Masticationpedia

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7° Klinischer Fall: Hirnstammneoplasie bei orofazialen Schmerzen (view source)

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[[File:Capsaicina.jpg|left|300x300px]]
[[File:Capsaicina.jpg|left|300x300px]]
This chapter presents a case of absolute epistemological importance in the sense that it highlights a gap in the diagnostic process based on evidence-based medicine (EBM). This last term, in fact, is inextricably linked to the basic scientific knowledge already known as <math>KB </math> (Basic knowledge).  
Dieses Kapitel stellt einen Fall von absoluter epistemologischer Bedeutung dar, da es eine Lücke im diagnostischen Prozess aufzeigt, der auf evidenzbasierter Medizin (EBM) beruht. Dieser letzte Begriff ist tatsächlich untrennbar mit dem grundlegenden wissenschaftlichen Wissen verbunden, das bereits als Basiswissen bekannt ist.  


Obviously, it depends on scientific progress and technological, methodological but also philosophical evolution as the interpretation of clinical data in a classic probabilistic model cannot fully represent the underlying reality as the variables are dependent and compatible while in a quantum variables are independent and incompatible. This paradigm shift would have allowed us to make detailed and early differential diagnosis without waiting for the basic knowledge on the specific topic of capsaicin on pain.
Offensichtlich hängt dies vom wissenschaftlichen Fortschritt sowie von technologischer, methodologischer, aber auch philosophischer Entwicklung ab, da die Interpretation klinischer Daten in einem klassischen probabilistischen Modell die zugrunde liegende Realität nicht vollständig darstellen kann, da die Variablen abhängig und kompatibel sind, während sie in einem quantenmechanischen Modell unabhängig und inkompatibel sind. Dieser Paradigmenwechsel hätte es uns ermöglicht, detaillierte und frühzeitige Differentialdiagnosen zu stellen, ohne auf das Basiswissen zum spezifischen Thema Capsaicin bei Schmerzen warten zu müssen.


This chapter was a milestone that led the author to the creation of Masticationpedia so that these cases can be taken in the right time to ensure at least a relatively peaceful end of life and not in 10 years of Orofacial Pain (OP) by collecting misdiagnoses.
Dieses Kapitel war ein Meilenstein, der den Autor zur Schaffung von Masticationpedia führte, damit diese Fälle rechtzeitig erfasst werden können, um zumindest ein relativ friedliches Lebensende zu gewährleisten und nicht erst nach 10 Jahren Orofazialer Schmerzen (OP) durch Fehldiagnosen gesammelt werden müssen.


