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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.
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molecules
Review
Capsaicin: Current Understanding of Its Mechanisms
and Therapy of Pain and Other Pre-Clinical
and Clinical Uses
Victor Fattori , Miriam S. N. Hohmann , Ana C. Rossaneis, Felipe A. Pinho-Ribeiro
and Waldiceu A. Verri Jr. *
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina,
Rodovia Celso Garcia Cid KM480 PR445, Caixa Postal 10.011, 86057-970 Londrina, Paraná, Brazil;
vfattori@outlook.com (V.F.); hohmann.miriam@gmail.com (M.S.N.H.); anacrossaneis@gmail.com (A.C.R.);
pinho.fe@gmail.com (F.A.P.-R.)
*Correspondence: waverri@uel.br or waldiceujr@yahoo.com.br; Tel.: +55-43-3371-4979
These authors contributed equally to this paper.
Academic Editor: Pin Ju Chueh
Received: 27 April 2016; Accepted: 27 April 2016; Published: 28 June 2016
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: analgesia; capsaicinoids; chili peppers; desensitization; TRPV1
1. Introduction
Capsaicin is a compound found in chili peppers and responsible for their burning and irritant
effect. In addition to the sensation of heat, capsaicin produces pain and, for this reason, is an important
tool in the study of pain. Although our understanding of pain mechanisms has evolved greatly through
the development of new techniques, experimental tools are still extremely necessary and widely used.
Among these basic experimental tools for the study of pain mechanisms and development of novel
analgesics, we can fairly consider capsaicin as one of the most important sources of knowledge in the
pain field. Curiously, many recent studies have confirmed scientifically what was already known by
some cultures: capsaicin can also be used to relieve pain [
1
]. This paradox can also be seen with opioids,
which have an established clinical use as analgesics, but also induce hyperalgesia [
2
]. Therefore,
the complexities of capsaicin-triggered responses as well as its therapeutic usefulness highlight the
importance of understanding its mechanisms of action not only in pain modulation, but also in other
pathological conditions. In this review, we will highlight the importance of capsaicin to the current
understanding of neuronal modulation of pain and explore some 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.
1.1. Discovery, Natural Sources, Role in Plants, Isolation, and Structure of Capsaicin
Chili peppers contain capsaicin (8-methyl-N-vanillyl-6-nonenamide), a phenolic compound
responsible for their characteristic taste and pungency. All plants from Capsicum genus produce varied
Molecules 2016,21, 844; doi:10.3390/molecules21070844 www.mdpi.com/journal/molecules
Molecules 2016,21, 844 2 of 33
amounts of capsaicin, except Capsicum annum, and all of them have been used as a spice ingredient and
consumed by humans for over 6000 years [
3
,
4
]. The quantities of capsaicin can represent up to 1% of the
mass of the chili peppers and, together with salt, represent the most consumed condiment by humans.
Capsaicin is an intriguing molecule since the consumption of chili peppers evokes opposing sensations
(pleasant and unpleasant) depending on the individual experience and chili pepper consumption
habits. The effects of capsaicin go well beyond the taste and its role in plants’ health help us to
understand how its use can improve human health [4].
The production of capsaicin among plants from the Capsicum genus was well conserved, likely
due to its roles in seed germination and protection from parasites. In fact, capsaicin is not equally
distributed in all parts of pepper fruit. Its concentration is higher in the area surrounding the seeds
(placental tissue) and this localization is related directly to the role of capsaicin in protecting seed
germination [
5
]. The aversion to eating large amounts of capsaicin keeps rodents and other mammals
away and this represents an important mechanism to increase the chances of germination since
mammals can grind and digest the seeds making them unable to germinate. Birds, on the other hand,
cannot feel this unpleasant taste of peppers [
6
]. Importantly, pepper seeds resist to birds
´
digestive
tract, making them the perfect consumers. Capsaicin also protects plants from parasites such as insects
and mold, and humans have been using this property to treat infectious diseases and to preserve
food [7,8].
Despite the unpleasant sensation that occurs when large quantities of chili peppers are consumed,
capsaicin promotes pain relief when used in the right dosage and frequency. These properties caught
the attention of researchers long ago and still do nowadays, boosting our knowledge about capsaicin.
Capsaicin was first purified in 1876 [
9
] but its structure started to be described only in 1919 [
10
].
Currently, the structure and properties of capsaicin are well defined (Figure 1). Capsaicin presents a
nonpolar phenolic structure and thus cannot be solubilized in water. The main solvents used to extract
and maintain capsaicin properties are nonpolar solvents such as ether, benzene, dimethyl sulfoxide
and acetone, but ethanol can also be used as a solvent due to its mixed properties.
Because of its chemical structure, capsaicin can be well absorbed when administered topically
or orally, reaching up to 94% of absorption [
11
]. Following its discovery and characterization, it was
observed that capsaicin is actually part of a family of compounds that share similar structural and
biologic characteristics.
Molecules 2016, 21, 844 2 of 31
1.1. Discovery, Natural Sources, Role in Plants, Isolation, and Structure of Capsaicin
Chili peppers contain capsaicin (8-methyl-N-vanillyl-6-nonenamide), a phenolic compound
responsible for their characteristic taste and pungency. All plants from Capsicum genus produce varied
amounts of capsaicin, except Capsicum annum, and all of them have been used as a spice ingredient
and consumed by humans for over 6000 years [3,4]. The quantities of capsaicin can represent up to 1% of
the mass of the chili peppers and, together with salt, represent the most consumed condiment by
humans. Capsaicin is an intriguing molecule since the consumption of chili peppers evokes opposing
sensations (pleasant and unpleasant) depending on the individual experience and chili pepper
consumption habits. The effects of capsaicin go well beyond the taste and its role in plants’ health
help us to understand how its use can improve human health [4].
The production of capsaicin among plants from the Capsicum genus was well conserved, likely
due to its roles in seed germination and protection from parasites. In fact, capsaicin is not equally
distributed in all parts of pepper fruit. Its concentration is higher in the area surrounding the seeds
(placental tissue) and this localization is related directly to the role of capsaicin in protecting seed
germination [5]. The aversion to eating large amounts of capsaicin keeps rodents and other mammals
away and this represents an important mechanism to increase the chances of germination since
mammals can grind and digest the seeds making them unable to germinate. Birds, on the other hand,
cannot feel this unpleasant taste of peppers [6]. Importantly, pepper seeds resist to birds´ digestive
tract, making them the perfect consumers. Capsaicin also protects plants from parasites such as insects
and mold, and humans have been using this property to treat infectious diseases and to preserve
food [7,8].
Despite the unpleasant sensation that occurs when large quantities of chili peppers are consumed,
capsaicin promotes pain relief when used in the right dosage and frequency. These properties caught the
attention of researchers long ago and still do nowadays, boosting our knowledge about capsaicin.
Capsaicin was first purified in 1876 [9] but its structure started to be described only in 1919 [10].
Currently, the structure and properties of capsaicin are well defined (Figure 1). Capsaicin presents a
nonpolar phenolic structure and thus cannot be solubilized in water. The main solvents used to
extract and maintain capsaicin properties are nonpolar solvents such as ether, benzene, dimethyl
sulfoxide and acetone, but ethanol can also be used as a solvent due to its mixed properties.
Because of its chemical structure, capsaicin can be well absorbed when administered topically
or orally, reaching up to 94% of absorption [11]. Following its discovery and characterization, it was
observed that capsaicin is actually part of a family of compounds that share similar structural and
biologic characteristics.
Figure 1. Chemical structure of capsaicin and capsaicinoids. Molecules of capsaicin and capsaicinoids
available in PubChem database [12–16]. Compound identifier (CID) number is provided in parentheses.
Molecules were drawn using Marvin JS, MarvinSketch in JavaScript.
Figure 1.
Chemical structure of capsaicin and capsaicinoids. Molecules of capsaicin and capsaicinoids
available in PubChem database [
12
16
]. Compound identifier (CID) number is provided in parentheses.
Molecules were drawn using Marvin JS, MarvinSketch in JavaScript.
