For some time, environmental illness experts have proposed that abherrant functioning of nociceptors, specifically TRPV1 and TRPA1, may contribute to the development of multiple chemical sensitivity and other environmental illnesses including chronic fatigue immunodeficiency syndrome and fibromyalgia. To understand environmental illness, it is pertinent to investigate and understand the normal functioning of nociceptors and their influence in these conditions. In the following research blog, we will describe the interaction between nociception and other proteins, the process of their pain initiation and other symptoms and describe new areas of research of nocifense that contributes to neuronal inflammation and possibly cell death. We will also explore the reasons why experts believe nociceptors are important factors in the development of neurogenic inflammation and also how they contribute to other health conditions including obesity and diabetes. Lastly, we will justify the neuroprotective role of Nrf2 in environmental illness even though it is often ignored in the literature as an important factor and explore how oxidative stress that is associated with nociceptor activation also provides the signal for activation of Nrf2 genes under normal circumstances. (This blog provides a list of electrophiles and toxicants that were recently noted in a study and that activates the Nrf2.) However, as we have mentioned on numerous occasions, awry cell signalling can lead to reduced sensitivity, inhibitory and impaired responses by Nrf2 and its associated proteins.

First of all, we need to review details about the nociceptive mechanism to provide a good background and to further clarify the activation process. Many health experts now suspect the involvement of these receptors in the generation of multiple chemical sensitivity. Because of the diverse agents that can stimulate them and their numbers located in the brain and other organs, these receptors are believed to be the key to the development of inflammation from exposures to environmental hazards including those from pollution, particulate matter and chemical irritants. In a recent study, it was reported that both TRPV1 and TRPA1 are susceptible to exposure from pthalates and their activation results in contact hypersensitivity of the skin. (Shiba) Generally, common activators of these receptors include tissue damage, metabolic stress, ischemia, and inflammation. It has also been noted that they can be stimulated by IGF-1 and chronic activation of TRPV1 may play a role in the development of metabolic syndrome. (Liu)

The tissue distribution of nociceptive receptors are receptor specific and there are several of them and other ion channels have actions that are considered nociceptive-like. TRPV1 is located in a variety of tissues and has been the most studied of all the receptors. Thus far, TRPV1 has been found in the skin, gut, airways, epithelia, keratinocytes, endothelia and also located in nonneuronal cells and the central nervous system. The receptors in the CNS (astrocytes, microglia) are generally responsible for inflammation and neurogeneration. Genetics often plays a part in how responsive nociceptors are to environmental insults and their numbers in a specific tissue will reflect the level of pain experienced. Previously we described that increased nociceptive sensitization occurs when an increased number is translocated to a cell surface or there is a structural change in the receptor itself which increases the likelihood of activation at a lower threshold. Overexpression of TRPV1 usually results in an increased level of inflammatory cytokines and up-regulation leads to chronic pain states and “hyperinflammatory responses”.

According to Veronesi, the activation of these nociceptors occurs by a exposures to a variety of agents including chemical irritants, inflammatory mediators and tissue-damaging stimuli. The activation of these channels produce calcium and sodium influx and result in the release of neuropeptides including substance P, immune cell (ie macrophages) and mediate neurogenic inflammation which is most recognizable by swelling, pain and redness. Veronesi further describes that neurogenic inflammation leads to the release of other inflammatory cytokines in other cells including mast cells and immune cells on their own which contribute to the inflammatory cascade. (Veronesi)

Inflammation produces a number of chemicals that sensitize nociceptors to elicit pain and chronic activation of them can lead to neurotoxicity. It is important to consider that nociceptors are present in high amounts in the DRG, the spinal cord, the hypothalamus and the hippocampus. Therefore, it is safe to assume that chronic activation of nociceptors will exert their neurotoxic effects on these areas. In general, neurotoxicity occurs upon activation of nociceptors when Ca+ and Na+ floods into the cells which can result in accumulation of these ions. In addition, this process leads to Ca+ associated proteases and enzymes that can lead to destruction of the cytoskeleton and accumulation of Ca+ ions have on their own been associated with conditions such as dementia, PTSD, TBI, etc. Stephan Jordan explains in his presentation to the audience at the Summer Conference of National Assoc of Veteran’s Home when speaking about TBI and PTSD that such Ca+ accumulation causes a number of different physiological changes in cells including higher glucose metabolism increases intracellular lactate and reduction in cerebral blood flow, activation of NMDA and NA+/K+ loss, eventual damage to mitochondria, cellular apoptosis and inability for the neurons to form new connections. According to this author, Ca+ accumulation and axonal injury can lead to subsequent disconnections in neurons for days and weeks after injury and that the hippocampus is the most vulnerable to neuron injury. (Jordan) (For simplification we are discussing on the activation of TRPV1 and subsequent cellular ion influxes but as we noted earlier there are a variety of substances that excite nociceptive nerve endings that transmit a subsequent signal to the spinal cord and dorsal horn.)