{{ArtBy|autore=Gianni Frisardi}}
{{ArtBy|autore=Gianni Frisardi}}


=== Introduction ===
===Einleitung===
The brain stem is the caudal portion of the brain that connects the diencephalon to the spinal cord and cerebellum.<ref>Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv. </ref> The brainstem mediates the sensory and motor pathways between the spinal cord and the brain and contains the nuclei of the cranial nerves, the ascending reticular activating system (ARAS), and the autonomic nuclei. It controls brainstem reflexes and the sleep-wake cycle and is responsible for autonomous control of the cardiovascular, respiratory, digestive and immune systems. Brainstem dysfunction can result from various acute or chronic insults, including stroke, infectious, cancer, inflammatory, and neurodegenerative diseases. In the context of critical illness, the brain stem can be susceptible to various insults that can be classified as structural and non-structural in origin. Brainstem dysfunction can therefore contribute to impaired consciousness, cardiocirculatory and respiratory insufficiency and therefore to increased mortality <ref>Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.</ref><ref>Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.</ref><ref>Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4. </ref><ref>Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.</ref> and especially manifest as orofacial pain (OP).[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945639/ Brainstem dysfunction in critically ill patients]:
Der Hirnstamm ist der kaudale Teil des Gehirns, der das Zwischenhirn mit dem Rückenmark und dem Kleinhirn verbindet.<ref>Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv. </ref> Der Hirnstamm vermittelt die sensorischen und motorischen Bahnen zwischen dem Rückenmark und dem Gehirn und enthält die Kerne der Hirnnerven, das aufsteigende retikuläre Aktivierungssystem (ARAS) und die autonomen Kerne. Er kontrolliert die Hirnstammreflexe und den Schlaf-Wach-Rhythmus und ist verantwortlich für die autonome Kontrolle des kardiovaskulären, respiratorischen, verdauungsmäßigen und immunologischen Systems. Eine Dysfunktion des Hirnstamms kann verschiedene akute oder chronische Schädigungen zur Folge haben, einschließlich Schlaganfall, Infektionen, Krebs, entzündliche und neurodegenerative Erkrankungen. Im Kontext schwerer Erkrankungen kann der Hirnstamm anfällig für verschiedene Schädigungen sein, die als struktureller und nicht-struktureller Ursprung klassifiziert werden können. Eine Hirnstammdysfunktion kann daher zu einer Beeinträchtigung des Bewusstseins, der kardiovaskulären und respiratorischen Insuffizienz und somit zu einer erhöhten Sterblichkeit beitragen<ref>Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.</ref><ref>Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.</ref><ref>Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4. </ref><ref>Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.</ref> und sich insbesondere als Orofazialschmerz (OP) manifestieren. Hirnstammdysfunktion bei kritisch kranken Patienten:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945639/ Brainstem dysfunction in critically ill patients]:


<blockquote>These important premises extracted from an interesting article by Sarah Benghanem<ref>Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. Brainstem dysfunction in critically ill patients. Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011</ref> are essential details, expression of a clinical experience which led the author of the chapter to scientific and epistemological reflections on the typology of language to be used in the creation of diagnostic models. and consequently to found Masticationpedia. One cannot, personal and responsible assertion of the author of the chapters, slavishly follow an axiom, a protocol such as the DRC or whatever and risk an error of differential diagnosis which can cost the life of a human being. If there is a gap in the model, which we will demonstrate during the implementation of Masticationpedia, then it should be noted as an anomaly, analyzed and eliminated or at least modified otherwise it is not a question of paradigmatic progress but only of intensive progress. </blockquote>
<blockquote>Diese wichtigen Voraussetzungen, die aus einem interessanten Artikel von Sarah Benghanem<ref>Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. Brainstem dysfunction in critically ill patients. Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011</ref> extrahiert wurden, sind wesentliche Details, die Ausdruck einer klinischen Erfahrung sind, die den Autor des Kapitels zu wissenschaftlichen und epistemologischen Überlegungen über die Art der Sprache geführt hat, die bei der Erstellung von Diagnosemodellen verwendet werden soll, und folglich zur Gründung von Masticationpedia geführt hat. Man kann nicht, wie es die persönliche und verantwortungsbewusste Aussage des Autors der Kapitel zeigt, sklavisch einem Axiom oder einem Protokoll wie dem DRC oder ähnlichem folgen und das Risiko eines Differentialdiagnosefehlers eingehen, der das Leben eines Menschen kosten kann. Wenn es eine Lücke im Modell gibt, die wir während der Implementierung von Masticationpedia nachweisen werden, dann sollte sie als Anomalie vermerkt, analysiert und beseitigt oder zumindest modifiziert werden, sonst handelt es sich nicht um paradigmatischen Fortschritt, sondern nur um intensiven Fortschritt. </blockquote>