Molecules 2016,21, 844 3 of 33
1.2. Capsaicin-Derived Molecules and Analogs
Plants from Capsicum genus produce many capsaicin-related compounds. Due to their similarity
with capsaicin, these molecules can be grouped in a family called capsaicinoids. Capsaicinoids include
dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin (Figure 1). All
these molecules share structural and activity similarities with capsaicin [
17
,
18
], but they are not as
abundant as capsaicin that can account for up to 80% of capsaicinoid content of chili peppers. The
pungency of all these molecules emphasizes the fact that this activity is defined mainly by the benzene
ring region, however, the length of acyl chain can modify it [
19
]. Besides capsaicinoids, there are
other groups of molecules that share similarities with capsaicin such as capsinoids, with reduced
pungency, and the extremely potent resiniferoids [
20
,
21
]. Importantly, all these capsaicin-related
molecules present therapeutic properties to treat pain and other conditions and have been used in
research to understand the pathophysiology of pain and diseases. Capsaicin has opened the path to
our understanding of pain mechanisms and demonstrated that, although counter-intuitive at first
sight, it is possible to treat pain by boosting algesic pathways. Furthermore, the ability of capsaicin to
cause activity-induced tolerance to pain demonstrates the complexity of a single pharmacological tool
that is able either to trigger or treat pathological pain.
2. Capsaicin and Pain
Capsaicin selectively stimulates nociceptive neurons and has been widely used to study
pain-related events. In this topic, we will highlight some aspects of how capsaicin induces pain
and its importance to the current understanding of neuronal mechanisms of pain.
2.1. Importance of Capsaicin in Pain Research
Before the discovery of the capsaicin-activated receptor, intradermal injection of capsaicin was
used to produce primary and secondary hypersensitivity to noxious and innocuous stimuli in both
monkeys and rats [
22
,
23
]. Seminal works demonstrated that capsaicin excites nociceptors by increasing
the influx of ions, such as calcium, in dorsal root ganglion (DRG) neurons [
24
,
25
]. Years later, cloning
transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor shed light on
the mechanism by which capsaicin induces pain [
26
]. This work is a landmark in the mechanisms of
pain since demonstrated that capsaicin induces pain-like behavior by activation of TRPV1 receptors
expressed by nociceptors. At that time, TRPV1 receptors were denominated vanilloid receptor 1
(VR1) [
26
]. More importantly, this discovery has changed our understanding of pain mechanisms since
it demonstrates that a receptor-coupled channel expressed by nociceptors detects environment stimuli
resulting in nociceptor depolarization and consequently producing pain. Also, this discovery opened
avenues to the development of new drugs since Mendelian disorders in these proteins can produce
pain [
27
]. After that,
in vivo
evidence demonstrated that mice lacking TRPV1 receptors exhibit reduced
thermal noxious response and capsaicin-induced paw licking [
28
]. Whole patch-clamp technique
demonstrated that mice lacking TRPV1 receptors present impaired calcium influx in DRG neurons [
28
].
Therefore, administration of capsaicin in animals was important to elucidate the function of TRPV1
as well as to aid our knowledge about pain processing and modulation. Therefore, the discovery of
TRPV1 was essential to validate capsaicin-induced pain models, which can now be used to study
neuronal mechanisms of pain, in addition to testing new TRPV1 antagonists and drugs that target the
consequences of TRPV1 activation before clinical trials.
2.2. Mechanisms of Capsaicin-Induced Pain
One of the first evidence of a selective action of capsaicin on C-polymodal nociceptors was
obtained by the capsaicin-evoked response of C-fibers in the cat saphenous nerve. In addition,
injection of capsaicin reduces the thermal threshold in both rats and humans [29]. This seminal work
demonstrates that capsaicin selectively acts on C-polymodal nociceptors and the thermodependency of
Molecules 2016,21, 844 4 of 33
sensory effects on animals and humans [
29
]. Spinal cord mechanisms of capsaicin-evoked mechanical
allodynia depend on G-protein and protein kinases (PKA and PKC) and could be reversed by both
G-protein and protein kinase inhibitors. For instance, kinase activity may result in an increase of
receptor activity as well as an increase of trafficking and cell-surface expression of molecules [
23
].
In fact, capsaicin activates PKA and PKC that phosphorylate NMDA receptor subunit NR1 at serine
residue 890 and 897, and serine residue 896, respectively, which enhances receptor activity [
30
,
31
].
Alongside with this, mitogen-activated protein kinase (MAPK) family has been involved in pain-related
states and, indeed, capsaicin administration increases the phosphorylation of p38 MAPK in the
periphery and spinal cord dorsal horn [
32
]. Therefore, inhibition of these kinases has helped to
define some of the intracellular mechanisms involved in capsaicin-induced central sensitization.
In addition to these kinases, the neuropeptide CGRP is another important component in central
sensitization. Capsaicin-induced TRPV1 activation stimulates the release of CGRP in the spinal
cord, and intrathecal treatment with CGRP antagonist reduces the development and maintenance of
mechanical hyperalgesia and secondary allodynia [33].
Capsaicin-induced pain model was also useful to demonstrate the role of reactive oxygen
species (ROS) in central sensitization. Despite their pro-hyperalgesic effect per se [
34
,
35
], ROS can
also be a source of post-translational modification due to their action on redox-sensitive protein
residues such as cysteine and serine [
36
]. In fact, treatment with the ROS scavenger Tempol
(4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl) and PBN (N-tert-butylnitrone) reduces the activation
of neurons in the dorsal horn as observed by the reduction of electrophysiological activity detected
by the number of neuronal spikes [
37
]. As a consequence of that, there is reduction of primary and
secondary hyperalgesia, and reduction of neuron responsiveness induced by capsaicin, suggesting a
role of ROS in the maintenance of persistent pain [
37
]. Keratinocytes are in proximity to nociceptors,
which may imply a role for these cells in pain. Using Cre-lox technique to promote expression of TRPV1
in keratinocytes demonstrated that capsaicin stimulates TRPV1-expressing keratinocytes inducing
c-fos expression in laminae I and II of the ipsilateral spinal cord dorsal horn, which contributes to evoke
acute paw-licking nociceptive behavior [
38
]. This addresses the interaction between keratinocytes and
nociceptors in pain-state.
Capsaicin has helped us to understand the mechanisms related to abdominal pain, a condition
inherent of patients with irritable bowel syndrome (IBS). Intracolonic injection of capsaicin induces
abdominal mechanical hyperalgesia, and pain-related behaviors such as abdominal licking in
a morphine-sensitive manner suggesting its nociceptive nature instead of a normal grooming
behavior [
39
]. IBS patients present abdominal mechanical hyperalgesia and allodynia [
40
]. Nociceptive
fibers present in the colon respond to TRPV1 agonist, and, therefore, highlight these receptors as
potential targets for abdominal pain [
35
]. In fact, TRPV1 co-localizes with substance P and calcitonin
gene-related peptide (CGRP) in a model of DSS (dextran sulfate sodium)-induced colitis. Substance
P and CGRP are two important neuropeptides in pain signaling that together with TRPV1 mediate
visceral pain [
41
]. This is important considering that TRPV1/CGRP pathway is considered an attractive
pharmacological approach to treat visceral pain [
42
].
In vivo
functional magnetic resonance imaging
(fMRI) further corroborates the importance of TRPV1 receptors and demonstrates the activity of
supraspinal mechanisms in capsaicin-induced pain. Injection of capsaicin in wild-type (WT) rats
activates putative pain neural circuit, such as Papez circuit, and the habenular system; and TRPV1
receptor deficiency reduces the activation in these same brain regions in response to capsaicin [
43
]. This
is important since it points out to the supraspinal modulation of TRPV1 in pain. And additionally to
these mechanisms, TRPV1 also modulates the emotional component of visceral pain [
44
]. Modulation
of TRPV1/CGRP pathway is important in arthritis as well [
45
]. In fact, intra-articular injection of CGRP
in normal or mono-iodoacetate (MIA)-induced arthritis rats reduces the mechanical threshold and
increases percentage of sensitized fibers [
46
], and treatment with CGRP antagonist reduces CGRP- and
MIA-induced sensory neuron firing [
46
], suggesting that peripheral release of CGRP contributes to
inflammation and sensitization of joint nociceptors [45].
