Teeth; TRP channels that sense pressure, cold, and promote remineralization in teeth with cavities.

Post too long for email, but it isn't 34 pages. ;-)

Are teeth pressure sensing sensory organs? Yes, they have TRPA1 channels which respond to mechanical stimulation - pressure.

“The transient receptor potential (TRP) family members are temperature-sensitive cation channels that play a major role in sensing hot and cold temperatures, as well as pain perception associated with temperature. TRP ankyrin 1 (TRPA1), a member of the TRP family, was initially identified as a cold-sensitive ion channel in a subset of nociceptive sensory dorsal root ganglion neurons.⁵ Recently, TRPA1 has been recognized as a polymodal nociceptor activated by mechanical stimulation and various chemical irritants, such as acyl isothiocyanate, acrolein, and formalin, as well as noxious cold stimulation (<17°C).⁶ TRPA1 is expressed in nerve fibers,⁵ but recent studies have revealed that TRPA1 is also expressed in nonneural cells and plays a role in various physiological functions.⁶ These functions include the release of IL-8 in human airway/lung epithelial cells,⁷ promotion of vasodilation in vascular endothelial cells,⁸ acceleration of insulin secretion in pancreatic β cells,⁹ and induction of erythema in keratinocytes and fibroblasts of human skin.¹⁰ Expression of TRPA1 has also been reported in dental pulp cells.¹¹ However, its physiological function in this tissue is not fully understood.” (Tazawa, et al., 2020)

The role of TRPA1 ion channels in the pulp layer of teeth is likely to sense pressure change as well as very cold temperatures if the enamel has deteriorated enough to expose the inner pulp layer.

“In general, an ankyrin protein has four functional domains, a membrane-binding domain (MBD), spectrin-binding domain (SBD), death domain, and a C-terminal regulatory domain (Figure 23-2).

The N-terminal MBD contains 24 tandem ankyrin repeats; these ankyrin repeats have inherent spring-link qualities, and it has been suggested that this elastic property of the ankyrin repeat could have a role in mechanotransduction and confer pliancy to the MBD from mechanical perturbations.^4” (Vaidyanathan, Makielski, 2014) Excerpt viewable at (ScienceDirect/ankyrin)

Mechanotransduction is the sensation of a mechanical change in the environment which may be converted by a TRPA1 ion channel into a nerve signal or a different type of action within a cell.

“Mechanotransduction describes the ability of a cell to actively sense, integrate, and convert mechanical stimuli into biochemical signals that result in intracellular changes, such as ion concentrations, activation of signaling pathways and transcriptional regulation (1).” From: Muscle, 2012, Excerpt viewable at (ScienceDirect/ankyrin)

I think we don’t have to go very far out on the limb to say that there may be pressure sensing TRP channels in the pulp of teeth because they take a lot of pressure when chewing or biting.

Review of this line:

“Expression of TRPA1 has also been reported in dental pulp cells.¹¹ However, its physiological function in this tissue is not fully understood.” (Tazawa, et al., 2020)

It would be protective to know when something seems too hard - too much pressure against the tooth, so stop biting or chewing that! A cherry pit must have been left in the cherry jam, so stop chewing and spit it out.

Inflammation significantly increases the amount of TRPA1 channels in teeth with cavity damage, while there is little/low amounts of TRPA1 expressed in the pulp of healthy teeth. This would explain the increased sensitivity to cold temperatures - ice water, and increased pain when chewing hard, crunchy foods. Increased expression of TRP channels in response to inflammation is kind of normal in an abnormal/not healthy function way.

“In dental pulp, enhanced expression of TRPA1 is observed in odontoblasts of carious teeth, whereas low or little expression of TRPA1 is detected in the pulp tissue of intact teeth.¹⁶ Tumor necrosis factor-α induces TRPA1 via p38/mitogen-activated protein kinases (MAPKs) in odontoblast-like cells in vitro¹⁷; however, precise mechanisms that induce TRPA1 expression in dental pulp cells or odontoblasts in response to infection or inflammation remain unclear. Furthermore, the function of TRPA1 in inflamed pulp tissue has not fully been elucidated.” (Tazawa, et al., 2020)

Excerpt from my pomegranate paper regarding stress and increased expression of TRPA1 channels in Irritable Bowel Syndrome:

Stress and/or ANS disruption may lead to over expression or over activation of TRP channels and result in microbiome dysbiosis and IBS or colitis.

Autonomic Nervous System disruption (which can be caused by trauma or illness) affects microbiome health. Gut dysbiosis may then lead to increased numbers of mast cells and histamine in the intestines. Disruption of the Autonomic Nervous System in trauma leads to microbiome changes via the Brain-Gut Axis. (Carabotti, et al, 2015, Martin, et al, 2018) Increased inflammation leads to NF-κB which inhibits Nrf2. Lack of Nrf2 led to increased risk for DSS-induced colitis in mice deficient in Nrf2. (Li W, et al, 2008)

Oxidative stress chemicals also activate TRP channels that can send pain signals. Chronic stress seems to lead to an over-expression of TRPA-1 channels in some conditions, which may remain for life (IBS/colitis) or may occur due to a variety of gene differences in the case of chronic itch. Histamine is an activator of TRPV1 channels and can cause pain. TRPV1 channels are also involved in colitis, (Kumar, Goswami, Goswami, 2013), so histamine excess itself adds to colitis risk.

