulate Trigeminal Neurite Outgrowth and Targeting through a BDNF-Dependent Mechanism

Animal Models of Orofacial Pain

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