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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 11  |  Issue : 2  |  Page : 89-93

Molecular mechanisms involved in making periodontitis – A painless disease entity


Department of Periodontics, SGT Dental College, Gurgaon, Haryana, India

Date of Submission02-Nov-2019
Date of Acceptance03-Jan-2019
Date of Web Publication15-Jul-2019

Correspondence Address:
Shruti Maroo Rathi
Flat 9A, Tower L, Central Park 2, Sector 48, Gurgaon, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jorr.jorr_6_19

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  Abstract 


Periodontitis is a chronic inflammatory disease that occurs in the tissues surrounding the tooth. It is due to the secretion of various inflammatory mediators from host as well as bacteria in response to microbial attack. Unlike any other inflammatory condition, even periodontitis is characterized by production of several inflammatory mediators such as leukotriene, cytokines, and arachidonic acid metabolites that are pro-algesic in nature, but still, patients with periodontitis do not present with “pain” as chief complaint nor do they self-medicate. Searches were carried out in the “Cochrane Library,” “MEDLINE,” “Web of Science,” “Scopus,” and “Google Scholar” databases, using the terms: “painless” and “periodontitis.” In this review, we discuss the role of various factors such as painless gene, calcitonin gene-related peptide and its receptors, endogenous opioids, butyric acid and CXC chemokine receptor 4 signaling by Porphyromonas gingivalis on hypoalgesia in periodontal disease. A detailed understanding of these mechanisms that are involved in making periodontitis, a unique painless inflammatory condition, is required as it can be used to develop new diagnostics and therapeutic modalities to treat severe chronic pain in other conditions.

Keywords: Inflammation, neurogenic, pain, periodontitis


How to cite this article:
Rathi SM. Molecular mechanisms involved in making periodontitis – A painless disease entity. J Oral Res Rev 2019;11:89-93

How to cite this URL:
Rathi SM. Molecular mechanisms involved in making periodontitis – A painless disease entity. J Oral Res Rev [serial online] 2019 [cited 2019 Aug 18];11:89-93. Available from: http://www.jorr.org/text.asp?2019/11/2/89/262763




  Introduction Top


Periodontitis is a plaque-induced chronic inflammatory disease resulting from interaction between plaque bacteria and the immune system. Like any other chronic inflammatory disease such as rheumatoid arthritis and inflammatory bowel disease, periodontitis is also characterized by a hyperinflammatory trait which causes exaggerated secretion of innate inflammatory mediators and systemic markers of inflammation such as cytokines, arachidonic acid metabolites, chemokines, and proteolytic enzymes that collectively result in the destruction of soft and hard tissue.[1] The usual signs and symptoms of any chronic inflammatory disease include pain, swelling, heat, redness, and loss of function and it has been accepted that effective treatment of pain is a priority and that treatment often involves the use of one or a combination of agents with analgesics.[2] However, in case of periodontitis, which affects approximately 80% of adults in the US, patients do not present with pain nor do they self-medicate analgesic. Only 6.2% of the participants with periodontitis seek treatment.[2] According to a study by Brunsvold et al. in 1999,[3] the most common chief complaints reported by chronic periodontitis participants are as follows: “I was told I have gum disease” or “I would like to save my teeth.” Neither of these chief complaints are true symptoms of chronic periodontitis.

It has now been established that, besides microbiological and immunological components, neurogenic inflammation also plays an essential role in the pathogenesis of periodontitis.[4] Neurons and neuropeptides not only play an important role in regulation of pain perception but they also have a pivotal role in the complex cascade of chemical activity associated with periodontal inflammation.

Therefore, the aim of this article is to highlight various neurologic as well as immunological factors responsible for making periodontitis, a painless condition besides the long-standing chronic inflammation.


  Crosstalk between Nervous and Immune Systems Top


More than a century ago, Bayliss in 1901[5] proposed the involvement of sensory nervous system in generating some of the manifestations of inflammation. He reported that vasodilatation followed cutaneous neural stimulation, suggesting that in addition to their sensory function, these neurons have an efferent neurosecretory role. Evidence for a role of neurogenic inflammation in periodontal disease was first found in the late 1980s. The periodontal tissues contain many nociceptors, a primary sensory neuron which when activated are capable of tissue damage.[6],[7] In rodents, an increased density of sensory nerves was demonstrated in periapical abscesses, and these innervations were intensified particularly at sites of severe periodontal inflammation and necrosis.[8]

Mengel et al.[6],[7] suggested that both A-delta and C fibers are present in the periodontal ligament and that they have a role in periodontal nociception. Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of these nociceptors. Furthermore, on activation, these receptors release neuropeptides leading to neurogenic inflammation. However, periodontitis is a unique disease, as besides all these factors, it is still painless.