Molecules 2016,21, 844 5 of 33
In the past few years, efforts have been made to identify ligand-receptor and receptor-receptor
interactions and their role with pain. Among the first interactions that were shown, we can highlight
the capsaicin-TRPV1. In fact, co-administration of capsaicin with QX-314 (a membrane-impermeable
sodium channel blocker) facilitates the access of the QX-314 that blocks sodium inward currents in
capsaicin-responsive DRG neurons producing analgesia [
47
]. Nevertheless, in this work, neither the
potentially dynamic of TRPV1 permeability to different ions size or charges (unknown at the moment),
nor the effect of pore size of the TRPV1 was addressed. TRPV1 receptor was considered a nonselective
cation channel with higher affinity for calcium than sodium. TRPV1 agonists such as capsaicin, changes
TRPV1 pore size leading to time-dependent discrimination between monovalent and divalent cations
over a time frame of seconds that can persist for several minutes [
48
]. Another striking feature was
that phosphorylation of TRPV1 serine 800 residue by PKC allows neurons to discriminate the size of
cations by increasing permeability to large cation, and proportionating sensitization of the TRPV1,
and enhancement of inward currents [
48
]. In fact, PKC phosphorylates TRPV1 at serine 800 residues,
but not at serine 502, in DRG neurons of rats and contributes to pain in MIA-induced osteoarthritis
model [
49
] (Figure 2). Inhibition of PKC, but not PKA, reduces capsaicin-induced pain-related behavior
in MIA-induced osteoarthritis rats [
49
]. TRPV1 agonists such as N-arachidonoyldopamine (NADA),
piperine and resiniferatoxin (RTX) provide distinct pattern of ion selectivity and discrimination [
48
].
Thus, suggesting that different TRPV1 agonist change the selectivity to inward ions, and the activity
of different kinases (such as PKA and PKC) [
48
,
49
] could provide different inward ion. Recent data
further advanced in this topic by demonstrating that capsaicin binds to TRPV1 pocket as a unique
molecule [50].
Molecules 2016, 21, 844 5 of 31
In the past few years, efforts have been made to identify ligand-receptor and receptor-receptor
interactions and their role with pain. Among the first interactions that were shown, we can highlight
the capsaicin-TRPV1. In fact, co-administration of capsaicin with QX-314 (a membrane-impermeable
sodium channel blocker) facilitates the access of the QX-314 that blocks sodium inward currents in
capsaicin-responsive DRG neurons producing analgesia [47]. Nevertheless, in this work, neither the
potentially dynamic of TRPV1 permeability to different ions size or charges (unknown at the
moment), nor the effect of pore size of the TRPV1 was addressed. TRPV1 receptor was considered a
nonselective cation channel with higher affinity for calcium than sodium. TRPV1 agonists such as
capsaicin, changes TRPV1 pore size leading to time-dependent discrimination between monovalent
and divalent cations over a time frame of seconds that can persist for several minutes [48]. Another
striking feature was that phosphorylation of TRPV1 serine 800 residue by PKC allows neurons to
discriminate the size of cations by increasing permeability to large cation, and proportionating
sensitization of the TRPV1, and enhancement of inward currents [48]. In fact, PKC phosphorylates
TRPV1 at serine 800 residues, but not at serine 502, in DRG neurons of rats and contributes to pain
in MIA-induced osteoarthritis model [49] (Figure 2). Inhibition of PKC, but not PKA, reduces
capsaicin-induced pain-related behavior in MIA-induced osteoarthritis rats [49]. TRPV1 agonists such
as N-arachidonoyldopamine (NADA), piperine and resiniferatoxin (RTX) provide distinct pattern of
ion selectivity and discrimination [48]. Thus, suggesting that different TRPV1 agonist change the
selectivity to inward ions, and the activity of different kinases (such as PKA and PKC) [48,49] could
provide different inward ion. Recent data further advanced in this topic by demonstrating that
capsaicin binds to TRPV1 pocket as a unique molecule [50].
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.
Capsaicin has a very high affinity, sensitivity, and selectivity for TRPV1 and does not activate the
homologous TRPV2–TRPV6 receptors [50]. In addition, an elegant work demonstrated how capsaicin
binds to TRPV1 and which amino acid residues are involved in this binding. Capsaicin binds to TRPV1
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.
Capsaicin has a very high affinity, sensitivity, and selectivity for TRPV1 and does not activate
the homologous TRPV2–TRPV6 receptors [
50
]. In addition, an elegant work demonstrated how
Molecules 2016,21, 844 6 of 33
capsaicin binds to TRPV1 and which amino acid residues are involved in this binding. Capsaicin
binds to TRPV1 in a “tail-up, head-down configuration” (as coined by the authors). The aliphatic
“tail” interacts with the channel through nonspecific van der Waals forces and contributes to binding
affinity. Hydrogen bonds between its vanillyl “head” and amide “neck” with residues of glutamic
acid E571 and T551 of the channel, respectively, grant specificity for ligand binding [
50
] (Figure 3).
Other interactions with TRPV1, such as Tyr511, Glu570, and Ile569; with the vanillyl “head” allows
capsaicin accommodation in this specific pocket (called as vanilloid pocket). On the other hand, RTX
(a TRPV1 agonist) molecule is bigger than capsaicin, and possesses a different electron cloud, which
does not allow its accommodation in the same vanilloid pocket because this pocket is too shallow for
RTX [
53
]. Therefore, this spatial allocation of both molecules accounts to the distinct agonist pattern
and potency explaining the increased potency of RTX compared to capsaicin [
53
]. In addition to the
spatial allocation, structure-activity relationship study demonstrates the functional groups that are
essential to these difference. For instance, the amide group is essential for capsaicin activity, while
for RTX the five-membered diterpene ring fulfills this role [
54
]. These studies had an enormous
impact because they demonstrated the fundamental pockets to capsaicin or other agonist binding and
activation of TRPV1. Therefore, these studies enable future pharmacological approaches based on
this knowledge since these agonists can act both as pro-hyperalgesic and anti-hyperalgesic as we will
discuss in the next topic.
Molecules 2016, 21, 844 6 of 31
in a “tail-up, head-down configuration” (as coined by the authors). The aliphatic “tail” interacts with
the channel through nonspecific van der Waals forces and contributes to binding affinity. Hydrogen
bonds between its vanillyl “head” and amide “neck” with residues of glutamic acid E571 and T551 of
the channel, respectively, grant specificity for ligand binding [50] (Figure 3). Other interactions with
TRPV1, such as Tyr511, Glu570, and Ile569; with the vanillyl “head” allows capsaicin accommodation
in this specific pocket (called as vanilloid pocket). On the other hand, RTX (a TRPV1 agonist)
molecule is bigger than capsaicin, and possesses a different electron cloud, which does not allow its
accommodation in the same vanilloid pocket because this pocket is too shallow for RTX [53].
Therefore, this spatial allocation of both molecules accounts to the distinct agonist pattern and potency
explaining the increased potency of RTX compared to capsaicin [53]. In addition to the spatial
allocation, structure-activity relationship study demonstrates the functional groups that are essential
to these difference. For instance, the amide group is essential for capsaicin activity, while for RTX the
five-membered diterpene ring fulfills this role [54]. These studies had an enormous impact because
they demonstrated the fundamental pockets to capsaicin or other agonist binding and activation of
TRPV1. Therefore, these studies enable future pharmacological approaches based on this knowledge
since these agonists can act both as pro-hyperalgesic and anti-hyperalgesic as we will discuss in the
next topic.
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 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.
Molecules 2016,21, 844 7 of 33
Regarding receptor-receptor interaction, TRPV1-TRPA1 is a well-documented one [
58
]. This
interaction is attributed to the formation of a heterodimer between TRPV1-TRPA1 receptors [
59
],
which is possible due to lipid raft movement and formation of a cluster of receptors in neurons [
60
].
Recent evidence demonstrated that a trans-membrane receptor called Tmem100 is co-expressed with
both TRPV1-TRPA1 complex in DRG neurons and is essential to modulate their activity by acting as
an adaptor molecule [
51
]. Nevertheless, forming TRPV1-TRPA1 complex without Tmem100 is also
possible [
51
,
52
]. In the TRPV1-TRPA1 complex without Tmem100, TRPV1 inhibits TRPA1 activity since
TRPV1-TRPA1 positive DRG neurons present reduction of inward current after mustard oil (TRPA1
agonist) as stimulus, but not to capsaicin. On the other hand, in the presence of Tmem100 TRPV1
increases TRPA1 activity and potentiates pain perception [
51
] (Figure 2). Additionally, TRPA1-initiated
calcium influx promotes PKA activation, thereby sensitizing TRPV1 channels [61].