Gene alleles affecting nociception may be an individual risk factor. Retinoid toxicity can be a cause of bowel symptoms and can affect gene transcription. Ulcerative colitis, but not Crohn's disease, was found by Crockett,et al, to be significantly associated with previous use of the retinoid medication isotretinoin. The association was dose related and more likely for higher doses or for patients taking the medication for longer than two months in a large survey-based study of patients with Inflammatory Bowel Disease. (Crockett, et al, 2010)

Stress seems to lead to increased bowel sensitivity and IBS or colitis for various reasons and results in hypersensitivity to many foods. Common seasonings seem “spicy” because they stimulate TRPA-1 channels. We all tear up with the fumes of raw onion (allicin), (Bautista, et al, 2005) (Macpherson, et al, 2005) or mustard gas, or grating raw wasabi or horseradish, (allyl isothiocyanate). (Jordt, et al, 2004) People with Irritable Bowel Syndrome (IBS) might feel pain and a sudden need for the bathroom after eating mustard or other TRPA-1 activating spices like black pepper, horseradish, ginger, or turmeric. (Namer, et al, 2005) See Table 2. Potentially Inflammatory Food Categories for more TRP activators and other inflammatory food categories.

Cinnamon (cinnamaldehyde) or mint (menthol), (Namer, et al, 2005), may cause migraines in people with overactive or too much expression of TRPA-1 channels. Formaldehyde, chemical name of formalin, may be from smoke, smog, vinyl furnishings, or can be endogenously made in response to stress, and it can add to pain by activating TRPA-1 channels. (McNamara, et al, 2007)

Oral therapeutic treatments have value in allowing the bitter taste receptors to help guide individual dosing needs. Bitter taste receptors are discussed more in the TRPC4 and -5 section as they have coordinated functions and regulatory roles over some TRP channel types. Bitter taste receptors and odor receptors are found in functional roles in various tissue types throughout the body performing other tasks than sending taste or odor signals to the brain. Taste receptors for bitter tastes are 10,000 times more sensitive than for sweet tastes which helps guide us to a therapeutic amount of the bitter tasting and medicinally valuable and/or potentially toxic phytonutrients. Dose makes the difference between benefit and harm. Bitter phytonutrients in pomegranate may be down-regulating TRP channels involved in nociceptive pain and inflammatory bowel conditions.

Whether a TRP activator leads to migraines or colitis flare-ups for hypersensitive patients may vary for them based on their current level of overall inflammation and daily stressors. Too much expression of TRP channels is seen in Irritable Bowel Syndrome (IBS) and in rectal hypersensitivity. (Hicks, 2006, González-Ramírez , et al, 2017) Childhood or chronic trauma can be causal of IBS, a milder form of colitis or Inflammatory bowel disease (IBD). (Sansone and Sansone, 2015)

»The hypersensitivity may decrease with time once health has been restored for a few years but may remain an intermittent problem for life as health or stress levels worsen again, for child trauma survivors who developed IBS.

GI symptoms and malabsorption may lead to malnutrition and poor absorption of B vitamins. Medications can also deplete nutrients, examples of nutrients depleted by commonly used psychiatric medications are in Table 5. Mitochondrial dysfunction is then more likely.

Back to TRPA1 channels in dental pulp of teeth with cavity damage.

“Deep Caries Increase the Number of TRPA1-Positive Odontoblasts”

“In intact teeth, odontoblasts expressing nestin were arranged regularly in the outermost layer of the pulp and extended long processes into the dentin (Figure 1, A and C). In teeth with deep caries, tertiary dentin was observed subjacent to the primary dentin (Figure 1F). The number of odontoblasts was decreased compared with intact teeth, and some odontoblastic processes were shortened (Figure 1H). TRPA1 expression was hardly observed in the dental pulp of intact teeth (Figure 1B), whereas TRPA1-positive cells were observed in the dental pulp of carious teeth (Figure 1G). In particular, TRPA1 was highly expressed in nestin⁺ odontoblasts located along the tertiary dentin-dental pulp interface (Figure 1J), compared with intact tooth odontoblasts (Figure 1E).” (Tazawa, et al., 2020)

Pomgranate would be helpful as it modulates MAPK signaling. ‘pomegranate inhibits MAPK signaling’ MAPK signaling and p38 are involved in the increased expression of TRPA1 channels.

“Up-regulation of p-p38/MAPK was induced in NOR5-applied hDPCs at 0.5 and 1 hour (Figure 2D). In addition, expression of TRPA1 mRNA in LPS-stimulated hDPCs was down-regulated significantly by application of SB202190, a typical p38/MAPK inhibitor (Figure 2E).” (Tazawa, et al., 2020)

Besides sensing pressure, TRP channels can do other things and in the case of odontoblasts in the inner pulp of teeth with cavities, they seem to be promoting the cells to increase mineralization by building a tertiary layer of dentin.