==== Presentation of the clinical case ====
====Vorstellung des klinischen Falls====
It was the year 1995 when the 60-year-old female patient, who we will call with a fancy name 'Capsaicin' (we will understand the reason below) presented herself to our observation reporting bilateral diffuse orofacial pain in the temporal muscles region and in the occipital region , in addition, to the presence of burning mouth (BMS), for more than 10 years. The pain lasted for hours especially at night and did not occur cyclically. The patient was the bearer of a long-standing upper and lower ceramic fixed prosthetic rehabilitation with various fractures of the ceramic structure and wear veneers on the remaining natural teeth. However, no occlusal discrepancies were found in the prosthetic rehabilitation, but a release plate was performed by other health professionals to be used at night. The patient reported pain even with the plate inserted and was initially considered to be affected by Atypical Orofacial Pain (AOP) with a strong psychosomatic component and subsequently, according to the RDC protocol, affected by 'Temporomandibular Disorders'.
Es war das Jahr 1995, als die 60-jährige Patientin, die wir mit einem ausgefallenen Namen "Capsaicin" nennen werden (den Grund werden wir unten verstehen), sich mit bilateralen diffusen Orofazialschmerzen in der Region der Schläfenmuskulatur und im okzipitalen Bereich, zusätzlich zum Vorhandensein von brennendem Mund (BMS), seit mehr als 10 Jahren bei uns vorstellte. Die Schmerzen dauerten stundenlang, besonders nachts, und traten nicht zyklisch auf. Die Patientin trug seit langem eine obere und untere keramische feste Prothesenrehabilitation mit verschiedenen Brüchen der keramischen Struktur und Abrieb-Veneers auf den verbleibenden natürlichen Zähnen. Es wurden jedoch keine Okklusionsdiskrepanzen in der prothetischen Rehabilitation festgestellt, sondern von anderen Gesundheitsfachkräften wurde eine Entlastungsplatte zur nächtlichen Anwendung angefertigt. Die Patientin berichtete auch bei eingelegter Platte über Schmerzen und wurde zunächst als von Atypischen Orofazialen Schmerzen (AOP) mit einem starken psychosomatischen Komponenten betroffen betrachtet und später, gemäß dem RDC-Protokoll, als von 'Temporomandibulären Störungen' betroffen.


Having come to our observation, as per the Masticationpedia protocol, the main gnathological tests were performed, such as paraocclusal axiography of the condylar tracings and an interferential EMG of the masseter muscles. In this case, an ATM CT was not requested, much less an MR. We present in a schematic and representative way reporting some paragraphs exposed in the previous chapters the Masticationpedia protocol in its schematization as: assertions in the dental, neurological context and finally the diagnostic conclusion through the 'Demarcator <math>\tau</math>':
Nach unserer Untersuchung, gemäß dem Masticationpedia-Protokoll, wurden die wichtigsten gnathologischen Tests durchgeführt, wie paraokklusale Axigraphie der kondylären Spuren und eine interferenzielle EMG der Massetermuskulatur. In diesem Fall wurde kein ATM-CT angefordert, geschweige denn ein MR. Wir stellen schematisch und repräsentativ einige Absätze aus den vorherigen Kapiteln dar, die das Masticationpedia-Protokoll in seiner Schematisierung als: Aussagen im zahnärztlichen, neurologischen Kontext und schließlich die diagnostische Schlussfolgerung durch den 'Demarcator' vorstellen <math>\tau</math>':


===== Significance of contexts =====
=====Bedeutung von Kontexten=====
For the ''dental context'' we will have the following sentences and statements to which we give a numerical value to facilitate the treatment and that is <math>\delta_n=[0|1]</math> where <math>\delta_n=0</math> indicates 'normality' and <math>\delta_n=1</math> 'abnormality and therefore positivity of the report:


{{:F:Delta1}} Paraocclusal axiographic tracing of the right condyle, negative in Figure 1, Normality, negative report
Für den "zahnmedizinischen Kontext" haben wir die folgenden Sätze und Aussagen, denen wir einen numerischen Wert zuordnen, um die Behandlung zu erleichtern, und das ist <math>\delta_n=[0|1]</math> wobei <math>\delta_n=0</math> 'Normalität' anzeigt und <math>\delta_n=1</math> 'Abnormalität und somit Positivität des Berichts' bedeutet:


{{:F:Delta2}} Paraocclusal axiography tracing of the left condyle, negative in Figure 2, Normality, negative report
{{:F:Delta1}} Paraokklusales axiografisches Nachzeichnen des rechten Kondylus, negativ in Abbildung 1, Normalität, negativer Bericht


