Research reportAlkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons
Introduction
The somatosensory system is important in producing sensations induced by mechanical, thermal and chemical stimuli, including the pain of real or potential tissue damage. Capsaicin, the active component of hot pepper, has been important in elucidating the neural basis of somatosensation. Specifically, capsaicin excites an important subpopulation of neurons that induce pain, the polymodal nociceptors (PMNs), as well as warm-sensitive neurons [1]which produce the associated warm sensations. Capsaicin has been used in the identification of a cloned receptor unique to this population of pain neurons [2]and it is being utilized to gain a deeper understanding of the mechanisms underlying pain generation and prevention.
In addition to frank pain, nociception encompasses a variety of other less intense but clinically significant sensations such as itch and tingle. Not all noxious sensations are mediated by PMNs. For instance, by blocking the transmission of cutaneous C fiber afferents using pressure, a tingling sensation can be produced [28]. The specific identity of the faster, myelinated axons that contribute to this induced tingling and other paresthesias has not been determined.
Plants from the genus Xanthoxylum have been used for centuries in culinary and medical practice. Known in Western folk medicine as the toothache tree [12], extracts of this plant were used as an anesthetic. Today, the dried fruit from these plants is consumed throughout Asia (Szechuan pepper and sansho) for the unique form of oral pungency that it imparts. The sensation is a form of tingling pungency that is distinct from that produced by capsaicin. It resembles various significant forms of paresthesia, the neural bases of which are not well understood.
We report here the characterization of several alkylamides which are active in producing the tingling sensation of Xanthoxylum extracts. The biological activity of these compounds was determined by using taste testing with humans. Moreover, the types of neurons activated by these compounds were determined by recording extracellular nerve activity in the lingual nerve of rats and by measuring changes in intracellular calcium in trigeminal sensory neurons cultured from rats. Active alkylamides excite different populations of sensory neurons than does capsaicin, suggesting the utility of these compounds for defining additional neural pathways of pain and irritation.
Section snippets
Isolation of sensory active compounds
Pure unsaturated hydroxy-alkylamides were isolated from dried fruit of commercially obtained Szechuan pepper using solvent extraction, flash chromatography and preparative reverse-phase HPLC (details to be published elsewhere). The following compounds were obtained: N-(2-methyl-2-hydroxypropyl)-dodeca-(2E,6Z,8E,10E)-tetraenamide (hydroxy-α-sanshool), N-(2-methyl-2-hydroxypropyl)-dodeca-(2E,6E,8E,10E)-tetraenamide (hydroxy-β-sanshool) and N-(2-methyl-2-hydroxypropyl)-dodeca-(2E,6Z,8E,10Z
Human oral testing
Human judgments of the sensation of HO-α-sanshool (HO-α-S; 25–50 μg) applied directly to the tongue, indicate that it does not elicit the same thermal sensations as do capsaicin or other similar pungent spices. Rather, after a delayed onset (30–90 s) the tingling sensation from HO α-S was more similar to a mild electric shock (5–7 V, either DC or AC) or a weakly carbonated solution applied to the tongue. Such tingling sensations were localizable to the correct side of the tongue and lasted from
Discussion
In this and prior studies 13, 30, it has been reported that alkylamides from Xanthoxylum species produce a tingling sensation on the tongue. Using in vivo and in vitro rat models for measuring trigeminal nerve responses to HO-α-S, we demonstrated that this compound activates low and high threshold cool receptors as well low threshold mechanoreceptors. These sensory neurons are distinct from previously described capsaicin-sensitive chemonociceptors, which are known to mediate some forms of
Acknowledgements
This research was supported by a NIH research grant (R03DC03639) to I.M. We would like to acknowledge the excellent technical assistance of Joseph Cox.
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2022, Trends in Food Science and TechnologyCitation Excerpt :Over the last two decades, scientists have researched more into how the tingling aspects of Sichuan pepper are brought about. An earlier study, published in 1999, demonstrated that hydroxyl-α-sanshool might stimulate thermal and tactile trigeminal nerves, which provide benign sensations different from capsaicin-induced chemo-nociceptors (Bryant & Mezine, 1999). However, contradictory studies have been suggested to elucidate the sensory process of sanshool due to the fact that, several transient receptor potential (TRP) channels are involved in the sensations elicited by different spices and food additives.