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Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
TRPV1 (also known as VR1) is the founding member of thermosensitive TRP channels that enables primary polymodal nociceptors to detect ambient temperature changes (>43°C) (15,17–20). In addition, TRPV1 can be activated by capsaicin, a principal pungent component of peppers, low pH, and numbers of molecules associated with inflammation and tissue damage, such as bradykinin, prokineticin, prostaglandins, anandamide, and retinoids (20–25). TRPV1 majorily marks a population of unmyelinated, slowly conducting neurons (C-nociceptor) that express neuropeptides substance P, neurokinin A, and calcitonin gene-related peptide and constitute approximately 30%–50% of all sensory neurons situated in the rodent sensory ganglia (19,26). TRPV1 functions as a polymodal receptor for noxious heat, pain, and itch (26,27). Previous researches have extensively investigated the functions of TRPV1 in acute and chronic pain. Current evidence suggests that TRPV1 also plays an important role in both acute and chronic itch conditions.
Basic Thermal Physiology: What Processes Lead to the Temperature Distribution on the Skin Surface
Published in Kurt Ammer, Francis Ring, The Thermal Human Body, 2019
Six thermo-transient receptor potentials (TRPs) have been characterized to date: TRP vanilloid (TRPV) 1 and 2 are activated by painful levels of heat with thresholds ≥42°C and ≥52°C, respectively. TRPV 1 can be expressed by capsaicin, the active ingredient in chilli peppers, also by EtOH allicin, an alcoholic extract from garlic. Camphor, low (acidic) pH-value, lipoxygenase, resiniferatoxin and an andamide act as agonists to temperature on TRPV1 expression. TRPV1 can be found in peripheral thermoreceptors located in the skin, tongue and the peripheral nerve system, but are also available in the bladder, the spinal cord and the brain.
Pruritus Ani
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Shahab A. Siddiqi, Arifa M. Siddika
Several other receptors are involved in processing of pruritus, including the endothelin-A receptor, proteinease-activated receptors and Toll-like receptors.7 Transient receptor potential (TRP) channels have a crucial role in the processing of pain and itch, especially TRPV1, the capsaicin receptor. TRPV1 is required for the transmission of histamine-dependent itch at multiple levels. TRPV1 also modulates other receptors in the histamine-dependent and histamine-independent pathways. Initial case series suggested that capsaicin has a beneficial effect in the treatment of itch and pain. However, the results of controlled trials in pain management are less convincing. The same likely applies to itch, probably because processing of pruritus is more complex than was once thought. TRPV1 antagonists have been studied, but none of these have progressed beyond Phase II clinical trials due to either lack of a therapeutic effect or side effects.7
Pharmacological approaches to treat intestinal pain
Published in Expert Review of Clinical Pharmacology, 2023
Mikolaj Swierczynski, Adam Makaro, Agata Grochowska, Maciej Salaga
Among TRP channels, the TRPV1 (also known as capsaicin receptor) has the best recognized involvement in intestinal pathological conditions and visceral pain, especially in IBD and IBS [91]. TRPV1 is mainly expressed in extrinsic primary afferents of neurons, which are mainly present in submucosal (Meissner) plexus within gastrointestinal tract [92]. Mechanistically, it is a nociceptive ligand-gated ion channel with high permeability to calcium (Ca2+) ions [93], however its functionality also comprises thermal, mechanical, voltage and chemosensivity [94]. Because of the nonselectivity of TRPV1, it can be activated by a variety of stimuli including biochemical ligands (including prostaglandins PGE2, PGI2, proinflammatory cytokines, chemokines, serotonin or histamine) and physicochemical environmental conditions (like temperature over 42°C, acidic environment, osmolarity alternations or voltage) with inflammation-related factors found in both categories.
Emerging therapies for dry eye disease
Published in Expert Opinion on Emerging Drugs, 2021
Lauren Mason, Saad Jafri, Isabelle Dortonne, John D Sheppard
Novel agents to target enzymes involved in the DED inflammatory cascade are also being developed. One of these, TOP1630, is a narrow-spectrum kinase inhibitor (NSKI). This class of drug is able to target multiple kinases involved in both innate and adaptive immune cell signaling, mainly mitogen activated protein kinase (MAPK) p38α, spleen tyrosine kinase (Syk), and Src family kinases (SFK), including Src and lymphocyte-specific protein tyrosine kinase (Lck) [86]. Short interfering RNA (siRNA) agents, such as SYL1001, are also in development to treat symptoms of DED. The siRNA target is transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is involved with pain sensation and inflammation modulation [87]. Isolation of specific anti-inflammatory or tear producing peptide biologics such as lacritin and thymosin B4 for treatment of DED is also being done, with promising results [88,89].
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Given the important role of TRPV1 in pain transduction and the side effects exhibited by known TRPV1 modulators, novel strategies to modulate its dysfunctional activity are particularly eagerly pursued. An interesting approach is the development of TRPV1 antagonists that can be dermally deactivated in a predictable and controlled way after having exerted their biological activity, the so-called soft drugs [95]. This strategy has been used in the design of capsaicinoid-based molecules that undergo dermal deactivation, thus preventing their long-term dermal accumulation [96]. Compound 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529, AntalGenics) is currently in pre-clinical trials with the expectation to enter in a Phase I/IIa clinical trial in the first quarter of 2021 as a topical anti-pruritic and anti-inflammatory medication.