Therefore, there is a complex interaction of capsaicin and other agonists with TRPV1 that shed
light in the complex pathway to understand TRPV1 modulation. TRPV1 crosstalks with other receptors
build up an entirely different pharmacology adding up complexity.
2.3. Targeting TRPV1 as a Pharmacological Approach
Currently, capsaicin-induced pain is also used to assess new molecules that target TRPV1
receptor. A whole body of evidence points out to natural product-derived molecules as potential
drugs. We recently demonstrated that the flavonoids naringenin [
62
], vitexin [
63
], and hesperidin
methyl chalcone [
64
] reduce inflammatory pain by targeting, at least in part, capsaicin-triggered
TRPV1 receptors. Other flavonoids also target TRPV1 and reduce pain such as eriodictyol [
65
] and
hesperidin [
66
], and reduces gastritis such as silymarin [
67
]. These data corroborate the concept
that flavonoids modulate TRPV1. Additionally, other molecules such as
α
-spinasterol isolated from
leaves of the medicinal plant Vernonia tweedieana (Baker) produce antinociceptive effect by TRPV1
antagonism [
68
]. Another well-recognized natural product-derived molecule is curcumin, which has
more than 100 different targets, among them TRPV1 [
69
,
70
]. Curcumin reduces capsaicin-induced
calcium rise and inward current in DRG neurons of both mice and rats [
69
] by antagonizing TRPV1
receptors [71].
Considering the prevalence of chronic pain and the relevance of TRPV1, the pharmaceutical
industry has been focusing its efforts in the development of synthetic drugs targeting TRPV1.
These drugs are divided into TRPV1 antagonists and TRPV1 agonists [
72
], and both groups present
considerable disadvantages. For instance, TRPV1 agonists can cause pain and/or erythema before
desensitization becomes effective, and TRPV1 antagonists usually present lower efficacy compared to
TRPV1 agonists and can cause hyperthermia [72,73].
SB-705498 was one of the first developed TRPV1 antagonists. A single oral administration of
400 mg of SB-705498 reduces capsaicin-evoked flare, alongside with elevation of thermal threshold of
the patients [
74
]. As mentioned, hyperthermia is an important side effect due to TRPV1 antagonist
administration. In fact, administration of lower doses (2 and 8 mg) of AMG 517 causes hyperthermia
that ranges between 39–40.2
˝
C. On the other hand, repeated administration of this drug for 7 days
at a dose of 10 mg reduces hyperthermia, suggesting dose-dependent effect and desensitization [
75
].
TRPV1 agonists will be discussed in the next section.
3. Mechanisms of Capsaicin-Induced Analgesia
The effects of capsaicin on nociception are not limited to its ability to produce pain. In fact, high
or repeated doses of capsaicin induces an initial pain sensation that is followed by analgesia [
76
]. This
loss of sensitivity to painful stimuli was noticed in response to not only thermal, but also mechanical
and chemical noxious stimuli [77].
The underlying mechanisms in capsaicin-induced analgesia are being increasingly studied.
After exposure to a high or repeated dose of capsaicin, the TRPV1 receptors begin a refractory
state commonly termed as desensitization that leads to inhibition of receptor function [
78
80
]
Molecules 2016,21, 844 8 of 33
(Figure 3). Capsaicin-induced desensitization involves mechanisms not entirely understood. There
is evidence that this process includes depletion of neuropeptides such as substance P in the nerve
fibers that express TRPV1 [
81
,
82
], and an increase of intracellular calcium levels by inhibition of high
voltage-activated (HVA) and low-voltage-activated (T-type) calcium channels [
83
85
]. A delayed or
secondary effect due to calcium influx is the activation of calcium-dependent proteins that leads to
desensitization of TRPV1 [
55
,
56
]. For instance, a multi-ligand-binding in the cytosolic ankyrin repeat
domain (ARD) of TRPV1 allows intracellular ATP binding to specific pockets of TRPV1-ARD and
sensitizes this receptor [
55
]. On the other hand, desensitization of TRPV1 occurs when calmodulin
(CaM) binds in a calcium-dependent manner in the same pockets of ATP, since mutation in these
pockets eliminates desensitization in the absence of ATP [
55
]. Specifically, calcineurin, a CaM and
calcium-dependent enzyme, dephosphorylates Thr370 residues that were previously phosphorylated
by PKA [56]. Additionally, calcineurin downregulates HVA calcium channels limiting calcium influx
in DRG neurons [
57
] (Figure 3). Altogether, these mechanisms lead to desensitization of TRPV1 and
account to capsaicin-induced analgesia.
In addition to the mechanism of TRPV1 desensitization, new evidence has emerged showing the
efficacy of capsaicin as an analgesic [
86
]. Capsaicin activates TRPV1, which inhibits Piezo proteins, a
family of mammalian cation-selective ion channels that respond to mechanical stretch [
86
]. Inhibition of
Piezo proteins occurs due to calcium-dependent activation of phospholipase C
δ
(PLC
δ
), which depletes
phosphoinositides. In fact, injection of phosphoinositides in the cytosol by excised inside-out patch
clamp reduces rundown inward current of Piezo channels and reverts inactivation [
86
]. Therefore, the
depletion of these phosphoinositides correlates with inhibition of mechanical-stimulation of Piezo
channels through inhibition of inward current [
86
]. This work uncovers, at least in part, how local
capsaicin produces mechanical analgesia.
Capsaicin-induced analgesia is also related to degeneration of sensory fibers [
87
90
]. The
mechanisms through which capsaicin causes cell death are not completely understood. Recent
studies indicate that one of the most likely mechanisms is apoptosis via caspase activation. An
in vitro
study demonstrated capsaicin induces DNA fragmentation and reduction of the nucleus
in a caspase-dependent manner secondary to cell death of sensory neurons. In addition, the cell
death process triggered by capsaicin via TRPV1 is directly related to mitochondrial permeability
transition [
91
]. On the other hand, capsaicin can promote cell death by apoptosis-independent
mechanisms such as cell swelling and bleb formation in the membrane. These mechanisms are
dependent on extracellular sodium influx via TRPV1, which in turn is controlled by the intracellular
concentration of calcium [
92
]. Capsaicin-induced analgesia is longer in inflammatory conditions than in
basal conditions [
93
,
94
]. While the intraplantar injection of 10
µ
g of capsaicin in control mice produced
analgesia for 2 days, in groups stimulated with carrageenan or CFA, the same dose of capsaicin
produces analgesic effect for 6 and 30 days, respectively [
94
]. This enhancement of capsaicin-induced
analgesia during inflammation is likely related to a facilitated TRPV1 desensitization [
93
,
94
] due to
TRPV1 expression [40,95].
In addition to peripheral changes, supraspinal mechanisms also modulate capsaicin-induced
analgesia. The subdermal injection of capsaicin significantly reduces the jaw-opening reflex and
increases the withdrawal threshold to mechanical stimulation in anesthetized rat, and both effects
are prevented by microinjection of dopaminergic or opioid antagonist into the nucleus accumbens.
The tonic GABAergic inhibition of neurotransmission in the rostral ventromedial medulla (RVM) is
also involved in capsaicin-induced analgesia modulation. In agreement, the injection of muscimol
(GABA-A receptor agonist), but not naloxone in the RVM prevents capsaicin-induced inhibition of the
jaw-opening reflex [
96
]. This analgesic effect was reversed by intrathecal injection of antagonists of
GABA-B and
µ
-opioid receptors indicating that activation of inhibitory spinal receptors is an important
mechanism of capsaicin-induced analgesia [
97
]. An increase of opioid activity is also observed in the
arcuate nucleus of the hypothalamus of rats as assessed by the proopiomelanocortin (POMC) mRNA
expression, a precursor of
β
-endorphin, 20 min after subcutaneous injection of capsaicin [
98
] (Figure 4).
