TRPA1 & Kava's Skin Effects
Today’s fact of the day will be diving into a topic known as TRP channels. TRP stands for “transient receptor potential”. These channels allow the influx of calcium into the cell and play an intricate role in the sensing of pain, irritation, hot and cold sensation, inflammation, mucous secretion, coughing and sneezing. They are part of a receptor family known as “nociceptors”. We’re going to be focusing on one of these receptors, TRPA1. The TRPA1 receptor is a target of the mediators that promote inflammatory pain in the nervous system [1]. Cinnamic acid and its derivatives were seen to act as an agonist at this TRPA1 nociceptor.
What is a nociceptor?
A nociceptor is a sensory receptor that is activated by noxious stimuli that damage or threaten the body’s integrity [2]. Nociceptive pain arises from tissues damaged in a physical, or chemical way. These receptors activate at certain temperatures, and certain pressures to trigger a response [3]. In short they’re pain receptors. They are a means of neural feedback to the body. A common reference to this is when dealing with pain relieving compounds. They are known as antinociceptives, and block pain.
What is TRPA1?
TRPA1 is defined as the thermoreceptive (temperature sensitive) transient receptor potential ankyrin. These sit at the ends of nociceptive nerve fibers. It’s calcium permeable and allows calcium ions into the cell. Ankyrins may seem difficult to grasp, but an easy way to remember its location is by looking at the greek word from which it is derived, ankyra, which translates to “anchor”. Ankyrins anchor ion channels among other transport mechanisms to the plasma membrane of the cell [4]. When this receptor is activated it tells the neuron to fire an action potential which is then processed as a pain or sensory signal by the body.
What is a TRPA1 agonist?
Any TRPA1 agonist is a chemical that binds to the receptor, and stimulates a biological response. Agonists cause action, where antagonists cause inaction, and block the action of the agonist [1]. Agonists in regards to the topic of today’s post will be those chemicals that activate this TRPA1 receptor. TRP channel agonists include common food items such as olive oil, horseradish, hot peppers and cinnamon. Cinnamic acid is a known TRPA1 agonist and will be the focus here.
What is cinnamic acid?
Cinnamic acid is an organic compound classified as an unsaturated carboxylic acid. It occurs in a number of plants naturally. This compound is mostly obtained from the oil extract of cinnamon [5]. Cinnamic acid and derivatives are not spoken about much in research papers with kava, however they have been identified as constituents of kava by means of chemical separation as cinnamic bornyl ester, and 3,4-methylenedioxy cinnamic acid [6,7]. These chemicals are important because they have been found to activate the TRPA1 receptor in a dose dependent manner [8].
What does this have to do with kava?
The hypothesis I’m making here is that a constituent of kava, cinnamic acids and derivatives, not the kavalactones, may be involved with feeling cold, the itch, and possibly even dermopathy in regards to kava consumption. It was seen that extracts of kava (aqueous and solvent based) promote proinflammatory responses from mast cells where individual kavalactones did not [9]. This study also noticed calcium influx that could not be explained by kavalactones. This was left open ended as the study was unable to uncover what part of aqueous extracts caused this proinflammatory response in mast cells. Coincidentally, the influx of Ca+ is exactly how the TRP channels operate [10]. More research is needed, but here I postulate that the influx of calcium in mast cells can possibly be explained by cinnamic acid and derivatives attaching to and activating TRPA1. It was found that by blocking TRPA1, they could prevent the degranulation of mast cells and thus reduce allergic skin effects [11]. This would explain the itch and dermatologic reactions such as dermopathy, as well as the cold feeling when TRPA1 is activated in areas outside that of the mast cell.