<math>\delta_3=</math> Symmetric EMG interference pattern in Figure 5. Normality, negative report<center>
{{:F:Delta2}} Paraokklusales Axiografie-Nachzeichnen des linken Kondylus, negativ in Abbildung 2, Normalität, negativer Bericht
 
<math>\delta_3=</math> Symmetrisches EMG-Interferenzmuster in Abbildung 5. Normalität, negativer Bericht<center>
<gallery widths="230" heights="200" perrow="3" slideshow""="">
<gallery widths="230" heights="200" perrow="3" slideshow""="">
File:Assiografia dx modificata.jpeg|'''Figure 1:''' Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline , h) consular hinge axis in maximum intercuspidation,
File:Assiografia dx modificata.jpeg|'''Abbildung 1:''' Rechtes konsuläres paraokklusales axiografisches Nachzeichnen: a) Zentrum der Scharnierachse, b) Orbitalebeneachse, c) prothetisches Nachzeichnen, d) medioprothetisches Nachzeichnen, e) medioprothetischer Kauzyklusbereich, f) lateroprothetischer Kauzyklusbereich, g) lateroprothetische Rücklinie, h) konsuläre Scharnierachse in maximaler Interkuspidation.
File:Assiografia sn.jpg|'''Figure 2:''' <math>\delta_2</math> Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline.
File:Assiografia sn.jpg|</math> and are represented with a ma Rechte konsulare paraokklusale axiografische Aufzeichnung: a) Drehachsezentrum, b) Orbitale Achsenebene, c) protrusive Aufzeichnung, d) mediotrusive Aufzeichnung, e) mediotrusiver kaubewegungsbereich, f) laterotrusiver kaubewegungsbereich, g) laterotrusive rücklinie.
File:Frisardi Gianni 0001.bmp.png|'''Figura 3:''' <math>\delta_3</math> Interferential EMG of right (top) and left (bottom) masseter muscles. Amplitude 200μV per division, time division 100 msec
File:Frisardi Gianni 0001.bmp.png|n often happen that some tests give a
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</center>
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File:Immagine5.bmp.png|'''Figura 6:''' <math>\gamma_1=</math> Mechanical silent period recorded on masseter muscles right (top black corresponds to mean) left (bottom black corresponds to mean)  
File:Immagine5.bmp.png|'''Figura 6:''' <math>\gamma_1=</math> Mechanical silent period recorded on masseter muscles right (top black corresponds to mean) left (bottom black corresponds to mean)  
</gallery>
</gallery>
</Center>
</center>


{{Q2|In this scenario both the statements <math>\Im_o </math> and <math>\Im_n </math> are compatible, consistent and therefore true until a 'Consistency Demarcator 'τ' is found which highlights the greater weight in terms of clinical severity.
{{Q2|In this scenario both the statements <math>\Im_o </math> and <math>\Im_n </math> are compatible, consistent and therefore true until a 'Consistency Demarcator 'τ' is found which highlights the greater weight in terms of clinical severity.
}}
}}