Molecules 2016,21, 844 9 of 33
Molecules 2016, 21, 844 9 of 31
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) [101–103]. DRG: dorsal root ganglion; NAc: nucleus accumbens; Hyp: hippocampus; RVM: rostral
ventromedial medulla; PAG: periaqueductal gray; vlPAG: ventrolateral periaqueductal gray; dPAG:
dorsal periaqueductal gray;
Capsaicin also induces analgesia when administered centrally in varied foci. For instance, the
intrathecal injection of capsaicin or RTX produces long-term regional analgesia with substance P
depletion [101–103]. The analgesic effect via supraspinal TRPV1 following intracerebroventricular
injection of capsaicin depends on the activation of Cav3.2 channels since mice lacking this receptor
present higher nociceptive response compared to WT mice [104]. The microinjection of capsaicin in
the periaqueductal gray (PAG) [79] or its dorsal portion (dPAG) in rats produces antinociception to
thermal stimulation and may be preceded by a short period of hyperalgesia [105]. The analgesic
effect of capsaicin in the PAG depends on the release of glutamate and local activation of TRPV1,
mGlu1, mGlu5 and NMDA receptors [79]. Additionally, there is a decrease of ON-cell and increase
of OFF-cell activation in the RVM [105]. In an animal model of diabetic neuropathy, the injection of
capsaicin into the ventrolateral PAG (vlPAG) reduces the thermal hyperalgesia [100]. The injection
of capsaicin in the vlPAG leads to the activation of inhibitory descending pain mechanisms. The
analgesic effect produced by capsaicin injection in vlPAG depends on local TRPV1 activation that
culminates in the release of glutamate into RVM and subsequent activation of OFF-cells and
activation of inhibitory descending pain pathway [106]. Additionally, the glutamate released act in
mGlu5 post-synaptic receptors leading to Gq-protein-coupled PLCβ-DAGLα pathway-dependent
formation of the endocannabinoid 2-arachidonolyglycerol (2-AG). In turn, 2-AG activates pre-synaptic
CB1 receptors, leading to retrograde disinhibition of GABA release [99]. In addition, there is
co-expression of µ-opioid and TRPV1 receptors in vlPAG. Combined administration of capsaicin and
µ-opioid receptor agonist sub-doses at this site produces thermal analgesia in rats with increased
glutamate release and inhibition of ON-cell activity in RVM [107]. The injection of capsaicin into the
RVM inhibits the overt pain-like response in the inflammatory phase of the formalin test in rats with
streptozocin-induced diabetic neuropathy, an effect that may be associated with the up-regulation of
TRPV1 receptors in the RVM [108] (Figure 4).
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
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;
Capsaicin also induces analgesia when administered centrally in varied foci. For instance, the
intrathecal injection of capsaicin or RTX produces long-term regional analgesia with substance P
depletion [
101
103
]. The analgesic effect via supraspinal TRPV1 following intracerebroventricular
injection of capsaicin depends on the activation of Cav3.2 channels since mice lacking this receptor
present higher nociceptive response compared to WT mice [
104
]. The microinjection of capsaicin
in the periaqueductal gray (PAG) [
79
] or its dorsal portion (dPAG) in rats produces antinociception
to thermal stimulation and may be preceded by a short period of hyperalgesia [
105
]. The analgesic
effect of capsaicin in the PAG depends on the release of glutamate and local activation of TRPV1,
mGlu1, mGlu5 and NMDA receptors [
79
]. Additionally, there is a decrease of ON-cell and increase
of OFF-cell activation in the RVM [
105
]. In an animal model of diabetic neuropathy, the injection of
capsaicin into the ventrolateral PAG (vlPAG) reduces the thermal hyperalgesia [
100
]. The injection
of capsaicin in the vlPAG leads to the activation of inhibitory descending pain mechanisms. The
analgesic effect produced by capsaicin injection in vlPAG depends on local TRPV1 activation that
culminates in the release of glutamate into RVM and subsequent activation of OFF-cells and activation
of inhibitory descending pain pathway [
106
]. Additionally, the glutamate released act in mGlu5
post-synaptic receptors leading to Gq-protein-coupled PLC
β
-DAGL
α
pathway-dependent formation
of the endocannabinoid 2-arachidonolyglycerol (2-AG). In turn, 2-AG activates pre-synaptic CB
1
receptors, leading to retrograde disinhibition of GABA release [
99
]. In addition, there is co-expression
of
µ
-opioid and TRPV1 receptors in vlPAG. Combined administration of capsaicin and
µ
-opioid
receptor agonist sub-doses at this site produces thermal analgesia in rats with increased glutamate
release and inhibition of ON-cell activity in RVM [
107
]. The injection of capsaicin into the RVM
inhibits the overt pain-like response in the inflammatory phase of the formalin test in rats with
streptozocin-induced diabetic neuropathy, an effect that may be associated with the up-regulation of
TRPV1 receptors in the RVM [108] (Figure 4).
Considering the aforementioned evidence, capsaicin has been used as a support pharmacological
agent in pain management. Treatment with capsaicin is effective in different types of painful conditions
Molecules 2016,21, 844 10 of 33
such as complex regional pain syndromes and neuropathic pain [
109
,
110
]; postsurgical neuropathic
pain [
111
,
112
]; post-herpetic neuralgia [
113
,
114
] and painful diabetic peripheral neuropathy [
115
,
116
].
There is also report that repeated use of nasal capsaicin prevents cluster headache attacks [
117
].
In humans, topical capsaicin (0.075%) applied four times a day during 3 weeks causes the degeneration
of nerve fibers of the skin and consequently decreases sensitivity to cold and tactile stimuli, but to heat
and mechanical stimuli [118].
In patients with post-herpetic neuralgia, topical application of 8% capsaicin patch produced a
significant decrease in pain for 12 weeks [
119
,
120
]. A patient with post-traumatic neuropathic pain
presented 80% reduction of the area of allodynia after the use of 8% capsaicin patch. This effect was
observed up to the 18th month after application [
112
]. Oral treatment with capsaicin candy temporarily
relieves pain caused by oral mucositis, a common side effect in cancer patients in chemotherapy or
radiotherapy treatment [121].
The repeated topical application of capsaicin can cause intense burning sensation at both low and
high doses. However, the pretreatment with local anesthetic avoids the initial discomfort caused by
the use of single high dose of capsaicin [
110
,
122
]. The association of local anesthetic lidocaine-derived
QX-314 with capsaicin applied in a sensory nerve produces long-lasting analgesia in the orofacial
area and inhibits the jaw opening reflex induced by stimulation of the tooth pulp in rats [
123
]. The
perisciatic application of lidocaine (2%) or QX-314 (0.2%) associated with capsaicin (0.05%) in rats
after plantar incisional surgery decreases the mechanical hypersensitivity 72 hours after incision and
delays the onset of mechanical hypersensitivity by the destruction of TRPV1-expressing afferents.
Nevertheless, the delay in the onset of mechanical hypersensitivity was also observed in naïve animals
as well as signs of neurotoxicity [
124
]. The topical association of 3.3% tricyclic antidepressant doxepin
and 0.025% capsaicin is able to accelerate the development of analgesia in patients with neuropathic
pain compared with the separate use of formulations [125].
4. Pre-Clinical and Clinical Uses, and Pharmacological Actions of Capsaicin in Conditions Other
than Pain
4.1. Capsaicin in Weight Reduction and Obesity
Obesity is an escalating public health challenge globally and a major risk factor for various
diseases, including coronary heart disease, hypertension, type 2 diabetes mellitus and
cancer [126,127]
.
Thus, there is urgent need for new therapeutic strategies to treat obesity. In the past decades,
numerous studies have shown capsaicin is effective in promoting weight loss and amelioration
of obesity [
128
130
]. Herein, we will discuss some of the most relevant mechanisms involved in
capsaicin’s anti-obesity effects.
Obesity is the result of an energy imbalance that develops when energy intake exceeds energy
expenditure. Capsaicin can limit energy intake while it contains only negligible amounts of energy
itself [
131
133
]. Thus, great focus has been turned to studying the effect of capsaicin on energy balance.
In humans, the addition of capsaicin to the diet enhances anorexigenic sensations, such as satiety
and fullness [
132
,
134
]. Moreover, capsaicin decreases ad libitum food intake and suppress orexigenic
sensations, i.e., the desire to eat and hunger, in negative and positive energy balance [
131
,
132
,
135
].