As described by Wall in 1994,[9] “sensory systems are not dedicated and hard wired but are held in a steady state by elaborate dynamic control mechanisms.” Following tissue damage due to periodontal pathogen, a number of changes take place within pain-conducting systems resulting in abnormal signal transmission patterns between immune and nervous systems. The factors that play a major role include:

  1. Painless gene and transient receptor potential family V member 1 cation channel (TRPV1) receptors
  2. Calcitonin gene-related peptide (CGRP)
  3. Endogenous opioids
  4. Butyric acid
  5. Role of CXC chemokine receptor 4 (CXCR4) signaling by Porphyromonas gingivalis (P. gingivalis).



  Role of “painless Gene” Top


Overstimulation of peripheral nociceptor terminals by injury or inflammation of tissues results in neurogenic inflammation. Painless gene or the “pain sensors” are responsible for the initiation of signaling pathway. They were first identified in Drosophila and is considered to be an evolutionary homolog of the mammalian “wasabi receptor” TRAP 1/ANKTM 1 (Transient Receptor Potential cation channel subfamily A member 1/Ankyrin-like with transmembrane domains protein 1).[10],[11],[12] It encodes an ion channel of TRPV1, which is the endpoint target of intracellular signaling pathways triggered by inflammatory mediators.[13] It is a nonselective channel that responds to noxious stimuli such as low pH, painful heat, and irritants and thus contributes to the integration of various stimuli and modulates nociceptor excitability, making it a true gateway for pain transduction.

In the gingival tissues, several types of nonneuronal cell express TRPV1, in particular, keratinocytes, fibroblasts, endothelial cells, and inflammatory cells indicating its involvement in the neuronal–nonneuronal cellular network in the periodontium.[14],[15] Furthermore, Avellan et al.[16] concluded that TRPV1 plays a role in the pathogenesis of periodontitis.

Wadachi and Hargreaves[10] further clarified its role by identifying Toll-like receptor 4 (TLR4) co-localized with TRPV1 on sensory nerves in inflamed pulp tissue and trigeminal nerves, and bacterial products, such as lipopolysaccharides (LPS), may directly activate these neurons through TLR4. Therefore, TRPV1 is upregulated in inflammatory diseases such as irritable bowel syndrome and visceral hypersensitivity, but surprisingly, in periodontitis, both TRPV1 and TLR4 are downregulated. This antinociception may be because of certain bacteria, such as Lactobacillus reuteri DSM 17938, that can target TRPV1.[11]

Another reason for such a downregulation may be due to prolonged and repeated exposure to LPS, indirectly through TLR4 or through other TRPV1 ligands produced during inflammation. This desensitizes both TLR4 and TRPV1 receptors similarly to the phenomenon known as capsaicin desensitization.[17] Subsequent downregulation of these receptors may have a role in sustaining the chronic nature of the disease and the ability to accomplish pain tolerance to bacterial challenge.[17]


  Role of Calcitonin Gene-Related Peptide Top


Studies demonstrate that CGRP and CGRP receptors are involved in the transmission and modulation of pain information in peripheral and central nervous systems.[18],[19] The role of CGRP in the development of nociceptive behaviors in response to peripheral inflammatory events has been confirmed in studies of CGRP knockout mice.[20] These neuropeptides are released in response to the efferent stimulation of sensory nerves that are mainly unmyelinated and of the C and A-delta subtypes.[21]

Lundy in 1999[18] reported that in patients with periodontitis, CGRP immunoreactivity was not detected in any periodontitis sites whereas it was detected in 89% of the healthy sites sampled in controls at levels comparable to those in healthy sites in periodontitis patients. This indicated that in periodontal inflammation, particularly in deep pockets, constituents of the gingival crevicular fluid process and degrade CGRP. Undetectability of CGRP in gingival crevicular fluid from periodontitis sites may partly explain the absence of pain as a major symptom in periodontitis.[18]


  Role of Endogenous Opioids Top


Interactions between neurons and immune system control pain through activation of opioid receptors on sensory nerves by immune-derived opioid peptides.

In the initial stages of inflammation (6 h), leukocyte-derived β-endorphin, dynorphin A, and met-enkephalin inhibits pain by activating peripheral μ-, δ-, and κ-receptors to inhibit nociception, whereas in the later stages of inflammation (4 days), antinociception is because of β-endorphin, derived from leukocyte, which acts on peripheral μ- and δ-receptors. Corticotropin-releasing hormone is an endogenous trigger of these effects at both stages.[22] This activation of opioid receptors occurs as a result of the release of formyl peptides by bacteria. An example of this includes the analgesic effect induced by Lactobacillus acidophilus, an important bacterium present in subgingival sites, via induction of expression of μ-receptors and cannabinoid receptors.[23]

Furthermore, with the progression of inflammation, the concentrations of endogenous opioids are increased in inflamed tissue, and the number of opioid-producing leukocytes, their opioid content, as well as their analgesic action becomes more pronounced.[22] Therefore, this mechanism becomes relevant with an increase in chronicity of inflammation.