Summary:
We’ve routinely seen, and personally experienced, the itch and skin effects associated with drinking kava. It’s still up in the air as to what exactly causes these issues, but today I theorize that it’s NOT the kavalactones themselves, but a lesser known part of kava known as cinnamic acid. Cinnamic acid is known to attach to and activate receptors known as “nociceptors” or pain/temperature receptors. These receptors are found on mast cells (cells involved with release of histamines) as well as in many other areas of the body. When these are activated it causes influx of calcium into the mast cell as well as activating these receptors. This may speak to the negative skin reaction such as itch and kava skin as well as may be tied to the cold feeling many kava drinkers report. More research in this area is needed to confirm my hypothesis, however this gives us one more avenue to search in regards to the skin effects with kava.
[1] Mihara, Satoru, and Takayuki Shibamoto. 2015. “The Role of Flavor and Fragrance Chemicals in TRPA1 (transient Receptor Potential Cation Channel, Member A1) Activity Associated with Allergies.” Allergy, Asthma, and Clinical Immunology: Official Journal of the Canadian Society of Allergy and Clinical Immunology 11 (1): 11.
(https://doi.org/10.1186/s13223-015-0074-0)
[2] Messlinger, K. 1997. “[What is a nociceptor?].” Der Anaesthesist 46 (2): 142–53.
(https://doi.org/10.1007/s001010050384) (In German)
[3] Talavera, Karel, Justyna B. Startek, Julio Alvarez-Collazo, Brett Boonen, Yeranddy A. Alpizar, Alicia Sanchez, Robbe Naert, and Bernd Nilius. 2020. “Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease.” Physiological Reviews 100 (2): 725–803.
(https://doi.org/10.1152/physrev.00005.2019)
[4] Wikimedia Foundation. (2021, February 2). Ankyrin. Wikipedia.
(https://en.wikipedia.org/wiki/Ankyrin)
[5] Wikimedia Foundation. (2021, March 21). Cinnamic acid. Wikipedia.
(https://en.wikipedia.org/wiki/Cinnamic_acid)
[6] Xuan, Tran Dang, Masakazu Fukuta, Ao Chang Wei, Abdelnaser Abdelghany Elzaawely, Tran Dang Khanh, and Shinkichi Tawata. 2008. “Efficacy of Extracting Solvents to Chemical Components of Kava (Piper Methysticum) Roots.” Journal of Natural Medicines 62 (2): 188–94.
(https://doi.org/10.1007/s11418-007-0203-2)
[7] Wu, Di, Muraleedharan G. Nair, and David L. DeWitt. 2002. “Novel Compounds from Piper Methysticum Forst (Kava Kava) Roots and Their Effect on Cyclooxygenase Enzyme.” Journal of Agricultural and Food Chemistry 50 (4): 701–5.
(https://doi.org/10.1021/jf010963x)
[8] Sadofsky, Laura R., Andrew N. Boa, Sarah A. Maher, Mark A. Birrell, Maria G. Belvisi, and Alyn H. Morice. 2011. “TRPA1 Is Activated by Direct Addition of Cysteine Residues to the N-Hydroxysuccinyl Esters of Acrylic and Cinnamic Acids.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 63 (1): 30–36.
(https://doi.org/10.1016/j.phrs.2010.11.004)
[9] Shimoda, Lori M. N., Christy Park, Alexander J. Stokes, Henry Halenani Gomes, and Helen Turner. 2012. “Pacific Island ’Awa (Kava) Extracts, but Not Isolated Kavalactones, Promote Proinflammatory Responses in Model Mast Cells.” Phytotherapy Research: PTR 26 (12): 1934–41.
(https://doi.org/10.1002/ptr.4652)
[10] Freichel, Marc, Julia Almering, and Volodymyr Tsvilovskyy. 2012. “The Role of TRP Proteins in Mast Cells.” Frontiers in Immunology 3 (June): 150.
(https://doi.org/10.3389/fimmu.2012.00150)
[11] Kang, Jun, Yong Ding, Baizhan Li, Hong Liu, Xu Yang, and Mingqing Chen. 2017. “TRPA1 Mediated Aggravation of Allergic Contact Dermatitis Induced by DINP and Regulated by NF-κB Activation.” Scientific Reports 7 (February): 43586.