Although the exact mechanism of action of capsaicin is not yet fully understood, several plausible
mechanisms have been proposed to explain these effects. An early study in rats demonstrated that
adding capsaicin in the diet caused an increase in catecholamine secretion in the adrenal medulla
via the activation of the central nervous system (CNS) [
136
,
137
]. There is an interaction between
sympathetic nervous system (SNS) activity and food intake behavior since food intake decreases when
SNS activity increases [
138
]. Therefore, increased SNS activity by capsaicin ingestion suggests that the
reduction in energy intake could be due to the anorexigenic effect of catecholamines [133]. Moreover,
the consumption of capsaicin increases the concentration of anorexigenic hormone glucagon-like
peptide 1 and decreases the concentration of orexigenic hormone ghrelin in humans [
139
]. Accordingly,
oral treatment with capsaicin can regulate high fat diet (HFD)-induced alterations in the expression of
Molecules 2016,21, 844 11 of 33
several anorectic and orexigenic genes and neuropeptides in the hypothalamus and prevent weight
gain in mice [140].
Numerous studies have highlighted the role of thermogenesis and increase in energy expenditure
(EE) in body weight regulation by capsaicin [
130
,
131
,
140
143
]. Among potential molecular mechanisms
involved in this regulatory effect of capsaicin, activation of TRPV1 appears to be critical as EE is
greatly attenuated in mice deficient in TRPV1 and in human individuals having a mutated (Val585Ile)
TRPV1 [
142
]. Increased thermogenesis and EE via capsaicin-induced TRPV1 activation is resultant of
catecholamine release and subsequent SNS activation of
β
-adrenoceptors [
143
,
144
]. This mechanism is
corroborated by studies showing that the administration of
β
-adrenergic blockers such as propranolol
attenuates thermogenesis [
144
]. The activation of brown adipose tissue (BAT), which is the major site
of sympathetically activated non-shivering thermogenesis, via the TRPV1/
β
-adrenergic axis, has been
shown to be central to the thermogenic effect of capsaicin [
142
,
145
]. Nevertheless, other effects such as
increased fat mobilization (triglyceride oxidation) in white adipose tissue (WAT) and improved energy
metabolism in skeletal muscle mediated by TRPV1 activation also seem to be important in increased
EE by capsaicin [142,146].
The amount of adipose tissue is tightly regulated and dependent on the differentiation of
preadipocytes to adipocytes, a process known as adipogenesis. The modulatory effect of capsaicin on
this process has been implicated in the reduction adipose tissue [
147
,
148
]. Previous studies have shown
that capsaicin reduces the expression of adipocyte differentiation-related proteins PPAR
γ
, C/EBP
α
,
and leptin in a concentration-dependent manner, and the differentiation of 3T3-L1 preadipocytes into
adipocytes [
149
151
]. Similarly, capsaicin also inhibits the differentiation of bone marrow mesenchymal
stem cells (BMSCs) into adipocytes [
152
]. Thus, capsaicin-mediated modulation of adipogenesis is
not limited to preadipocytes. The inhibitory effect of capsaicin on this process seems to involve
the activation of 5’ adenosine monophosphate-activated protein kinase (AMPK) in conjunction with
intracellular ROS release [
150
]. Activated AMPK blocks anabolic pathways and promotes catabolic
pathway. Thus, AMPK activation is also linked to inhibition of cell proliferation and apoptosis [
153
,
154
].
In support of this concept, capsaicin targets preadipocyte proliferation by blocking the S-phase of
the cell cycle [
149
]. Capsaicin also reduces the number of BMSCs in S phase and induces cell cycle
arrest at G0-G1 [
152
]. Interestingly, capsaicin induces apoptosis in preadipocytes via the activation of
caspase-3, Bax, and Bak, cleavage of PARP, and down-regulation of Bcl-2 [
151
]. Furthermore, capsaicin
induces apoptosis in BMSC via increased production of ROS and reactive nitrogen species (RNS) [
152
].
Thus, the reduction in preadipocyte/adipocyte population and adipose tissue by capsaicin can also be
attributed to the inhibition of proliferation and apoptosis.
In addition to the previously discussed mechanisms of capsaicin’s anti-obesity effect, the capsaicin
alteration in gut microbial population also seems to be important in preventing HFD-induced weight
gain. Oral administration of capsaicin regulated HFD-induced alterations in the abundance of
certain bacterial groups in the cecum of Swiss mice, e.g., Bacterioidetes,Firmicutes,A. muciniphila,
and Enterobacteriaceae [
145
]. Gut microflora is important in the regulation of host metabolism and
energy harvest and may contribute to the development of obesity [
155
]. In fact, dysbiosis in gut
microflora is commonly observed in obese humans and animals [
156
158
]. Therefore, the beneficial
alteration in gut microbial population may also be beneficial in HFD-induced obesity.
It is noteworthy that, despite abundant evidence supporting the beneficial role of capsaicin in
weight management, some studies have reported no or minimal effects of capsaicin on weight loss in
humans [
159
,
160
]. Other studies have suggested that the magnitude of capsaicin
´
s effects on weight
loss in humans is actually quite small [
131
,
160
]. For instance, 10 kcal negative energy balance, which
is the predicted for hedonically acceptable capsaicin doses, in an average weight, middle-aged man
would produce an ultimate weight loss of 0.5 kg over 6.5 years [
131
]. This is important considering
that the long-term sustainability is uncertain due to factors such as desensitization upon long-term
intake, side effects, and pungency of capsaicin [
131
,
160
]. Nevertheless, on a population scale, modest
sustained weight loss can be predicted to generate substantial health and economic benefits [
161
].
Molecules 2016,21, 844 12 of 33
Furthermore, it is likely that the analgesic therapy using capsaicin would not reduce the life quality of
patients as observed with tricyclic antidepressants, which increase weight gain [
162
]. Indirectly, the
reduction of weight gain will diminish co-morbidities such as knee pain.
4.2. Capsaicin in Glucose Homeostasis and Diabetes
In addition to the effects of capsaicin on body metabolism [
130
,
146
], this pungent compound
may also have beneficial effects on glucose and insulin homeostasis and diabetes. Dietary and
supplementation with capsaicin display an impact on glucose and insulin levels in humans [
163
165
].
Regular consumption of capsaicin-containing chili attenuates postprandial hyperinsulinemia in healthy
adults [
163
] and supplementation with it improves postprandial hyperglycemia and hyperinsulinemia
in women with gestational diabetes mellitus (DM) [
165
]. Further, a crossover study performed on
healthy male volunteers revealed that capsaicin lowers glucose and increases insulin levels shortly after
oral administration in an oral glucose tolerance test [
164
]. Importantly, this study not only determined
that capsaicin could be detected in the blood as early as 10 min after ingestion and levels maintained
for up to 90 min, but also that capsaicin levels correlates with the lower glucose levels and maintenance
of the insulin levels [164].
Animal studies have reported similar beneficial effects of capsaicin administration on glucose and
insulin homeostasis [
166
168
]. Additionally, these studies have also shed light on the mechanisms that
may be involved in these effects. For instance, capsaicin may inhibit glucose tolerance by inhibiting
adipose tissue inflammatory responses in obesity [
169
,
170
].
In vitro
, capsaicin suppresses IL-6 and
MCP-1 gene expression and protein release from adipose tissue and adipocytes of obese mice [
169
].
Further, dietary capsaicin markedly reduces adipose tissue macrophages and levels of inflammatory
adipocytokines (TNF-
α
, MCP-1, IL-6, and leptin) and normalizes fasting glucose levels in obese
mice [
170
]. Obesity-related inflammatory proteins can block insulin signaling [
171
,
172
]; therefore,
capsaicin may reduce glucose tolerance by suppressing their production in obese mice.
Similarly to many of the other actions described for capsaicin (reviewed herein), there is evidence
that the modulation of blood glucose levels and insulin secretion by capsaicin is TRPV1-dependent.
Capsaicin induces the secretion of insulin and antihyperglycemic hormone glucagon like peptide-1
in the ileum of WT but not TRPV1
´/´
mice [
173
]. Moreover, improved glucose tolerance, insulin
levels, and blood glucose profiles by chronic dietary capsaicin are absent in TRPV1
´/´
mice [
173
].
In support of this concept, TRPV1 is functionally expressed in islet
β
-cells, neurons, rat pancreas,
and rat
β
-cell lines RIN and INS1, and capsaicin can modulate insulin secretion by these cells via
TRPV1 [
167
,
174
176
]. In rats, for instance, capsaicin dose-dependently increases insulin secretion
and plasma insulin concentrations in TRPV1 expressing islet
β
-cells and this effect is inhibited by the
TRPV1 inhibitor capsazepine [176].
