Sichuan Pepper’s Hydroxy-α-sanshool: Deep Dive
The mechanisms for how hydroxy-α-sanshool interact with our neurons and receptors are still debated, but overall there are a variety of ion channels that are activated by the hydroxy-α-sanshool. Activating these channels produce an electrical impulse that then travels down the neuron and tells the brain that a stimulus occurred [15].
Action potential
The electrical impulses that are triggered by these stimuli are called action potentials (AP). They travel down the axon and deliver the signal to the other end of the neuron. This traverse is aided by myelination to mitigate signal dissipation, and once the signal reaches the axon terminal, neurotransmitters are released to signal the next neuron. An action potential is triggered once a stimulus causes some sodium (Na+) ion channels to open, increasing the cell membrane voltage from -70mV to -55mV. At this point, the action potential has reached the AP threshold, and more Na+ ion channels open, depolarizing the cell even further. If a small stimulus is too insignificant and does not activate enough Na+ channels, the voltage does not reach the threshold and no AP is activated. When the AP peaks at approximately +40mV, the Na+ channels close and potassium (K+) ion channels open, repolarizing the cell. Once the cell membrane potential dips below the threshold, the K+ ion channels close and the membrane potential overshoots into what is called the refractory period, during which another AP cannot be activated. This is necessary so that APs do not travel in the wrong direction. To better understand how this works, you can visualize a long rope that you flick on one end. This pulse travels the length of the rope, just as the electrical impulse travels down an axon.
Hydroxy-α-sanshool mechanisms
Since hydroxy-α-sanshool does not actually produce any physical input for the mechano-sensing neurons, it is likely that it utilizes a different way to activate the migration of ions to trigger the AP. Different mechanisms have been proposed. In 2007, Koo et. al. suggested that hydroxy-α-sanshool caused an influx of calcium (Ca2+) through transient receptor potential cation channel (TRP) subfamily A member 1(wasabi receptor) and subfamily V member 1(capsaicin receptor)[16]. However, earlier in 2005 Sugai et. al. found that hydroxy-α-sanshool only weakly interacts with TRPV1 [17]. And in 2008, Bautista et. al. showed that hydroxy-α-sanshool actually interacts with two-pore K+ channels that are pH or anesthetic sensitive [18]. In their review, Ji et. al. hypothesize that the use of pluronic acid as the solvent by Koo et. al. might have resulted in a false positive[2]. Tsunozaki et. al. found that in the context of nociceptors (pain neurons), voltage gated Na+ channels had reduced sensitivity. This means the neurons had a more negative membrane potential and would need a greater stimulus to activate (lower red resting state line in AP figure)[5].
When discussing the variety of different neurons that were impacted by hydroxy-α-sanshool, Bryant et. al. suggested that hydroxy-α-sanshool affects the Na+/K+ pumps and/or Ca2+ activated K+ channels [1]. These move ions across the membrane, and since ions are either positively or negatively charged, this can impact the cell’s membrane potential. Slightly depolarizing or polarizing the cell membrane (seen in the figure as two possible red resting state lines) results in needing either a smaller or larger stimulus, respectively, to push the membrane potential above -55mV to produce an AP. This would respectively make the neuron more or less sensitive.
The ways in which our bodies react to the world around us is complex and multifaceted. Our response to hydroxy-α-sanshool in Zanthoxylum is no different. By stimulating a wide variety of neurons through mechanisms that are still not completely determined, our bodies create the unique experience of paresthesia that makes it the heart of many dishes and even capable of reducing pain. Further research into other uses of hydroxy-α-sanshool as an antibacterial or antioxidant highlight the complicated interaction it has with the body [2].