==== Coherence Demarcator <math>\tau</math>====
====Coherence Demarcator <math>\tau</math>====
The <math>\tau</math>is a representative clinical specific weight, complex to research and develop because it varies from discipline to discipline and for pathologies, essential for not colliding logical assertions <math>\Im_o</math> and <math>\Im_n</math> in diagnostic procedures and fundamental for initializing the decryption of the machine code. Basically it allows to confirm the coherence of one union <math>\Im\cup\{\delta_1,\delta_2.....\delta_n\}</math> with respect to another <math>\Im\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> and vice versa, giving greater weight to the seriousness of the assertions and of the report in the appropriate context. Sometimes the doctor is faced with a series of positive reports to which he must give the right weight, he must consider the positivity of a report which highlights, for example, an osteoarticular renewal of the TMJ cannot have the same weight as a positivity of a report confirming latency delay of a trigeminal reflex. The demarcation <math>\tau</math> weight, therefore, gives more significance to the more serious assertions in the clinical context from which they derive and therefore beyond the positivity of the assertions <math>\delta_n=1</math> or which <math>\gamma_n=1</math> in any case are always verified and respected, these must be multiplied by a <math>\tau=[0|1]</math> where <math>\tau=0</math> indicates 'Low seriousness ' while <math>\tau=1</math> 'Severe Gravity'.  
The <math>\tau</math>is a representative clinical specific weight, complex to research and develop because it varies from discipline to discipline and for pathologies, essential for not colliding logical assertions <math>\Im_o</math> and <math>\Im_n</math> in diagnostic procedures and fundamental for initializing the decryption of the machine code. Basically it allows to confirm the coherence of one union <math>\Im\cup\{\delta_1,\delta_2.....\delta_n\}</math> with respect to another <math>\Im\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> and vice versa, giving greater weight to the seriousness of the assertions and of the report in the appropriate context. Sometimes the doctor is faced with a series of positive reports to which he must give the right weight, he must consider the positivity of a report which highlights, for example, an osteoarticular renewal of the TMJ cannot have the same weight as a positivity of a report confirming latency delay of a trigeminal reflex. The demarcation <math>\tau</math> weight, therefore, gives more significance to the more serious assertions in the clinical context from which they derive and therefore beyond the positivity of the assertions <math>\delta_n=1</math> or which <math>\gamma_n=1</math> in any case are always verified and respected, these must be multiplied by a <math>\tau=[0|1]</math> where <math>\tau=0</math> indicates 'Low seriousness ' while <math>\tau=1</math> 'Severe Gravity'.  


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{{Q2|Unfortunately, the patient died a few years later of trochoencephalic neuroma.|.......leaving a doubt, that of the correlation between pain and capsaicin as reported by the patient on the occasion of a spicy diet.}}
{{Q2|Unfortunately, the patient died a few years later of trochoencephalic neuroma.|.......leaving a doubt, that of the correlation between pain and capsaicin as reported by the patient on the occasion of a spicy diet.}}