Recent advances in research have revealed that TRPV1 receptors play a central role in the
development and progression of type 1 and 2 diabetes [
175
,
177
]. In fact, the ablation TRPV1
expressing sensory nerves by capsaicin has been shown to modulate disease development and/or
progression [
174
,
175
]. Sensory nerves innervating the pancreas are considered major players in
the development of pancreatitis and islet inflammation and destruction [
174
]. Capsaicin-induced
permanent elimination of TRPV1-expressing pancreatic sensory neurons reduces islet infiltration,
insulin resistance, and
β
-cell stress in neonatal diabetes-prone non-obese diabetic (NOD) mice [
174
].
Therefore, capsaicin-induced depletion of TRPV1-expressing neurons prevents the development
of diabetes in mice that are genetically predisposed to type 1 diabetes [
174
]. Similarly, in Zucker
diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes, the
selective elimination of TRPV1 expressing sensory fibers in the islets of Langerhans by capsaicin
prevents plasma glucose levels increase and glucose tolerance, and enhances insulin secretion [
175
].
Interestingly, capsaicin also protects mice from the development of type 1 diabetes via TRPV1 by a
mechanism related to gut-mediated immune tolerance. Oral administration of capsaicin attenuates
the proliferation and activation of autoreactive T cells in pancreatic lymph nodes (PLNs), protecting
Molecules 2016,21, 844 13 of 33
mice from diabetes development [
177
]. The engagement of TRPV1 enhances a discreet population of
CD11b
+
/F4/80
+
macrophages in PLNs, which is essential for capsaicin-mediated attenuation of T-cell
proliferation in an IL-10-dependent manner [
177
]. Therefore, capsaicin/TRPV1 signaling can limit
glucose levels increase and diabetes development.
4.3. Capsaicin in Cardiovascular Conditions
There is evidence that capsaicin has potential beneficial effects on the cardiovascular
system [178180]
. The cardiovascular system is rich in capsaicin-sensitive sensory nerves that play
a major role in regulating cardiovascular function through the release of neurotransmitters such as
CGRP and substance P [
180
,
181
]. CGRP is considered to be one of the most powerful vasodilators and
plays an important role in regulating blood pressure under both physiological and pathophysiological
conditions [
182
184
]. Capsaicin stimulates the release of CGRP through the activation of TRPV1
and therefore decreases blood pressure [
180
,
185
]. However, the protective effects of endogenous
CGRP rely on the intact function of capsaicin-sensitive sensory nerves since high dose of capsaicin
pretreatment, which selectively depletes transmitters in capsaicin-sensitive sensory nerves, could
abolish the protective effects of CGRP or even enhance hypertension [
186
188
]. Although blood
pressure regulation by capsaicin-stimulated CGRP release is more widely described, dietary capsaicin
has also been shown to reduce blood pressure in hypertensive rats and delay the onset of stroke in
stroke-prone spontaneously hypertensive rats (SHRsp) by increasing the phosphorylation of PKA and
endothelial nitric oxide synthase (eNOS) via TRPV1 activation [
189
,
190
]. It is noteworthy to mention
that CGRP antagonists, such as Olecegepant (BIBN4096BS), BI44370A, Telcagepant (MK-0970), and
MK-3207 do not alter basal blood pressure despite the role of CGRP in regulating blood pressure [
191
].
In addition to the regulatory effects on blood pressure, other cardioprotective effects have also
been described for capsaicin. Long-term activation of TRPV1 by capsaicin decreases lipid storage
and atherosclerotic lesions in aortic sinus and thoracoabdominal aorta of mice [
192
]. Additionally,
activation of TRPV1 by capsaicin impedes foam cell formation by inducing autophagy in oxidized
low-density lipoprotein (oxLDL)-treated vascular smooth muscle cells and ultimately slows down the
process of atherosclerosis [
193
]. Moreover, it is likely that the antioxidant property of capsaicin also
contributes to their protective effects on cardiovascular system. The oxidation of LDL is an initiating
factor for the development and progression of atherosclerosis [
194
].
In vitro
, capsaicin increases the
resistance of LDL to oxidation by delaying the initiation of oxidation and/or slowing the rate of
oxidation [
195
]. In HFD rats, capsaicin treatment reduces lipid peroxide levels in the serum [
196
,
197
].
Moreover, it has been reported that regular consumption of chili for 4 weeks increases the resistance
of serum lipoproteins to oxidation in adult men and women [
198
]. These reports further support the
potential clinical value of capsaicin on the prevention of cardiovascular diseases, such as atherosclerosis
and coronary heart disease.
Capsaicin has been shown to inhibit platelet aggregation [
199
,
200
], which may also provide
protection against cardiovascular diseases [
201
]. Capsaicin’s anti-aggregating effect on platelets
is attributed to the alteration in the fluidity of platelet membrane [
202
,
203
]. The anti-aggregating
effect of capsaicin on platelets seems to be TRPV1-independent since a selective competitive TRPV1
inhibitor A-993610 does not affect the ability of capsaicin to inhibit platelet aggregation [
200
].
However, there is conflicting data showing TRPV1-dependent pro-aggregating effect of capsaicin,
via serotonin release, and adenosine diphosphate- and thrombin-induced platelet activation [
204
].
Therefore, further investigation is needed to verify the anti-haemostatic property of capsaicin and the
mechanisms involved.
4.4. Capsaicin in Cancer
Despite several advances in therapies, cancer is still a major cause of morbidity and mortality
worldwide [
205
]. In the past decades, the anticancer activity of capsaicin has been broadly
investigated for a variety of cancer types. Capsaicin has been shown to possess chemopreentive
Molecules 2016,21, 844 14 of 33
and chemotherapeutic effects [
206
,
207
], and
in vivo
studies support the antitumorigenic activity of
capsaicin [
207
,
208
]. In contrast, there is conflicting evidence that capsaicin may also act as carcinogenic
or co-carcinogenic [209], thus capsaicin might play a role in either preventing or causing cancer.
The exact cellular mechanisms involved in capsaicin’s anticancer effects are still not completely
understood, however, numerous studies have attributed it to apoptosis, cell-cycle arrest, and
anti-angiogenic effects [
207
,
210
,
211
]. Many types of cancer disrupt apoptotic pathways and/or enhance
anti-apoptotic ones, and the loss of apoptotic signaling is highly associated with malignancy [
212
].
Capsaicin can induce apoptosis in over 40 different types of cancer cell lines [
213
,
214
]. Some of the
mechanisms that have been described are activation of cAMP-activated protein kinase [
215
] in human
osteosarcoma cells and PPAR
γ
-induced apoptosis in HT-29 human colon, endoplasmic reticulum stress
in human nasopharyngeal carcinoma and pancreatic cancer cells, down-regulation of STAT3 target
genes Bcl2 and survivin in multiple myeloma cells, among others [
213
]. Interestingly, in many types
of cancers, capsaicin exhibits pro-apoptotic activity, which seems to be related to TRPV1 or TRPV6
activation. The activation of these receptors by capsaicin induces calcium-mediated mitochondrial
damage and subsequent cytochrome c release [216,217].
Cell cycle and growth arrest are important defense mechanisms against cancer and targets for
cancer prevention and therapy [
218
], and capsaicin has been shown to modulate both. In human
bladder cancer cell line 5637, capsaicin induces G0/G1 phase arrest by inhibiting cyclin-dependent
kinases (CDK) 2, CDK4 and CDK6 [
210
]. Similarly, capsaicin reduces in a concentration-dependent
manner cyclin D1 in colon cancer cell lines [
213
,
219
]. In breast cancer cells, on the other hand, capsaicin
induces cell-cycle arrest by modulating the epithelial growth factor receptor/HER2 pathway and p27
expression in estrogen receptor-positive and -negative cells [
220
]. Taken together, these data show that
capsaicin may halt growth and division of cancer cells by targeting cell cycle regulators. Nevertheless,
it is important to mention that several other mechanisms of capsaicin-induced cell-cycle arrest have
also been described for capsaicin [213].
Angiogenesis is an essential factor for the progression of most types of cancer. It has been
demonstrated that capsaicin has anti-angiogenic properties both
in vitro
and
in vivo
by interfering
with angiogenic signaling pathways [
221
]. Treatment of endothelial cells with capsaicin suppresses
VEGF-induced proliferation, migration and tube formation in mice via down-regulation of p38 MAPK,
protein kinase B (PKB or AKT) and focal adhesion kinase (FAK) activation [
221
]. Further, capsaicin
increases the degradation of hypoxia inducible factor 1
α
in non-small cell lung cancer, which is a key
transcription factor for VEGF transcription [
222
]. Collectively, these studies highlight the anticancer
potential of capsaicin by regulating several mechanisms that are commonly altered in cancer cells and
are important for tumor growth.
