It’s gonna be hot! Capsaicin and spice

What feelings do you have about spice? Whether you love it or hate it, it’s undeniable that for most people, spicy foods elicit some sort of reaction – usually the burning, painful kind. But as uncomfortable and irritating as it may seem, it is actually a powerful tool when researching pharmaceuticals.

By now, most people know that a primary chemical that causes the “spicy” feeling is capsaicin, found in plants of the Capsicum genus (commonly recognized as chili peppers). Its mode of action is by exciting nociceptors – specialized sensory neurons responsible for detecting heat and pain (Fattori et al 2016). Notice how these are the primary reactions felt when ingesting chili peppers. To excite these neurons, capsaicin increases the flux of ions – like calcium – across their membranes, creating a larger potential difference until it reaches an action potential. When the action potential is reached, the neuron is fired, signaling to the brain; in this case, the nociceptors are specialized to send pain and heat signals, which is what you experience. As with regular neuron signaling, these ion fluxes (and subsequent action potentials) are controlled by ion channels, as the membrane is selectively permeable and non-polar, preventing ions from naturally flowing across it. Thus, the capsaicin must somehow interact with ion channels within the nociceptors to activate the painful sensation.

Normally, ion receptors within neurons are not open or closed all the time – there are often conditions that need to be reached. These channels are said to be “gated”. Some are dependent on the change in membrane potential (voltage-gated), others require specific molecules to be bound to them first (ligand-gated), and others still are stretch-gated and thermo-gated (physical deformation and temperature respectively). In this case, the ion channel TRPV1 is the one affected by capsaicin (Yang and Zheng 2017). This channel is actually multiply gated, affected by both temperature and the presence of capsaicin – it is both thermo-regulated and ligand-regulated.


Figure 1: A diagram of capsaicin. The chemical structure can be observed, as well as the areas where it hydrogen-bonds to TRPV1 – these are highlighted in red (Yang and Zheng 2017).

Now that we know how capsaicin and its receptor TRPV1 work, we can examine how it helps when researching medication. As established, TRPV1 is also a pain receptor. Knowing that capsaicin is able to excite this channel in nociceptors means that it can be used to locate where these channels are present (González-Ramírez et al 2017). For example, it has helped with the understanding of abdominal pain (particularly useful for helping people suffering from IBS) by highlighting potential targets for pain within the colon via capsaicin injections to deliberately induce pain (Fattori et al 2016). Having the ability to induce pain “on-demand” is what makes capsaicin very valuable, especially in the development of pain medication. It also allows for further study on the TRPV1 receptor and how other agonists may potentially interact. Agonists like capsaicin change the pore size of the channel (capsaicin expands the size, allowing more ion flux). Due to how different agonists like N-arachidonoyldopamine (NADA), piperine and resiniferatoxin (RTX) provide distinct patterns of ion selectivity and discrimination to TRPV1, it’s possible to alter the ion channel such that it affects different ions (Fattori et al 2016), potentially allowing ways to prevent the activation of the nociceptor and allowing for pain relief. The large role of TRPV1 in pain and pain medicine research allows one of its most well-known agonists, capsaicin, to be an extremely helpful tool.

Now, the next time you feel the heat and pain from a spicy food, you know which ion channel its triggering, and maybe recall how useful the same chemical causing you that pain is at developing and researching pain prevention and mitigation.

References:
Fattori, Victor, Miriam S. N. Hohmann, Ana C. Rossaneis, Felipe A. Pinho-Ribeiro, and Waldiceu A. Verri. “Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses.” Molecules 21, no. 7 (2016): 844.https://doi.org/10.3390/molecules21070844.

González-Ramírez, Ricardo, Yong Chen, Wolfgang B. Liedtke, and Sara L. Morales-Lázaro. “TRP Channels and Pain.” In Neurobiology of TRP Channels, edited by Tamara Luti Rosenbaum Emir. Frontiers in Neuroscience. CRC Press/Taylor & Francis, 2017. http://www.ncbi.nlm.nih.gov/books/NBK476120/.

Yang, Fan, and Jie Zheng. “Understand Spiciness: Mechanism of TRPV1 Channel Activation by Capsaicin.” Protein & Cell 8, no. 3 (2017): 169–77. https://doi.org/10.1007/s13238-016-0353-7.