Unravelling the mystery of capsaicin: a tool to understand and treat pain

Abstract

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes.

Fig. 1.

The Scoville Scale. The Scoville rating indicates how “spicy” a pepper is, which depends on its respective capsaicin content. Pure capsaicin is more than 3 times hotter than pepper spray used in the United States and 200 times hotter than the average jalapeno!

Fig. 2.

Pain pathways. Incoming peripheral afferent fibers input into the DH of the spinal cord. Spinal projection neurons extend and synapse in regions such as the thalamus and brainstem. From these sites, interactions are also made with the limbic system and cortical structures. Descending pathways originate in the RVM and PAG and may act on both projection neurons and afferent fibers to modulate the pain signal.

Fig. 3.

Uses of capsaicin. Capsaicin is used as both an investigative tool into pain mechanisms and a treatment for chronic pain. Currently, although basic science exploits the sensitizing effects of the compound, pharmacological interventions usually rely on the desensitizing.

Fig. 4.

The molecular structure of capsaicin.

Fig. 5.

Pharmacokinetics of capsaicin showing absorption, metabolism, and distribution after oral application of capsaicin in rats (left) and humans (right).

Fig. 6.

The distribution of capsaicin in various tissues after subcutaneous administration in rats. The numerical values refer to concentrations after distribution to brain, blood, and skin. In the case of the spinal cord, the values refer to concentrations after local administration. Because administration is subcutaneous, the values cannot be compared with the experimental pain models in which capsaicin is administered intradermally.

Fig. 7.

Phosphorylation of peripheral TRPV1. There are a number of endogenous inflammatory mediators, such as PGE₂, ATP, BK, and ET-1, which are able to act at their respective receptors located on TRPV1-expressing afferent fibers. Through various intracellular signaling cascades, they are able to phosphorylate, and sensitize, TRPV1 (although certain lipids and acid may act directly on TRPV1 itself)—resulting in the lowering of activation thresholds and heightened activity to further stimuli. Furthermore, this effect may also be achieved through Ca²⁺-dependent activation of CaMKII, which also phosphorylates TRPV1. This phosphorylation may lead to both thermal and mechanical hypersensitivity at this site. AC, adenylyl cyclase; PLC13, phospholipase C13. (See section VIII.C for details.)

Fig. 8.

Spinal activators TRPV1. The endogenous agonists of spinal TRPV1 remain unclear; however, a number of possible substances have been suggested, including anandamide, metabolites of lipoxygenases, ω-3 polyunsaturated fatty acids, N-arachidonoyldopamine (NADA), and N-oleoyldopamine (OLDA).

Fig. 9.

Cellular events underpinning central sensitization. A, an example of wind up in a single neuron, which is believed to be a key event for the induction of central sensitization. B, the flow of neuronal changes and their behavioral correlates. C, intracellular mechanisms play a role in the development of central sensitization. Excess Ca²⁺ entry into projection neurons, mainly through the NMDA receptor, results in activation of Ca²⁺-dependent enzymes such as PKA, PKB, PKC, and CamKII, which phosphorylate NMDA and AMPA receptors, both enhancing activity directly by promoting channel opening as well as increasing trafficking and insertion into the postsynaptic membrane. Furthermore, activation of the transcription factor CREB may also be involved, which results in increased gene expression and thus production of receptors. (Other heterosynaptic mechanisms are outside the scope of this review.).

Fig. 10.

Capsaicin-induced hyperexcitability of dorsal horn neurons. Peripheral application of capsaicin (such as by intradermal injection) excites afferent Aδ and C fibers. The ongoing input into the dorsal horn of the spinal cord is believed to underlie the development of hyperexcitability of spinal neurons and leads to secondary hyperalgesia and allodynia.

Fig. 11.

Pathophysiological pain conditions in which central sensitization has been implicated. Central sensitization is believed to be a key phenomenon contributing to the development of a number of these chronic pain conditions. Increased knowledge of CS may therefore lead to the development of new compounds, which can help improve the outcome of such conditions.

Fig. 12.

Capsaicin was injected intradermally in the forehead to induce trigeminal sensitization as a model of migraine. Capsaicin induced sex-specific sensory responses, here assessed as referred pain areas, which was most apparent in women during menstruation (left, menstrual phase; center, luteal phase; right, men).