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Molecular Mechanisms of Nociception
Published in Gary W. Jay, Chronic Pain, 2007
Agonists of the TRPV1, such as capsaicin, will also induce an analgesic effect after an initial excitatory response. The vanilloid system plays in important role in inflammatory hyperalgesia. TRPV1 antagonists such as capsazepine can prevent thermal hyperalgesia in animal carrageenan or Complete Fruend’s Adjuvant models in mice. The analgesic effects of capsaicin appear to be enhanced during inflammation (44). It is felt that capsaicin induces desensitization by stimulating the TRPV1 receptors, which would induce the output of algetic chemicals such as SP and CGRP. When this has been done repeatedly, the amount of colocalized and other algetic chemicals induced by capsaicin from the free C-fiber nerve endings decreases and desensitization occurs (44).
What Is Sensitive Skin?
Published in Golara Honari, Rosa M. Andersen, Howard Maibach, Sensitive Skin Syndrome, 2017
Renée J. H. Richters, Natallia E. Uzunbajakava, Piet E. J. van Erp, Peter C. M. van de Kerkhof
Sensitive skin has a predominantly subjective character, as stinging, burning, itching, and sensations of tightness are reported, implying that the neurons of subjects with a sensitive skin dysfunction easily respond to mild stimuli. Stander et al. also addressed the role of the neural system and neuromediators in skin sensitivity (60). Differences in pain perceptions were observed in subjects with sensitive skin by functional magnetic resonance imaging (46). Skin discomfort induced by lactic acid leads to the activation of different parts of the cerebral cortex. Quatresooz et al. also measured the electrical current perception threshold (CPT) in subjects with reactive and nonreactive skin and concluded that some subjects with reactive skin and a lower CPT showed a higher density of mast cells in the dermis (54). This is in line with the findings of Kim et al., who detected a lower CPT to 5 Hz electric current on the forearm in subjects with sensitive skin compared to CPT in subjects with nonsensitive skin (38). Five hertz is a selective stimulator of the C fibers of sensory nerves (38). C fibers are unmyelinated fibers playing a role in the perception of pain, itch, and warmth. Additionally, an inverse correlation was shown between the clinical detection thresholds of capsaicin and sensitive skin indexed by questionnaire (61). When the skin comes in contact with capsaicin, noxious heat, or low pH, transient receptor potential vanilloid 1 is activated (62,63) and results in nociceptor-mediated burning pain. An overexpression of this receptor could play a key role in the pathomechanism of sensitive skin, as inhibition results in reduced burning sensation following capsaicin application (64).
A review of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, for the treatment of peripheral neuropathic pain
Published in Expert Opinion on Pharmacotherapy, 2021
Jitsu Kato, Teruyoshi Inoue, Mizuka Yokoyama, Masanori Kuroha
Current systemic treatment options for NeP include Ca2+ channel α2δ ligands, TCAs, SNRIs, tramadol, and strong opioids [23,36]. For many patients, the efficacy of these treatment options is limited and can be associated with a range of adverse effects [37]. Although some potential pharmacological candidates, including cannabis-deprived compounds and transient receptor potential vanilloid 1 antagonists, have proved effective for the treatment of NeP in phase 3 clinical studies, further evaluations are needed [38]. The guidelines for the pharmacologic management of NeP published by the Japan Society of Pain Clinicians recommended pregabalin, gabapentin (this drug is not approved for NeP in Japan, but NeP patients could claim insurance reimbursement for gabapentin), duloxetine, amitriptyline, nortriptyline, and imipramine as drugs for NeP in 2016 [1]. Mirogabalin was added as a drug that can be used for P-NeP in 2019 [39]. Mirogabalin was launched in Japan, with the reported sales to be approximately 8 billion Japanese yen between April, 2020 and March, 2021, whereas in Taiwan and Korea, mirogabalin was approved in 2020 but they are still preparing for its launch in their markets.
Protective Effects of Dietary Capsaicin on the Initiation Step of a Two-Stage Hepatocarcinogenesis Rat Model
Published in Nutrition and Cancer, 2021
Luis Manuel Sarmiento-Machado, Guilherme Ribeiro Romualdo, Joyce Regina Zapaterini, Mariana Baptista Tablas, Ana Angélica Henrique Fernandes, Fernando Salvador Moreno, Luís Fernando Barbisan
In the past few years, the potential of dietary CPS to act as a chemopreventive agent was widely postulated and reviewed. Herein, we unveiled the molecular events of the pretreatment with CPS on DEN-induced carcinogenic injury (week 3) and their potential implications on the preneoplastic lesion in a later timepoint (week 12). Noteworthy, the estimated CPS intake in rats (2.4 and 4.9 mg/rat/day) resembled human consumption of this vanilloid from Capsicum genus plants. The 0.02% CPS dietary intervention showed more pronounced results than 0.01% CPS pretreatment. In summary, 0.02% CPS decreased oxidative stress (lipid hydroperoxide levels) by inducing antioxidant GSH-axis at week 3. Reduced oxidative damage at this timepoint led to decreased ALT serum levels and proinflammatory CD68+ macrophage infiltration in centrilobular areas. In addition, 0.02% CPS intervention induced Trpv1 and upregulated anti-inflammatory epoxygenase Cyp2j4 and liver regeneration-related Grb2 gene. At the late timepoint (week 12), 0.02% CPS reduced the number of GST-P-positive preneoplastic foci development. Differently from previous hepatocarcinogenesis bioassays (23,24), our work shed light on some of the anti-initiating molecular events and modifying effects involved CPS-mediated attenuation of chemically-induced hepatocarcinogenesis. Thus, the inhibition of DEN-induced oxidative damage is proposed as the primary protective effect of CPS on the initiation stage of hepatocarcinogenesis.
A patent review of transient receptor potential vanilloid type 1 modulators (2014–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Mengkang Gao, Yusui Wang, Lanqi Liu, Zhenrui Qiao, Lin Yan
Early studies were mainly focused on the development of TRPV1 agonists as analgesics. In-depth study found that systemic administration of capsaicin (CAP, a pungent ingredient of chili peppers) and resiniferatoxin (RTX, an ultrapotent capsaicin analogue) failed to separate analgesic and adverse effects. Therefore, many clinical trials of agonists have been focused on topical or local administration strategies, and some analgesic creams, patches, and site-specific injections containing capsaicin as the active agent have been launched on the market to treat neuropathic pain [7] including post-herpetic neuralgia [8] and diabetic neuropathy [9], etc. After capsaicin treatment, the expression of pro-algesic substances (such as SP) was down-regulated, while endogenous analgesic peptides (such as galanin and somatostatin) were increased. The main mechanism of its analgesic effect was referred to as ‘vanilloid-induced messenger plasticity’ [3,10]. However, the initial transient irritation and the desensitization to various noxious stimuli caused by constant activation of channels are the main obstacles to the development of TRPV1 agonists. Therefore, some pharmaceutical companies have shifted the focus of drug research and development to TRPV1 antagonists.