Biological factors involved in sensory responses to chemesthetic stimuli
Open Access
- Author:
- Nolden, Alissa Allen
- Graduate Program:
- Food Science
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 23, 2016
- Committee Members:
- John E Hayes, Dissertation Advisor/Co-Advisor
John E Hayes, Committee Chair/Co-Chair
Kathleen Loralee Keller, Committee Member
Joshua D Lambert, Committee Member
Sheila Grace West, Outside Member - Keywords:
- capsaicin
ethanol
TRPV1
bitter
burn
psychophysics
TAS2Rs - Abstract:
- Chemesthetic agents consist of chemical compounds known to activate receptors involved with pain, touch and thermal perception, such as warming, cooling, stinging, pricking, burning and buzzing. Many chemesthetic agents are regularly consumed, including capsaicin, ethanol, menthol, mustard oil, cinnamonaldehyde, and piperine. Psychophysical responses to these compounds have been well investigated in terms of chemesthetic sensations (e.g. the burn of capsaicin); however, little is known regarding their secondary qualities, mainly taste responses. The first section of this dissertation will explore the chemesthetic and taste sensations from capsaicin and ethanol. Both of these stimuli are consumed regularly, with capsaicin being the active ingredient in chili peppers while ethanol is a key component in alcoholic beverages, both of which are widely used by numerous peoples around the world. Psychophysical response to these compounds is known to vary greatly across concentrations and individuals. Here, I will establish dose response functions for both ethanol and capsaicin, reporting on both burning and bitterness response to these stimuli. I will then take two different approaches to investigate individual differences in bitterness response. The first approach will explore single nucleotide polymorphisms (SNPs) in bitter taste receptor (TAS2Rs) and transient receptor potential vanilloid (TRPV1) genes. Multiple bitter compounds are known to vary in the bitterness they evoke due to variability within bitter taste receptor genes (TAS2Rs). Whether similar effects are seen for TRPV1 agonists will be tested here. Second, I will explore the influence of prior experience with and exposure to these stimuli on the sensations they evoke, as differences in response to capsaicin and ethanol have been attributed to intake frequency of chili peppers and alcohol, respectively. Several theories have been proposed in order to explain reduced responses, including differences in scale usage due to dissimilarities in prior experience, greater familiarity with the compound or, genetic variability in chemosensory receptors. For ethanol, the difference in response will be explored across consumption, but additional research is needed to investigate the mechanism further. In the case of chili pepper intake, reduced responses to capsaicin are widely believed to be due to hypoalgesia or desensitization. Numerous studies show that perceptual responses to capsaicin are reduced following repeated intermittent exposure to a constant concentration; this phenomenon is commonly known as capsaicin desensitization, but is more accurately called hypoalgesia. Hypoalgesia to capsaicin, and other compounds (e.g. menthol and zingerone) is thought to be unique to chemesthetic agents. Hypoalgesia can be conceptualized as being acute or chronic, depending on the duration of reduced response, with acute hypoalgesia occurring within a test session while chronic hypoalgesia lasts across days. Here, we are interested in the effects of repeated capsaicin exposure, and the development of chronic capsaicin hypoalgesia. There are several purported mechanisms that may result in acute hyperalgesia, including depletion of substance P and calcium ions. However, there is a gap in the literature regarding the mechanism(s) that result in chronic capsaicin hypoalgesia. To gain insight into the mechanism(s) leading to chronic capsaicin hypoalgesia, I investigate the mRNA expression of TRPV1. TRPV1 is activated by both capsaicin and ethanol, along with other exogenous and endogenous compounds. I describe the variability of TRPV1 expression in human oral tissue as a function of capsaicin exposure, which may provide an explanation for chronic capsaicin hypoalgesia. These results have the potential to translate to human health, as patients with oral cancer and burning mouth syndrome are known to have increased mRNA expression of TRPV1 in lingual tissues. Understanding this mechanism of hypoalgesia and TRPV1 regulation may help to inform future treatments to reduce TRPV1 expression and possibly reduce inflammation and pain. This dissertation is focused on extending our knowledge of the psychophysical response to chemesthetic stimuli and exploring the effects of repeated exposure on perception. Here, I investigate how individual differences in response to stimuli associate with prior intake along with genetic variability in chemosensory receptors. I evaluate TRPV1 mRNA expression in humans and explore whether variability in expression is associated with capsaicin response and development of capsaicin hypoalgesia. To do so, the dissertation is broken down into four aims, which are detailed here. The first aim is to determine the response to capsaicin and ethanol across a wide range of concentrations. Developing a dose response curve for these two stimuli is important in order to determine appropriate concentrations for subsequent research. These stimuli were examined for their variability in burn and bitterness responses, while also exploring whether reported intake of foods containing these compounds is associated with their perception. The second aim is to explore the relationship between the variability of the reported burn and bitterness of sampled ethanol and individual’s genetic differences in TRPV1 and TAS2Rs. My findings complement prior work showing a relationship between alcoholic beverage intake and genetic variability in TAS2Rs by providing novel data on the variation of sensations from ethanol with TAS2R SNPs. This is also the first report linking differences in ethanol sensations to variability in the TRPV1 gene. The third aim is to determine the extent of the effects of repeated capsaicin exposure on the perceptual responses to capsaicin. This will be evaluated i) by measuring self-reported intake free-living individuals and ii) in controlled experiments where participants are systemically and repeated exposed to capsaicin. The development of a robust capsaicin exposure protocol is essential to achieving our fourth aim. This is the first evidence of chronic hypoalgesia after participants rinsed with low concentrations capsaicin for two weeks. The fourth aim is to determine if capsaicin hypoalgesia, brought on by either dietary chili pepper intake or controlled repeated capsaicin exposure, is associated with a decrease in TRPV1 expression. The relationship between capsaicin exposure and TRPV1 expression will be explored in two different studies, the first will use free-living participants and collect self-reported intake of chili peppers, and the second will use a laboratory controlled exposure protocol. These experiments will explore the relationship between TRPV1 mRNA expression with the perceived burn of sampled capsaicin and the effects of capsaicin exposure. The second study will be designed to measure the change in expression following repeated oral exposure to capsaicin, in order to determine if the development of hypoalgesia is associated with a down-regulation or decrease in TRPV1 expression. This will be one of the first studies to explore the effects of dietary exposure on expression of chemosensory receptors, and the first related to capsaicin and the TRPV1 receptor. The findings from this dissertation have the potential to influence multiple areas of inquiry. For example, the dose response curves generated from aim one can influence development and design of sensory studies exploring responses from chemesthetic agents. Aims 3 and 4 have the potential to inform the development of new therapies or treatment options for patients with oral pathologies associated with altered TRPV1 expression, including burning mouth syndrome or oral cancer. Furthermore, these findings may provoke additional research in other systems and organs that could impact other chronic inflammatory diseases such as irritable bowel syndrome. This work has strong public health relevance, as TRPV1 is involved with the inflammation pathway, inflamed tissues express increased levels of TRPV1, and chronic inflammation is associated with seven of the top ten leading causes of mortality in the United States.