A lot has been made of capsaicin lately as a future pharmaceutical compound to help with analgesia. The news continues, even today. Check out this article from the AP:

Doctors Test Hot Sauce for Pain Relief

More interesting than the novelty of using capsaicin is the cellular physiology of the TRPV1 itself, which is the cellular gate which really allows capsaicin to work its magic. Check out this description of it from a researcher from the University of St. Andrews in Scotland:

Capsaicin, the main pungent component of chilli peppers, has long been known to produce a painful irritant effect if injected into the skin, applied to sensitive structures such as the cornea, or tasted. [1] Despite this, the molecular target of capsaicin has only recently been elucidated. [2] The ‘capsaicin receptor’ or TRPV1 is a cation selective ligand-gated ion channel first cloned by Julius and co-workers in 1997 (FIgure 1). [2] This receptor is activated by capsaicin and other vanilloid moiety-containing compounds including resiniferatoxin (RTX, Figure 2). TRPV1 is also activated by heat above ~45 degrees Celcius and conditions below pH 5.5. [2] Activation of TRPV1 causes depolarisation, and excitation of the nociceptive nerve terminals, on which TRPV1s are located, leads to the perception of pain. [1] Additionally, the large influx of calcium, resulting from TRPV1 activation, results in release of substance P, which cause intense responses local to the sight of receptor stimulation. Despite the adverse effects, the use of topically applied capsaicin to treat painful skin disorders has met with some success. The analgesic effect of capsaicin can be rationalised by prolonged activation of TRPV1 causing the receptor to desensitise. Longer-term resistance to capsaicin can be attributed to the large influx of Ca2+ causing nerve terminal degeneration. Therefore, TRPV1 antagonists rather than agonists are likely to be the therapeutically most important compounds.

Capsaicin, the main pungent component of chilli peppers, has long been known to produce a painful irritant effect if injected into the skin, applied to sensitive structures such as the cornea, or tasted. [1] Despite this, the molecular target of capsaicin has only recently been elucidated. [2] The ‘capsaicin receptor’ or TRPV1 is a cation selective ligand-gated ion channel first cloned by Julius and co-workers in 1997 (FIgure 1). [2] This receptor is activated by capsaicin and other vanilloid moiety-containing compounds including resiniferatoxin (RTX, Figure 2). TRPV1 is also activated by heat above ~45 degrees Celcius and conditions below pH 5.5. [2] Activation of TRPV1 causes depolarisation, and excitation of the nociceptive nerve terminals, on which TRPV1s are located, leads to the perception of pain. [1] Additionally, the large influx of calcium, resulting from TRPV1 activation, results in release of substance P, which cause intense responses local to the sight of receptor stimulation. Despite the adverse effects, the use of topically applied capsaicin to treat painful skin disorders has met with some success. The analgesic effect of capsaicin can be rationalised by prolonged activation of TRPV1 causing the receptor to desensitise. Longer-term resistance to capsaicin can be attributed to the large influx of Ca2+ causing nerve terminal degeneration. Therefore, TRPV1 antagonists rather than agonists are likely to be the therapeutically most important compounds.

Figure 2: Capsaicin, RTX and 5-iodo RTX

Since the report by Julius and co-workers that capsaicin exerts its main biological effects via activation of TRPV1, [2] there has been huge interest in the synthesis of both agonists and antagonists of this receptor.[3] We are interested in the synthesis of compounds that will interact selectively with TRPV1 and assist our studies of this receptor.

1. H. P. Rang, M. M. Dale, J. M. Ritter and P. K. Moore, Pharmacology; 5th ed., Churchill Livingstone: London, 2003.

2. M. J. Caterina, M. A. Schumacher, M. Tominaga, T. A. Rosen, T. A. Levine, and D. Julius, The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997, 389, 816-824.

3. A. Szallasi, G. Appendino, Vanilloid Receptor TRPV1 Antagonists as the Next Generation of Painkillers. Are we putting the Cart before the Horse? J. Med. Chem. 2004, 47, 2717-2723.

While this may seem like scientific mumbo-jumbo to many people, the ramifications are huge. No drug is utilized best until we know its mechanism of action and how to make it work on our cells the way we want it to do so. To have this increased understanding of this receptor makes it likely that capsaicin research will continue to ramp up and that some novel pain management is in our future. For all of us. Think about that the next time you’re sucking wind after eating something that’s laden with capsaicin heat!

(Article above reprinted with courtesy and credit given to the researchers at St. Andrews University)

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