=== Thoughts and conclusions ===
===Thoughts and conclusions===


The mammalian gustatory system is made up of taste buds, which are clusters of 50-100 taste cells found throughout the oral cavity. On the tongue, which is the central topic of the case report 'Capsaicin', the taste buds are located on circumvallate, foliate and fungiform papillae. Taste cells synapse with afferent fibers from branches of the cranial facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves which, in turn, transmit information to the central nervous system (CNS) about gustatory attributes , intensity and hedonic nature. <ref>Gutierrez, R., and S.A. Simon. 2011. Chemosensory processing in the taste-reward pathway. Flavour Fragr J, 26(4): 231–238.</ref><ref>Carleton, A., R. Accolla, and S.A. Simon. 2010. Coding in the mammalian gustatory system. Trends Neurosci, 33(7): 326–334.</ref><ref>Vincis, R. and A. Fontanini. 2016. A gustocentric perspective to understanding primary sensory cortices. Curr Opin Neurobiol, 40: 118–124</ref> The taste buds are embedded in a stratified squamous epithelium, which contains somatosensory branches of the trigeminal (CN V), glossopharyngeal (CN IX), and vagus (CN X) cranial nerves. Information from these general sensory nerves provides information to the central nervous system about mechanical, thermal, and pain stimuli.<ref name=":1" /><ref>Kaneko, Y., and A. Szallasi. 2014. Transient receptor potential (TRP) channels: A clinical perspective. Br J Pharmacol, 171(10): 2474–2507. </ref> Painful stimuli can result from strong or sharp mechanical stimuli, abnormally high or low temperatures, or chemical stimuli such as capsaicin, which is found in hot peppers and causes a burning taste sensation through the intervention of Transient Receptor Potentials (TRPs).<ref name=":0" /> These TRPs are divided into six subfamilies including TRPV1, which we are interested in to hypothesize the phenomenon of pain exacerbation of the patient 'Capsaicin' in spicy diet. [[File:Trpv1 pip2 bilayer.png|thumb|'''Figura 9:''' TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. [[wikipedia:TRPV1|Wikipedia]]]]
The mammalian gustatory system is made up of taste buds, which are clusters of 50-100 taste cells found throughout the oral cavity. On the tongue, which is the central topic of the case report 'Capsaicin', the taste buds are located on circumvallate, foliate and fungiform papillae. Taste cells synapse with afferent fibers from branches of the cranial facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves which, in turn, transmit information to the central nervous system (CNS) about gustatory attributes , intensity and hedonic nature. <ref>Gutierrez, R., and S.A. Simon. 2011. Chemosensory processing in the taste-reward pathway. Flavour Fragr J, 26(4): 231–238.</ref><ref>Carleton, A., R. Accolla, and S.A. Simon. 2010. Coding in the mammalian gustatory system. Trends Neurosci, 33(7): 326–334.</ref><ref>Vincis, R. and A. Fontanini. 2016. A gustocentric perspective to understanding primary sensory cortices. Curr Opin Neurobiol, 40: 118–124</ref> The taste buds are embedded in a stratified squamous epithelium, which contains somatosensory branches of the trigeminal (CN V), glossopharyngeal (CN IX), and vagus (CN X) cranial nerves. Information from these general sensory nerves provides information to the central nervous system about mechanical, thermal, and pain stimuli.<ref name=":1" /><ref>Kaneko, Y., and A. Szallasi. 2014. Transient receptor potential (TRP) channels: A clinical perspective. Br J Pharmacol, 171(10): 2474–2507. </ref> Painful stimuli can result from strong or sharp mechanical stimuli, abnormally high or low temperatures, or chemical stimuli such as capsaicin, which is found in hot peppers and causes a burning taste sensation through the intervention of Transient Receptor Potentials (TRPs).<ref name=":0" /> These TRPs are divided into six subfamilies including TRPV1, which we are interested in to hypothesize the phenomenon of pain exacerbation of the patient 'Capsaicin' in spicy diet. [[File:Trpv1 pip2 bilayer.png|thumb|'''Figura 9:''' TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. [[wikipedia:TRPV1|Wikipedia]]]]
==== TRPV1 and neuroinflammation ====
====TRPV1 and neuroinflammation====
TRPV1s constitute a distinct subset of non-selective cation channels (Transient Receptor Potential) responsible for many cellular responses. They are activated by various stimuli such as acids, extracellular protons, high temperatures, plant toxins and vanilloid agonists. The TRPV1s present in mammals can be considered as sensors of chemical substances (capsaicin), thermal substances (heat) and/or harmful stimuli. The activation of TRPV1 leads to the depolarization necessary for the propagation of action potentials along the axons of the dorsal root ganglia (DRG) of neurons that project to the spinal cord and consequently also to the nociceptive trigeminal nuclei. What makes TRPV1 so critical for pain signaling is undeniably its ability to transduce inflammatory signals into electrical signals with the activation of both voltage-gated sodium and calcium channels located at the nociceptor level.<ref>Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. Calcium permeable ion channels in pain signaling. Physiol Rev 2014; 94: 81–140.</ref> The implication of TRPV1 in pathological pain prompted a careful study of these proteins. The limiting element in pharmacological research at the application level was the peculiarity of the TRPV1 channel, i.e. its polymodal mechanism of activation (heat, capsaicin, pH), which led to a high level of complexity in the design of a specific modality inhibitor.  
TRPV1s constitute a distinct subset of non-selective cation channels (Transient Receptor Potential) responsible for many cellular responses. They are activated by various stimuli such as acids, extracellular protons, high temperatures, plant toxins and vanilloid agonists. The TRPV1s present in mammals can be considered as sensors of chemical substances (capsaicin), thermal substances (heat) and/or harmful stimuli. The activation of TRPV1 leads to the depolarization necessary for the propagation of action potentials along the axons of the dorsal root ganglia (DRG) of neurons that project to the spinal cord and consequently also to the nociceptive trigeminal nuclei. What makes TRPV1 so critical for pain signaling is undeniably its ability to transduce inflammatory signals into electrical signals with the activation of both voltage-gated sodium and calcium channels located at the nociceptor level.<ref>Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. Calcium permeable ion channels in pain signaling. Physiol Rev 2014; 94: 81–140.</ref> The implication of TRPV1 in pathological pain prompted a careful study of these proteins. The limiting element in pharmacological research at the application level was the peculiarity of the TRPV1 channel, i.e. its polymodal mechanism of activation (heat, capsaicin, pH), which led to a high level of complexity in the design of a specific modality inhibitor.  