  Role of Butyric Acid Top


Butyric acid is an extracellular metabolite produced by periodontopathic bacteria. Seki et al. in 2016[24] experimented the role of butyric acid on rat pheochromocytoma PC12 cells and found that during the early stages of periodontitis, the accumulation of butyric acid is low and it leads to neurite nonproliferation, whereas during the later stages, high amounts of butyric acid accumulations favor neurodegeneration. The authors concluded that the absence of neuropathic pain at any stage of periodontal disease progression is related to butyric acid accumulation. Another research article by the same group of authors hypothesized that butyric acid, possibly through heme-related oxidative stress induction, have a detrimental effect on neurite outgrowth of PC12 cells.[25] The following sequences of heme-related events occur in PC12 cells treated with high amounts of butyric acid:

(a) Concentration of heme increases which causes oxidative stress. This leads to (b) decrease in heme levels which can be attributable to both oxidative stress as well as failure to synthesize heme due to neuro-degeneration. This further leads to (c) heme deficiency which in turn results in apoptosis i.e., neurite degeneration via MAP kinase activation.[26],[27],[28],[29]


  Role of Cxc Chemokine Receptor 4 Signaling by Porphyromonas Gingivalis Top


P. gingivalis is a Gram-negative anaerobic bacterium in chronic periodontitis. It produces a myriad of virulence factors that help to maintain periodontitis.[30],[31] Fimbria acts as a major colonizing factor[32],[33] and is responsible for initiation of intracellular signaling that occurs via TLR2.[34] It interacts with CXCR4 on macrophages and inhibits nitric oxide (NO) production by nuclear factor-kappa B activation. This reduces pulpal upregulation of cyclooxygenase-2 which further limits the production of prostaglandin E2 leading to desensitization of C-fibers to mechanical stimuli.[35] Reduction of NO also limits the release of interleukin-1 beta and tumor necrosis factor-alpha from resident and infiltrating immune cells, thus decreasing the mechanical sensitivity of peripheral nociceptors.[30],[31] This leads to gingival antinociception in periodontal disease.[36]


  Difference in Phenotype of Sensory Neuron in Pulp and Periodontium Top


Dental pulp and periodontium are both richly innervated by nociceptive tropomyosin receptor kinase A-expressing neurons, but patients with pulpitis experience intense pain sensations whereas chronic periodontitis is relatively pain free.[37] This variance in pain arises due to difference in phenotypes of sensory neurons innervating dental pulp and periodontium. The pulpal neurons are larger and nerve growth factor-dependent A-fiber nociceptors with no affinity toward isolectin (IB4), but the gingival neurons are smaller C-fiber nociceptors with affinity toward IB4.[37]


  Lack of Pain: the Good, the Bad, the Ugly Top


Nociceptive pain system is a key early warning device, an alarm system that announces the presence of a potentially damaging stimulus.[38] Nociceptive pain is, therefore, a vital physiologic sensation. Lack of pain in periodontitis makes patient unaware about the disease, and therefore, it often goes undiagnosed until progression has reached moderate to advanced degrees of severity which is characterized by obvious radiographic bone loss and/or tooth mobility.[39] This severely affects the prognosis of the treatment.

Furthermore, periodontitis has been linked to various other diseases which include diabetes,[40] cardiovascular diseases,[41] and head-and-neck cancers.[42] Therefore, untreated periodontitis can also lead to an increase in the incidence of these medical conditions.

On the brighter end, lack of pain is an obvious advantage to the periodontitis patient. A thorough understanding of mechanisms involved in making periodontitis painless can be exploited to develop new diagnostics and therapeutic modalities to treat severe chronic pain in other conditions.


  Conclusion Top


Exponential growth in research in the past few decades has increased our understanding of underlying mechanisms of the pathophysiology of periodontitis. There is growing evidence for bidirectional signaling between nervous and immune systems that not only control the pathogenesis of periodontitis but also that of pain. Several other mechanisms that can produce pain have been identified and it comprises the complex processes of transduction, conduction, transmission, and perception. Further understanding of this complex regulatory system, in particular, those governing neuropeptide inactivation, is required to truly determine the causes of painless periodontitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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  In this article
Abstract
Introduction
Crosstalk betwee...
Role of “p...
Role of Calciton...
Role of Endogeno...
Role of Butyric Acid
Role of Cxc Chem...
Difference in Ph...
Lack of Pain: th...
Conclusion
References

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