(https://doi.org/10.1038/srep43586)
Today’s fact of the day will be diving into a topic known as TRP channels. TRP stands for “transient receptor potential”. These channels allow the influx of calcium into the cell and play an intricate role in the sensing of pain, irritation, hot and cold sensation, inflammation, mucous secretion, coughing and sneezing. They are part of a receptor family known as “nociceptors”. We’re going to be focusing on one of these receptors, TRPA1. The TRPA1 receptor is a target of the mediators that promote inflammatory pain in the nervous system [1]. Cinnamic acid and its derivatives were seen to act as an agonist at this TRPA1 nociceptor.
What is a nociceptor?
A nociceptor is a sensory receptor that is activated by noxious stimuli that damage or threaten the body’s integrity [2]. Nociceptive pain arises from tissues damaged in a physical, or chemical way. These receptors activate at certain temperatures, and certain pressures to trigger a response [3]. In short they’re pain receptors. They are a means of neural feedback to the body. A common reference to this is when dealing with pain relieving compounds. They are known as antinociceptives, and block pain.
What is TRPA1?
TRPA1 is defined as the thermoreceptive (temperature sensitive) transient receptor potential ankyrin. These sit at the ends of nociceptive nerve fibers. It’s calcium permeable and allows calcium ions into the cell. Ankyrins may seem difficult to grasp, but an easy way to remember its location is by looking at the greek word from which it is derived, ankyra, which translates to “anchor”. Ankyrins anchor ion channels among other transport mechanisms to the plasma membrane of the cell [4]. When this receptor is activated it tells the neuron to fire an action potential which is then processed as a pain or sensory signal by the body.
What is a TRPA1 agonist?
Any TRPA1 agonist is a chemical that binds to the receptor, and stimulates a biological response. Agonists cause action, where antagonists cause inaction, and block the action of the agonist [1]. Agonists in regards to the topic of today’s post will be those chemicals that activate this TRPA1 receptor. TRP channel agonists include common food items such as olive oil, horseradish, hot peppers and cinnamon. Cinnamic acid is a known TRPA1 agonist and will be the focus here.
What is cinnamic acid?
Cinnamic acid is an organic compound classified as an unsaturated carboxylic acid. It occurs in a number of plants naturally. This compound is mostly obtained from the oil extract of cinnamon [5]. Cinnamic acid and derivatives are not spoken about much in research papers with kava, however they have been identified as constituents of kava by means of chemical separation as cinnamic bornyl ester, and 3,4-methylenedioxy cinnamic acid [6,7]. These chemicals are important because they have been found to activate the TRPA1 receptor in a dose dependent manner [8].
What does this have to do with kava?
The hypothesis I’m making here is that a constituent of kava, cinnamic acids and derivatives, not the kavalactones, may be involved with feeling cold, the itch, and possibly even dermopathy in regards to kava consumption. It was seen that extracts of kava (aqueous and solvent based) promote proinflammatory responses from mast cells where individual kavalactones did not [9]. This study also noticed calcium influx that could not be explained by kavalactones. This was left open ended as the study was unable to uncover what part of aqueous extracts caused this proinflammatory response in mast cells. Coincidentally, the influx of Ca+ is exactly how the TRP channels operate [10]. More research is needed, but here I postulate that the influx of calcium in mast cells can possibly be explained by cinnamic acid and derivatives attaching to and activating TRPA1. It was found that by blocking TRPA1, they could prevent the degranulation of mast cells and thus reduce allergic skin effects [11]. This would explain the itch and dermatologic reactions such as dermopathy, as well as the cold feeling when TRPA1 is activated in areas outside that of the mast cell.
