TRPV1 and Nrf2 Activities Effect Fibromyalgia Pain and Neuropathy!

Activation of TRPV1 receptors has been associated with fibromyalgia-type pain (1) and the pain in peripheral neuropathy.  In one review the author writes that with new technology, the TRPV1 receptor has been  found in all ports of entry to the body including the skin, lung and the gut. In addition, they are found in regions of the brain, major organs and the cells responsible for inflammation and neurodegeneration.  They are activated by a number of things including inflammatory mediators, capsaicin, endogenous ligands, high temperature and acidic pH. The activation of TRPV1 produces a response by a variety of cells which may include neurogenic inflammation that in turn, produces the pro-inflammatory mediators such as TNF-a, Il-1b, Il-6 and others. It has also been reported that TNF-a can enhance its expression leading to more pain sensation. (2) The widespread distribution of TRPV1 suggests that it is the key to inflammation caused by environmental chemicals and responsible for airway hyperactivation and inflammation to chemical irritants and airborne pollutants, such as ozone and particulate matter. Because this receptor is a common responder to numerous toxicants it may explain how pollutants and inhaled substances can cause respiratory dysfunction by environmental contaminants. (3)

With so many targets of TRPV1 function, it has been a focus for pharmacological intervention for a number of health conditions. Also, studies have demonstrated that natural flavonoids, which are found in fruits and vegetables, can alter the behavior of TRPV1.  These actions include reducing inflammatory pain, cytokine production and oxidative stress.  Pinko-Ribeiro describes how a flavonoid, hesperidin methyl chalcone (HMC) in citrus , acts on TRPV1 to do all three. According to this author, it "inhibited pain-like behavior induced by varied stimuli, which include acetic acid, PBQ, formalin, capsaicin, CFA and carrageenan, and also the biomarkers of tissue inflammation such as oxidative stress, leukocyte recruitment, cytokine production and NF-κB activation." Further, he also noted that they are "different in chemical nature to induce the inflammatory response, they share some of the same mechanisms that may explain the broad protective activity of this flavonoid." (4) Curcumin, another phenol, inhibits pain hypersensitivity by blocking TRPV1 signals. (5)   

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The communication of TRPV1 is bi-directional with Nrf2. Capsaicin, is a phytochemical that activates TRPV1.  Then TRPV1 mediates expression of nitic oxide synthase (eNOS), uncoupling protein 2 (UCP2), KLF2, PPARdelta, PPARgamma, and LXRα, nrf2-responsive antioxidant enzymes, while decreasing expression of proinflammatory proteins. Capsaicin has been found to have health benefits on a number of diseases in studies such as atherosclerosis, metabolic syndrome, diabetes, obesity, non-alcoholic fatty liver, cardiac hypertrophy, hypertension and stroke risk. (6)Incidentally, all of these diseases present with higher levels of oxidative stress and are positively influenced by Nrf2 expression. In another study, the Nrf2 pathway activation by sulphoraphane from broccoli inhibited TRPV1 expression, reduced oxidative stress and protected mitochondrial function preventing peripheral neuropathy caused by chemotherapy drug oxalplatin. (7) 

1.  Analgesic Effect of Electroacupuncture in a Mouse Fibromyalgia Model: Roles of TRPV1, TRPV4, and pERK. PloS one, Vol. 10, No. 6. (2015) by Jaung-Geng G. Lin, Ching-Liang L. Hsieh, Yi-Wen W. Lin

2.Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain. Oncology letters, Vol. 15, No. 4. (April 2018), pp. 5013-5019 by Ying Wang, Chenyang Feng, Haoying He, et al.

3. The TRPV1 receptor: target of toxicants and therapeutics. Toxicological sciences : an official journal of the Society of Toxicology, Vol. 89, No. 1. (January 2006), pp. 1-3, doi:10.1093/toxsci/kfj034 by Bellina Veronesi, Marga Oortgiesen

4. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB. Chemico-biological interactions, Vol. 228 (25 February 2015), pp. 88-99 by Felipe A. Pinho-Ribeiro, Miriam S. Hohmann, Sergio M. Borghi, et al.

5.Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. Journal of dental research, Vol. 89, No. 2. (February 2010), pp. 170-174 by K. Y. Yeon, S. A. Kim, Y. H. Kim, et al.

6.. Capsaicin may have important potential for promoting vascular and metabolic health. Open heart, Vol. 2, No. 1. (2015) by Mark F. McCarty, James J. DiNicolantonio, James H. O'Keefe

7. Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. Free radical biology & medicine, Vol. 120 (20 May 2018), pp. 13-24 by Yang Yang, Lan Luo, Xueting Cai, et al.