Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses

Abstract

In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.

Keywords: TRPV1; analgesia; capsaicinoids; chili peppers; desensitization.

Figure 1

Chemical structure of capsaicin and capsaicinoids. Molecules of capsaicin and capsaicinoids available in PubChem database [12,13,14,15,16]. Compound identifier (CID) number is provided in parentheses. Molecules were drawn using Marvin JS, MarvinSketch in JavaScript.

Figure 2

Mechanisms of capsaicin-induced pain. Schematic representation of the phosphorylation at Ser800, which allows TRPV1 discriminating cation influx [50], and participation of Tmem100 in the mechanism of capsaicin-induced pain [49,51,52]. In the presence of Tmem100 (A) activation of TRPV1-TRPA1 complex increases the influx of calcium and contributes to higher perception of pain. On the other hand, without Tmem100 (B) TRPV1-TRPA1 complex produces lower influx of calcium since TRPA1 is found in an inactivated conformation [49,51,52]. Black thin arrow: lower calcium influx; Black thicker arrow: higher calcium influx; DRG: dorsal root ganglion; ER: endoplasmic reticulum; PKC: protein kinase C.

Figure 3

Mechanisms of capsaicin-TRPV1 interaction and desensitization. Capsaicin bounds to TRPV1 in a “’tail-up, head-down configuration” and increases the influx of calcium [50]. A secondary effect due to calcium influx is the activation of calcium-dependent enzymes, such as calcineurin, which dephosphorylates TRPV1 [55,56], downregulates HVACC [57], which culminates in TRPV1 desensitization. Additionally, CaM prevents ATP-induced sensitization of TRPV1 by competing for the same intracellular pocket [55]. CaM: calmodulin; HVACC: high voltage-activated calcium channels; ER: endoplasmic reticulum.

Figure 4

Supraspinal mechanisms of capsaicin-induced analgesia. Subdermal injection of capsaicin produces analgesia by modulating dopaminergic pathway in the NAc (1) [96], opioid pathway in the hippocampus (2) [98], and GABAergic activity in the RVM (3) [96,97]. In addition, vlPAG injection of capsaicin activates endocannabinoid pathway (4) [99], and dPAG by modulating glutamate signaling pathway (5) [100]. Intrathecal injection of capsaicin depletes substance P and also produces analgesia (6) [101,102,103]. DRG: dorsal root ganglion; NAc: nucleus accumbens; Hyp: hippocampus; RVM: rostral ventromedial medulla; PAG: periaqueductal gray; vlPAG: ventrolateral periaqueductal gray; dPAG: dorsal periaqueductal gray;

Figure 5

Summary of the current knowledge on capsaicin activities-related to diseases. Green arrow indicates the diseases in which capsaicin presents beneficial effects, and therefore, could be useful as a treatment. Blue arrow indicates diseases in which the effect of capsaicin is still controversial and the therapeutic effect of capsaicin and TRPV1 agonists and antagonists need further investigation. Red arrow indicates that capsaicin might play a role in either preventing or causing cancer.