Summary:
We’ve routinely seen, and personally experienced, the itch and skin effects associated with drinking kava. It’s still up in the air as to what exactly causes these issues, but today I theorize that it’s NOT the kavalactones themselves, but a lesser known part of kava known as cinnamic acid. Cinnamic acid is known to attach to and activate receptors known as “nociceptors” or pain/temperature receptors. These receptors are found on mast cells (cells involved with release of histamines) as well as in many other areas of the body. When these are activated it causes influx of calcium into the mast cell as well as activating these receptors. This may speak to the negative skin reaction such as itch and kava skin as well as may be tied to the cold feeling many kava drinkers report. More research in this area is needed to confirm my hypothesis, however this gives us one more avenue to search in regards to the skin effects with kava.
[1] Mihara, Satoru, and Takayuki Shibamoto. 2015. “The Role of Flavor and Fragrance Chemicals in TRPA1 (transient Receptor Potential Cation Channel, Member A1) Activity Associated with Allergies.” Allergy, Asthma, and Clinical Immunology: Official Journal of the Canadian Society of Allergy and Clinical Immunology 11 (1): 11.
(https://doi.org/10.1186/s13223-015-0074-0)
[2] Messlinger, K. 1997. “[What is a nociceptor?].” Der Anaesthesist 46 (2): 142–53.
(https://doi.org/10.1007/s001010050384) (In German)
[3] Talavera, Karel, Justyna B. Startek, Julio Alvarez-Collazo, Brett Boonen, Yeranddy A. Alpizar, Alicia Sanchez, Robbe Naert, and Bernd Nilius. 2020. “Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease.” Physiological Reviews 100 (2): 725–803.
(https://doi.org/10.1152/physrev.00005.2019)
[4] Wikimedia Foundation. (2021, February 2). Ankyrin. Wikipedia.
(https://en.wikipedia.org/wiki/Ankyrin)
[5] Wikimedia Foundation. (2021, March 21). Cinnamic acid. Wikipedia.
(https://en.wikipedia.org/wiki/Cinnamic_acid)
[6] Xuan, Tran Dang, Masakazu Fukuta, Ao Chang Wei, Abdelnaser Abdelghany Elzaawely, Tran Dang Khanh, and Shinkichi Tawata. 2008. “Efficacy of Extracting Solvents to Chemical Components of Kava (Piper Methysticum) Roots.” Journal of Natural Medicines 62 (2): 188–94.
(https://doi.org/10.1007/s11418-007-0203-2)
[7] Wu, Di, Muraleedharan G. Nair, and David L. DeWitt. 2002. “Novel Compounds from Piper Methysticum Forst (Kava Kava) Roots and Their Effect on Cyclooxygenase Enzyme.” Journal of Agricultural and Food Chemistry 50 (4): 701–5.
(https://doi.org/10.1021/jf010963x)
[8] Sadofsky, Laura R., Andrew N. Boa, Sarah A. Maher, Mark A. Birrell, Maria G. Belvisi, and Alyn H. Morice. 2011. “TRPA1 Is Activated by Direct Addition of Cysteine Residues to the N-Hydroxysuccinyl Esters of Acrylic and Cinnamic Acids.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 63 (1): 30–36.
(https://doi.org/10.1016/j.phrs.2010.11.004)
[9] Shimoda, Lori M. N., Christy Park, Alexander J. Stokes, Henry Halenani Gomes, and Helen Turner. 2012. “Pacific Island ’Awa (Kava) Extracts, but Not Isolated Kavalactones, Promote Proinflammatory Responses in Model Mast Cells.” Phytotherapy Research: PTR 26 (12): 1934–41.
(https://doi.org/10.1002/ptr.4652)
[10] Freichel, Marc, Julia Almering, and Volodymyr Tsvilovskyy. 2012. “The Role of TRP Proteins in Mast Cells.” Frontiers in Immunology 3 (June): 150.
(https://doi.org/10.3389/fimmu.2012.00150)
[11] Kang, Jun, Yong Ding, Baizhan Li, Hong Liu, Xu Yang, and Mingqing Chen. 2017. “TRPA1 Mediated Aggravation of Allergic Contact Dermatitis Induced by DINP and Regulated by NF-κB Activation.” Scientific Reports 7 (February): 43586.
(https://doi.org/10.1038/srep43586)