But First Coffee... Then Lidocaine

So I was just thinking about voltage-gated sodium channels, you know, the normal things kids think about these days. Anyway, I started wondering what happens when we are at the dental office receiving lidocaine because you’re about to get treatment, but you love your coffee, and you have to have your coffee every morning, per usual, so you do. Will caffeine impact the effects of lidocaine?

Caffeine, a widely consumed drug, is a competitive antagonist of adenosine and, when consumed, can influence cognitive functioning by altering adenosine receptors and promoting calcium influx into the sarcoplasmic reticulum, releasing neurotransmitters such as glutamate and dopamine (Fiani et al., 2021; Alasmari, 2020). When caffeine enters the body, it will block the adenosine A2A receptor, which is a G protein-coupled receptor that regulates sleep and responds to stress in the brain (Vlajkovnic, 2024). With caffeine, adenosine won't be able to inhibit the synapse as effectively; therefore, excitatory synaptic transmission will take place, altering cortical neurons (Kerkhofs et al., 2018). 

If caffeine increases excitatory synaptic transmission by inhibiting the adenosine receptors, could caffeine influence how pain signals are transmitted while lidocaine is blocking the voltage-gated sodium channels?

Voltage-gated sodium channels play an important role in initiating and propagating action potentials and are highly involved in local anesthetic drugs (Xu et al., 2019). Lidocaine is widely used in dentistry to inhibit pain sensation by targeting presynaptic calcium channels in the dorsal root ganglion and inhibiting them, as well as G protein-coupled receptors that mediate inflammation (Karnina et al., 2021). Lidocaine targets the voltage-gated sodium channels, an intracellular target (Reham et al., 2022; Sheets et al., 2003). When caffeine is consumed, as previously discussed, it inhibits the G protein-coupled receptor (Xu & Stevens, 2011); chronic caffeine consumption upregulates the expression of pain-related voltage-gated sodium channels, increasing mRNA expression in the dorsal root ganglion, which are the targets for lidocaine, increasing the potency and duration of lidocaine's anesthetic effects (Reham et al., 2022). 

This, of course, would require more trials with mice to better understand how chronic consumption of caffeine can potentially decrease pain sensation with lidocaine, which is already inhibiting pain by targeting the voltage-gated sodium channels and blocking them. Caffeine can be consumed in different forms; there are different energy drinks with caffeine and coffee, so being able to further analyze how caffeine from redbull to coffee can be interesting in understanding the impacts on pain sensations. 

References: 

Alasmari, F. (2020). Caffeine induces neurobehavioral effects through modulating neurotransmitters. Saudi Pharmaceutical Journal, 28(4), 445–451. https://doi.org/10.1016/j.jsps.2020.02.005 

Fiani, B., Zhu, L., Musch, B. L., Briceno, S., Andel, R., Sadeq, N., & Ansari, A. Z. (2021). The Neurophysiology of Caffeine as a Central Nervous System Stimulant and the Resultant Effects on Cognitive Function. Cureus, 13(5). https://doi.org/10.7759/cureus.15032 

Karnina, R., Arif, S. K., Hatta, M., & Bukhari, A. (2021). Molecular mechanisms of lidocaine. Annals of Medicine and Surgery, 69, 102733. https://doi.org/10.1016/j.amsu.2021.102733 

Kerkhofs, A., Xavier, A. C., da Silva, B. S., Canas, P. M., Idema, S., Baayen, J. C., Ferreira, S. G., Cunha, R. A., & Mansvelder, H. D. (2018). Caffeine Controls Glutamatergic Synaptic Transmission and Pyramidal Neuron Excitability in Human Neocortex. Frontiers in Pharmacology, 8. https://doi.org/10.3389/fphar.2017.00899 

Sheets, M. F., & Hanck, D. A. (2003). Molecular Action of Lidocaine on the Voltage Sensors of Sodium Channels. Journal of General Physiology, 121(2), 163–175. https://doi.org/10.1085/jgp.20028651 

Reham A., Zainab A., Zahrah A., Hawraa A., Hussain A., Omar, O., & Hatem A. (2022). Caffeine Consumption Influences Lidocaine Action via Pain-Related Voltage-Gated Sodium Channels: An In Vivo Animal Study. Pain Research & Management, 2022, 1–8. https://doi.org/10.1155/2022/6107292 

Vlajkovic, S. M. (2024). Special Issue “Adenosine Receptors in Health and Disease.” International Journal of Molecular Sciences, 25(22), 12370. https://doi.org/10.3390/ijms252212370 

Xu, F., & Stevens, R. C. (2011). Trapping Small Caffeine in a Large GPCR Pocket. Structure, 19(9), 1204–1207. https://doi.org/10.1016/j.str.2011.08.007 

Xu, L., Ding, X., Wang, T., Mou, S., Sun, H., & Hou, T. (2019). Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discovery Today, 24(7), 1389–1397. https://doi.org/10.1016/j.drudis.2019.05.014