The interaction between neurons and immune cells is a well-known phenomenon.<ref>Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes". ''Mucosal Immunology''. '''14''' (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. <nowiki>PMID 33542493</nowiki>.</ref> TRPV1 plays its role, too, in neuroinflammation by being expressed in both neurons and immune cells. Significant importance should be given to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in the vicinity of neurons. The neuro-immune axis is the site of production of neuroinflammatory molecules and receptors that interact between the two systems and ensure a complex response to external stimuli (or to the body's own pathologies). TRPV1 is said to contribute to microglia autophagy through its Ca<sup>2+</sup> signaling, which leads to mitochondria-induced cell death. Basically, TRPV1 is a pro-apoptotic element.  
The interaction between neurons and immune cells is a well-known phenomenon.<ref>Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes". ''Mucosal Immunology''. '''14''' (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. <nowiki>PMID 33542493</nowiki>.</ref> TRPV1 plays its role, too, in neuroinflammation by being expressed in both neurons and immune cells. Significant importance should be given to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in the vicinity of neurons. The neuro-immune axis is the site of production of neuroinflammatory molecules and receptors that interact between the two systems and ensure a complex response to external stimuli (or to the body's own pathologies). TRPV1 is said to contribute to microglia autophagy through its Ca<sup>2+</sup> signaling, which leads to mitochondria-induced cell death. Basically, TRPV1 is a pro-apoptotic element.  


===== Ligands =====
===== Ligands=====


===== Antagonists =====
=====Antagonists=====
Antagonists block the ''activity of TRPV1'', thereby reducing pain. Antagonists identified include the [[wikipedia:Receptor_antagonist#Competitive|competitive antagonist capsazepine and the non-competitive antagonist]] [[wikipedia:Ruthenium_red|ruthenium red]]. These agents could be beneficial if applied systematically.<ref>Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". ''Trends in Molecular Medicine''. '''15''' (1): 14–22. doi:10.1016/j.molmed.2008.11.004. <nowiki>PMID 19097938</nowiki>.</ref> TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.<ref>Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". ''The European Journal of Neuroscience''. '''22''' (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. <nowiki>PMID 16045489</nowiki>. S2CID 24664751.</ref> This provides evidence that TRPV1 is the sole receptor for [[wikipedia:Capsaicin|capsaicin]].<ref>Story GM, Crus-Orengo L (2008). "Feel the Burn". ''American Scientist''. '''95''' (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.</ref> In humans, drugs that target TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.<ref>Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". ''Current Pharmaceutical Design''. '''14''' (1): 32–41. doi:10.2174/138161208783330754. <nowiki>PMID 18220816</nowiki>.</ref>
Antagonists block the ''activity of TRPV1'', thereby reducing pain. Antagonists identified include the [[wikipedia:Receptor_antagonist#Competitive|competitive antagonist capsazepine and the non-competitive antagonist]] [[wikipedia:Ruthenium_red|ruthenium red]]. These agents could be beneficial if applied systematically.<ref>Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". ''Trends in Molecular Medicine''. '''15''' (1): 14–22. doi:10.1016/j.molmed.2008.11.004. <nowiki>PMID 19097938</nowiki>.</ref> TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.<ref>Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". ''The European Journal of Neuroscience''. '''22''' (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. <nowiki>PMID 16045489</nowiki>. S2CID 24664751.</ref> This provides evidence that TRPV1 is the sole receptor for [[wikipedia:Capsaicin|capsaicin]].<ref>Story GM, Crus-Orengo L (2008). "Feel the Burn". ''American Scientist''. '''95''' (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.</ref> In humans, drugs that target TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.<ref>Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". ''Current Pharmaceutical Design''. '''14''' (1): 32–41. doi:10.2174/138161208783330754. <nowiki>PMID 18220816</nowiki>.</ref>


