Difference between revisions of "7° Klinischer Fall: Hirnstammneoplasie bei orofazialen Schmerzen"

In the rare but real clinical cases in which the ' <math>\tau</math> Demarcator' is reset, we are motivated to carry out an even more extensive and in-depth check, hypothesizing serious pathologies <ref>Chloé Gibeili, Arek Sulukdjian, Audrey Chanlon, Nathan Moreau. Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour. BMJ Case Report.. 2022 Apr 12;15(4):e249408.doi: 10.1136/bcr-2022-249408.

</ref> including head and neck tumors which simulate symptoms that can be superimposed on other pathologies. It is a serious mistake to consider the patient with such clinical manifestations and the simultaneous absence of systemic anomalies as a patient with psychosomatic disorders. Elements of psychophysical damage can certainly coexist but, if the 'Demarcator' fails, it is mandatory to deepen the diagnostics. In fact, head and neck cancer (HNC) affects over 890,000 people each year worldwide and has a 50% mortality rate. Aside from poor survival, HNC pain impairs eating, drinking and speaking, severely reducing quality of life. The different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between tumors<ref>'''Advances''' in '''Head''' and '''Neck''' '''Cancer''' '''Pain'''.

Ye Y, Jensen DD, Viet CT, Pan HL, Campana WM, Amit M, Boada MD.J Dent Res. 2022 Aug;101(9):1025-1033. doi: 10.1177/00220345221088527. Epub 2022 Apr 13.PMID: 35416080 </ref>. Glial and immune modulation of the tumor microenvironment, as well explained in the article by [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305840/ '''Ye et al.'''], influences not only cancer progression but also pain signaling among which transient receptor potentials contained in gustatory somatosensory systems are an example.<ref name=":0">Ramsey, I.S., M. Delling, and D.E. Clapham. 2006. An introduction to TRP channels. Annu Rev Physiol, 68: 619–647.</ref><ref name=":1">Julius, D. 2013. TRP channels and pain. Annu Rev Cell Dev Biol, 29: 355–584.</ref>

<center>

File:Capsaicina.jpg|'''Figura 7:''' Axial section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame

File:Capsaicina 1.jpeg|'''Figura 8:''' Coronal section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame

{{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===

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]]]]

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.  

=====Ligands=====

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=====

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.  

An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A) a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.

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.

TRPV1 is activated by several agonists of natural origin. 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 TRPV1-mediated release of inflammatory molecules following administration. exposure to noxious stimuli.  

{{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).

{{Q2|We are sure we know everything|}}{{bib}}