Dr. Epstein, DVM explains that the termination of the nociceptive signal terminates in the dorsal horn and release molecules across other neurons, including glutamate which binds to AMPA. This allows NA+/K+ channels to open and transmit a signal to the brain. The author writes that if the signal is sustained and these channels stay open, the accumulation of intracellular NA+ leads to activation of nearby NMDA receptors resulting in intracellular accumulation of Ca+ leading to NMDA-associated neuropathic pain and hypersensitization. (Epstein) Park explains the Na+/Ca+ exchanger is responsible for Ca+ accumulation and overload in cells and in addition to environmental insults, structural changes occur over time in these channels which can make older adults and the aged more susceptible to intracellular accumulation of metabolites. (Park)

Chronic activation of TRPV1, nociceptors, and nociceptor-like channels that lead to accumulation of metabolites, NMDA and neuronal injury have been implicated in a number of diseases. Of course, some of the most common is the multitude of neurodegenerative diseases and those health conditions that are considered environmental illnesses. In addition, as more studies are done, more and more chemicals and irritants are shown to activate these channels that can initiate the cascade to chronic inflammation and neuronal injury. As we described earlier there are a variety of factors that determine the extent of injury and potential for disease. A few of these factors include the intensity or concentration of the stimulus, the length of time of exposure, the exposure agent and potentiating effects including genetics, stress and other environmental factors. One example that we have discussed at length in other blogs, is how catalase which is the major detoxifyer of hydrogen peroxide is inhibited by metals. Unfortunately, hydrogen peroxide is produced as a by-product of detoxification of phenols and also produced by processes in the mitochondria. Insuling resistance (Kim) and excessive amounts of H2O2 are produced as a consequence of mitochondrial dynsfunction and additional cellular stress by environmental insults potentiated by heavy metal inhibition on catalase production by nrf2 will increase H2O2 accumulation. It has now been shown that nociceptive activation is initiated by hydrogen peroxide and therefore, one may assume that accumulation of H2O2 from mitochondrial dysfunction or for any other reason that activates nociception can lead to neuronal injury or possible neuronal death. In one study, researcher’s determined H2O2 activated TRPA1 which led to an intracellular influx of calcium in the dorsal root ganglion and therefore concluded that ”TRPA1 nociceptors may be involved in pain sensation caused by H2O2.” (Sawada)

The list of activators for nociceptive defense seems to grow on a daily basis and there are literally thousands of chemicals that have not been tested for general safety, let alone if they can activate nociceptors or nociceptive-like channels that lead to inflammation and neurotoxicity. However, there are several that are now known activators of these channels and include ammonia and hydrogen sulfide. It has now been documented that xylene which is a known irritant and sensitizing agent activates TRPV afferents and contributes to neurogenic inflammation but the latter is independant of TRPV activation. (Sandor) Human airways have a particularly high number of nociceptive receptors and produce defensive behaviors that contribute to aggravating health conditions including “sleep apnea, coughing, mucus secretion and avoidance behavior.” Just a few of the chemicals that initiate such responses in airways include capsaisin, mustard, wasabi, hydrogen peroxide, chlorine, acrolein, nicotine, formaldehyde and cigarette smoke. Cigarette smoke contains over 5,000 chemicals so the exact stimulus from smoke that initiates nocifensive behavior is hard to define. (Simon)

There is a growing number of studies that provide evidence that in addition to neurodegenerative diseases, nociceptor activation contributes to other diseases or conditions which may cause disease. We noted recently a study that pointed out a strong relationship of obesity in participants to the bioaccumulation of 6 different environmental xenobiotics and stressed that obesity is an increased risk factor for diabetes and insulin resistance and the participants who were not obese had minimal amounts of bioaccumulation of those 6 environmental pollutants. (Gaby) Motter provides evidence TRPV may be a contributing factor for the development of obesity. For this reason we can suggest that chronic activation of nociception potentiates the consequences of bioaccumulation of harmful chemicals by changing the regulation of energy and metabolism (Motter) through the inhibition of PPAR-gamma. (Cioffi) Because insulin resistance and obesity are characteristics of metabolic syndrome and is fast becoming a public health concern, the importance of the relationship of chronic nociceptive activation on PPAR-gamma inhibition, obesity and bioaccumulation should not be overlooked.

A new study suggests that TRPA1 “confers a sensitivity to ultraviolet (UVA) light and generates painful and burning sensations. Further investigation showed that this sensitivity was attributed to oxidative stress generated by TRPA1 and was potentiated by the presense of intracellular iron. The author of this study made comments that pain from TRPA1 activation by UVA should be considered when experiencing discomfort from photodynamic therapy or cutaneous application of hydrogen peroxide. (Hill) Both photo therapy and hydrogen peroxide are used as alternative therapeutics in environmental illness.