===== Agonists =====
=====Agonists=====
TRPV1 is activated by several agonists of natural origin.<ref>Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.</ref> Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of the TRPV1-mediated release of inflammatory molecules upon exposure to noxious stimuli.  
TRPV1 is activated by several agonists of natural origin.<ref>Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.</ref> Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of the TRPV1-mediated release of inflammatory molecules upon exposure to noxious stimuli.  


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These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.
These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.


{{Q2|Why, then, did the capsaicin taken in the food reported by the patient generate an exacerbation of pain?|....for chronic damage to the brainstem nerve fibers with consequent alteration of the neuro-immune homeostasis and contextual paradoxical effect of the analgesic action of capsaicin.}}In these cases, as stated in other chapters, we are dealing with an epistemological profile in which the basic knowledge, what we have called <math>KB</math> (Knowledge Base) corresponds to a temporal limit of scientific information and consequently serious  difficulties of differential diagnosis. We had to wait 12 years to reach an ezipathogenetic conclusion overwritten from 1995, a period in which the patient 'Capsaicin' was being treated, to 2007 in which a research gave the elements to suspect the presence of an organic neurological damage with manifestations of pain and burning mouth.<ref>Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.
{{Q2|Why, then, did the capsaicin taken in the food reported by the patient generate an exacerbation of pain?|....for chronic damage to the brainstem nerve fibers with consequent alteration of the neuro-immune homeostasis and contextual paradoxical effect of the analgesic action of capsaicin.}}In these cases, as stated in other chapters, we are dealing with an epistemological profile in which the basic knowledge, what we have called <math>KB</math> (Knowledge Base) corresponds to a temporal limit of scientific information and consequently serious  difficulties of differential diagnosis. We had to wait 12 years to reach an ezipathogenetic conclusion overwritten from 1995, a period in which the patient 'Capsaicin' was being treated, to 2007 in which a research gave the elements to suspect the presence of an organic neurological damage with manifestations of pain and burning mouth.<ref>Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.
</ref> Burning mouth syndrome (BMS) is often an idiopathic, chronic intractable pain condition, affecting 1.5-5.5% of middle-aged and older women. We investigated heat and capsaicin receptor TRPV1, and its regulatory nerve growth factor (NGF), in BMS. BMS patients (n=10) and controls (n=10) were evaluated for baseline and post-topical capsaicin pain scores, and their tongue biopsies were immunostained for TRPV1, NGF, and neurofilament structural nerve markers and periphery. Nerve fibers penetrating the epithelium were less abundant in the BMS (p<0.0001), indicating ''small fiber neuropathy''. TRPV1-positive fibers were overall significantly increased in BMS (p=0.0011), as were NGF fibers (p<0.0001) and NGF staining of basal epithelial cells (p<0.0147). There was a significant correlation between baseline pain score and TRPV1 (p=0.0143) and NGF (p=0.0252) fibers. A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006).
</ref> Burning mouth syndrome (BMS) is often an idiopathic, chronic intractable pain condition, affecting 1.5-5.5% of middle-aged and older women. We investigated heat and capsaicin receptor TRPV1, and its regulatory nerve growth factor (NGF), in BMS. BMS patients (n=10) and controls (n=10) were evaluated for baseline and post-topical capsaicin pain scores, and their tongue biopsies were immunostained for TRPV1, NGF, and neurofilament structural nerve markers and periphery. Nerve fibers penetrating the epithelium were less abundant in the BMS (p<0.0001), indicating ''small fiber neuropathy''. TRPV1-positive fibers were overall significantly increased in BMS (p=0.0011), as were NGF fibers (p<0.0001) and NGF staining of basal epithelial cells (p<0.0147). There was a significant correlation between baseline pain score and TRPV1 (p=0.0143) and NGF (p=0.0252) fibers. A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006).




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