“Discussion: TRPA1 was expressed in odontoblasts aligned along tertiary dentin formed under a carious lesion (Figure 1G), TRPA1 expression was increased in LPS-stimulated hDPCs (Figure 2A), and TRPA1 induced differentiation and promoted mineralization of dental pulp cells (Figure 4, A and B). These findings suggest that TRPA1 plays a role in the defense or repair processes of the dentin or pulp complex represented by tertiary dentinogenesis, where new mineralized tissue is formed by newly generated odontoblast cells originating from undifferentiated precursors in response to dentinal tubule-derived bacterial stimulation.^28” […]

“Activation of TRPA1 promotes a wide range of physiological events in various cell types.⁴² Insulin release in rat pancreatic β cell lines,⁹ adrenomedullin synthesis in rat small intestines,⁴³ and proliferation of stem cells in drosophila midgut⁴⁴ are accelerated by TRPA1 activation. The major intracellular process induced by activated TRPA1 is Ca²⁺ influx⁶ that was detected in JT010-stimulated hDPCs (Figure 3). Following the Ca²⁺ influx, nuclear factor of activated T cells and Ras-ERK/MAPK are induced by TRPA1 activation.44, 45, 46 Nuclear factor of activated T cells is involved in the development and function of regulatory T cells and osteoclast differentiation, and regulates cell cycle–, apoptosis-, angiogenesis-, and metastasis-related genes.47, 48, 49” […]

“These findings suggest that the activated TRPA1 potentially induces odontoblastic/osteoblastic differentiation via ERK1/2 signaling. Icilin is reported to activate not only TRPA1 but TRPM8,⁵ and thus involvement of TRPM8-derived signaling in odontoblastic/osteoblastic differentiation cannot be ruled out. Expression of TRPM8 in freshly isolated human odontoblasts has been previously reported.⁵³” […]

“In conclusion, TRPA1 expression was induced via NO/p38 MAPK signaling in LPS-stimulated hDPCs, and TRPA1 agonists induced odontoblastic/osteoblastic differentiation and mineralization via Ca²⁺ influx followed by activation of ERK1/2 signaling.” (Tazawa, et al., 2020)

TRPM8 ion channels are also cold and pressure sensing and mint/menthol is an agonist in addition to PIP2. Changes in osmolarity may also be detected by TRPM8 channels.

“The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs.” […]

“Initially isolated from prostate cancer cells [16], TRPM8 channels are mainly expressed in a subpopulation of sensitive primary afferent neurons [17], which innervate highly cold-sensitive tissues, including skin, the oral cavity epithelium, teeth, nasal mucosa, tongue, and cornea [18,19,20,21,22,23,24,25].” (Izquierdo, et al., 2021)

TRP channel activation frequently is sending a pain signal if it isn’t performing some other function within the cell. It would make sense to have an increase in cold and pressure sensing TRP channels if a tooth has a cavity. The inner pulp needs to be protected from ice water - so the body makes drinking ice water too painful.

With an improvement in the inflammatory condition, that lasts a few years, the good news is that the increased sensitivity caused by an over-expression of TRP channels can become milder - less sensitized. The increased number of TRP channels seem to decrease in my personal experience. I like a really crunchy diet but at certain stages of worse inflammation I had to stop eating crunchy things or drinking ice water.

TRP channels are portals through a cell membrane. When opened minerals may pass through from extracellular fluid to the inside of the cell and cause actions to occur or a nerve signal to be sent. “Narrow channels in Venice” Photo by Aleksei Zhivilov on Unsplash

Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

(Izquierdo, et al., 2021) Izquierdo C, Martín-Martínez M, Gómez-Monterrey I, González-Muñiz R. TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. International Journal of Molecular Sciences. 2021; 22(16):8502. https://doi.org/10.3390/ijms22168502 https://www.mdpi.com/1422-0067/22/16/8502

(Tazawa, et al., 2020) Tazawa, K., Kawashima, N., Kuramoto, M., Noda, S., Fujii, M., Nara, K., Hashimoto, K., Okiji, T., Transient Receptor Potential Ankyrin 1 Is Up-Regulated in Response to Lipopolysaccharide via P38/Mitogen-Activated Protein Kinase in Dental Pulp Cells and Promotes Mineralization, The American Journal of Pathology, Vol 190, Issue 12, 2020, pp 2417-2426, ISSN 0002-9440, https://doi.org/10.1016/j.ajpath.2020.08.016. https://www.sciencedirect.com/science/article/pii/S0002944020304156

(Vaidyanathan, Makielski, 2014) Vaidyanathan, R., Makielski, J.C., 23 - Scaffolding Proteins and Ion Channel Diseases, Editor(s): Zipes, D.P., Jalife, J., Cardiac Electrophysiology: From Cell to Bedside (Sixth Edition), W.B. Saunders, 2014, Pages 229-234, ISBN 9781455728565, https://doi.org/10.1016/B978-1-4557-2856-5.00023-6. https://www.sciencedirect.com/science/article/pii/B9781455728565000236