Environmental pollution is a source that influences the chronic activation of TRPVand other nociceptors. An important study authored by N. Agopyan describes how particulate matter a contaminant of environmental pollution has become an important public health issue whereby exposure to it can lead to inflammation and neuronal loss. We have described how PM exacerbates a number of health conditions including respiratory and cardiovascular disease. Agopyan’s study mentions how PM is small enough to stay suspended for a long period of time and may contain metals, aromatic hydrocarbons, endotoxin and other chemicals that can effect the immune system. According to the researcher, the way that PM binds to cell surfaces contributes to PM-induced toxicity by activating ion channels and the consequent sustained calcium influx is a source for mitochondrial damage and neuronal apoptosis and for which antioxidants have no preventative effect. (Agopyan)

Recently we discusses the report of a study where ASIC3 channels contribute to chronic inflammation that leads to vasculitis and may be influential in symptoms in fibromylagia. Yen’s study shows that these channels participate in the “sub-acute-phase primary hyperalgesia in subcutaneous inflammation” (Yen) and Agopyan’s research has showed that PM chronically activates these receptors, in addition to TRPV1, and results in chronically-induced influx of calcium which as we have shown can lead to cell injury and death. In addition, his findings provide evidence that nociceptive activation and chronic calcium influx can also induce cell death by activating calcium-dependant proteases, lipases, and other proteins associated with apoptosis all of which are dependant on TRPV1. He notes PM activation of TRPV causes significant mitochondrial calcium accumulation and disruption in mitochondrial function in addition to the up-regulation of the expression of these receptors. In summary, this researcher concludes that “TRPV1 activation is the underlying mechanism of PM-induced apoptosis.” (Agopyan) Since air pollution is a consistent environmental concern which most individuals are exposed, one must consider PM as a regular source for exposure and toxicity.

As we have mentioned several times in other research posts, Nrf2 is a major gene promoter for over 100 enzymes and antioxidants for phase 1 and phase 2 detoxification. It has also been discovered that nrf2 controls many of the efflux transporters which are responsible for shuttling toxicants from inside cells to the outside to reduce the overall toxic load inside a cell. New research is providing evidence of the importance of nrf2 for protection of neurodegenerative diseases and has been implicated in having neuroprotective activities against Parkinson’s, amyotrophic lateral sclerosis , Friedreich’s ataxia, Alheimer’s disease and a variety of others. Nrf2 activation is dependant and inhibited by a number of factors. The inhibition, activation or delayed activation of nrf2 can be caused by fluctuations in insulin, mold, ethnically derived mutations, modulation by the AhR, and protein interactions that are closely associated with nrf2, such as keap1 and the ARE. Luo describes the initiating cellular events for the ARE through nrf2 as an alkalization of keap1 by reactive species and xenobiotic electrophiles. (Luo) In simpler terms, keap1 acts somewhat like a molecular sensor for activities in cells which could cause harm and activation of “nrf2 -ARE leads to the increased resistance to oxidative stress and mitochondrial dysfunction and neuroprotection from toxic insults such as mitochondrial complex 1 &2 inhibitors, glutamate, hydrogen peroxide and increased cellular calcium which can be generated from, as we have just seen, activation of the nociceptive signalling pathway. Johnson explains that nrf2 deficiency increases cell death in neurons and its neural protective effect is achieved through a mechanism associated with astrocytes and is probably the reason why upregulation of nrf2 protects against Parkinson’s-like neural behavior. In addition, this research shows nrf2-ARE activation in astrocytes provides neural protection from glutamate and hydrogen peroxide through glutathione secretion that protects cortical and motor neurons. This researcher’s recent research shows that Nrf2 causes astrocytes to synthesize glutathione which motor neurons use to synthesize their own glutathione and therefore they participate in protecting themselves from oxidative damage. While Johnson’s research involves ALS patients and currently believes their condition is associated with a mutation in SOD, these breakthroughs have exciting implications for anyone with antioxidants depletion “issues” or neuronal injury. In mice, Johnson has demonstrated how nrf2 can be manipulated to reduce complications associated with neurodegenerative diseases and has been found to be a “glutathione booster” and improves glutathione recycling through an efflux transporter. We recently reported a Stanford researcher announced that glutatione depletion could be considered as a biomarker for mitochondrial dysfunction (Stanford) and considering the recent advances in knowledge of the ability of nrf2 to boost glutathione this news offers hope and supporting evidence to anyone with a health condition associated with mitochondrial dysfunction, the creation of effective therapies may be on the horizon. These findings no doubt will impact patients that suffer from any number of illnesses where mitochondria dysfunction and oxidative overload are characteristic including conditions such as neurdegerative disease, fibromyalgia, chronic fatigue immunodeficiency, ischemia, in addition to numerous others.

Notes:

PPAR-gamma protects the brain against neuroinflammation and can prevent brain damage from neuropsychological insults. (Garcia-Bueno)

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Luo, Y., Eggler, A. L., Liu, D., Liu, G., Mesecar, A. D., and van Breemen, R. B. (2007). Sites of alkylation of human keap1 by natural chemoprevention agents. Journal of the American Society for Mass Spectrometry, 18(12):2226-2232. http://www.citeulike.org/user/HEIRS/article/4038229

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Shiba, T., Maruyama, T., Kurohane, K., Iwasaki, Y., Watanabe, T., and Imai, Y. (2009). Trpa1 and trpv1 activation is a novel adjuvant effect mechanism in contact hypersensitivity. Journal of neuroimmunology. http://www.citeulike.org/user/HEIRS/article/4037169

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