Despite the mounting evidence supporting a chemo-preventive role for capsaicin in cancer cell
culture and animal models, a consensus about whether capsaicin prevents or promotes cancer has not
yet been reached [
223
]. Several animal studies have shown that capsaicin is potentially carcinogenic.
For instance, approximately 60% of rats fed a semisynthetic diet containing 10% chilies develop
neoplastic changes in the liver [
224
]. Also, mice fed 0.03% capsaicin in a semisynthetic diet over their
lifetime develop benign polypoid adenomas of the cecum [
225
]. Moreover, studies report that capsaicin
may also have co-carcinogenic potential. Topical application of capsaicin on the dorsal skin of mice
with 9, 10-dimethylbenz(a)anthracene (DMBA)/12-Otetradecanoylphorbol-13-acetate (a known skin
tumor inducer) significantly accelerated tumor formation and growth and induced more and larger
skin tumors. Mechanistic study revealed that pre-treatment with capsaicin elevated cyclooxygenase-2
and iNOS and up-regulated the phosphorylation of nuclear factor-kappa B (NF-
κ
B), ERK, and p38,
indicating that inflammation, ERK and p38 collectively play a crucial role in cancer-promoting effect
of capsaicin in carcinogen-induced skin cancer in mice [
226
]. Chili extract and hot chili pepper
containing capsaicin promoted the development of stomach tumors initiated by methyl-acetoxy
methylnitrosamine in mice and increased the incidence of N-methyl-N-nitrosoguanidine–induced
gastric cancer in rats, respectively [
227
,
228
]. Furthermore, capsaicin (125 mg/kg)-induced systemic
Molecules 2016,21, 844 15 of 33
denervation of sensory neurons results in significant increase of lung and cardiac metastases in adult
mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells [
229
]. In line with these
findings, many epidemiologic studies indicate that consumption of hot peppers, containing capsaicin,
might be associated with an increased risk of cancer, especially gallbladder or gastric cancer [
230
,
231
].
However, many of these epidemiologic studies present considerable limitations.
4.5. Capsaicin in Airway Diseases
Nociceptors play important role in airway diseases such as allergic rhinitis and asthma [
232
,
233
],
which are accompanied by intense inflammatory infiltrate [
232
234
]. Nociceptors also play an active
role in the regulation of immune response since they can recognize and respond to danger and
environment stimuli [
235
,
236
]. Therefore, the inhibition of their activity in airway diseases may
be beneficial to the host [
232
,
233
]. In fact, injection of capsaicin in mice exposed to ovalbumin
exacerbates airway inflammation by increasing the number of leukocytes in the broncho alveolar
lavage fluid (BALF) [
232
]. Further corroborating this concept, the ablation of the nociceptor by using
the Nav1.8-Cre/DTA mice strain [
232
] or using interference RNA for TRPV1 [
233
] reduce these same
parameters in allergic rhinitis and asthma models, suggesting an endogenous role for TRPV1. In
this sense, QX-314 silences nociceptors, which leads to the reduction of the number of infiltrating
leukocytes in the BALF, IL-5 production, and improvement of airway inflammation [
232
]. IL-5 is one
of the main cytokines in asthma. In a cascade of events, IL-5 activates in a calcium-dependent manner
capsaicin-responsive nodose ganglia and Nav1.8-positive nociceptors, which in turn release vasoactive
intestinal polypeptide (VIP). VIP activates innate lymphoid cells 2 (ILC2) and culminates in airway
inflammatory exacerbation [232].
Non-allergic rhinitis (NAR) or idiopathic rhinitis (IR) may be described as chronic nasal symptoms,
such as obstruction and rhinorrhea that occur in relation to non-allergic, non-infectious triggers such
as change in the weather, exposure to caustic odors or cigarette smoke, and barometric pressure
differences [
237
]. Intranasal application of capsaicin has beneficial effects in this type of rhinitis,
although this application is initially irritating to the applied area, it can eventually desensitize the
sensory neural fibers and reduce nasal hyper-responsiveness [
238
]. The desensitization of sensory
nerves with capsaicin has been shown to provide symptom relief for up to 9 months. Patients
treated with intranasal capsaicin reported significantly reduced visual analog scale scores for overall
nasal symptoms, rhinorrhea, and nasal blockage [
239
]. In agreement with previous reports, in a
placebo-controlled study with of 24 patients with non-allergic non-infectious perennial rhinitis, the
group treated with 0.15 mg capsaicin spray solution over 2 weeks showed significant and long-term
reduction in the visual analogue scale scores. However, no significant difference was observed in the
concentrations of leukotriene C4, D4 or E4, prostaglandin D2, and tryptase when compared to placebo
group [
240
]. On the other hand, the same dose and treatment protocol used in the previous work
showed no significant therapeutic effect in patients with perennial allergic rhinitis due to house dust
mite [
241
], suggesting that the application of capsaicin would be benefit only in non-allergic-related
rhinitis. A recent study has shown that NAR/IR is associated with an increased expression of TRPV1
in the nasal mucosa and substance P levels in nasal secretions. Mechanistic studies revealed that
capsaicin exerts its therapeutic action by ablating TRPV1-substance P nociceptive signaling pathway
in the nasal mucosa [242].
The role of capsaicin as a therapeutic agent was not addressed in the work of Talbot et al. [
232
],
therefore, the question whether prolonged administration of capsaicin could produce similar results to
those in NAR still remains. In spite of that, this study has shed some light on the role of nociceptors in
airway diseases, which highlight these cells as key players in the physiopathology of several diseases.
Additionally, this study highlights QX-314 as a solid candidate for the treatment of diseases that TRPV1
plays a role since QX-314 requires an opener (endogenous or exogenous activator of TRPV1) to access
nociceptors and inhibit them [47,123,232].
Molecules 2016,21, 844 16 of 33
4.6. Capsaicin in Itch
Itch (pruritus) elicits scratching response, whereas pain causes withdrawal responses. Both itch
and pain are detected by primary sensory neurons in DRG and trigeminal ganglion, and therefore,
share transduction machinery involving TRPV1, TRPA1, and Toll-like receptors (TLRs) [
243
]. Despite
these similarities, whole population analysis of nociceptors reveals the presence of three distinct
populations, which are further divided into seven subgroups. These subgroups are differentiated
by the expression of neuronal receptors or ion channels [
244
]. For instance, DRG neurons of the
group VI co-express B-type natriuretic polypeptide b (Nppb) receptor and IL-31ra, which implies these
DRG neurons as mediators of itch sensation [
244
]. This also reveals the highly complex machinery of
peripheral nociceptors and uncovers novel receptors as targets for pain or itch relief. In fact, nociceptors
play an important role in pruritic diseases [
245
,
246
] since silencing nociceptors with QX-314 reduces
non-histaminergic and histaminergic itch [
245
]. Both non-histaminergic and histaminergic itch activate
TRPV1 and TRPA1 channels and allow QX-314 entry in DRG neurons [
245
]. In addition, ablation
of nociceptors reduces skin inflammation and psoriatic plaque formation [
246
]. These set of data
highlight specific subsets of nociceptors as important players in itch.
Supporting the role of TRPV1-expressing neurons in itch, treatment with dermal patch of
0.025% of capsaicin reduces itch in psoriatic patients [
247
,
248
], although in one of these studies,
18 of 44 patients refer burning, stinging, itching, and redness of the skin [
248
]. In two other studies,
treatment with 8% capsaicin patch reduces itch intensity and frequency in three patients with nostalgia
paresthetica [
249
], and in 7 patients with neuropathic pruritus [
250
]. Also, in these studies, the majority
of the patients referred erythema and moderate pain, pointing out to an important common side effect
due to dermal capsaicin treatment. Of note, capsaicin 0.1% reduces allyl isothiocyanate (AITC)-evoked
scratching in mice [
245
]. Regardless of the above mentioned efficacy capsaicin in itch, robust data and
further clinical trials are needed to confirm the beneficial properties of capsaicin. In addition, the side
effects mentioned can be a drawback to the use of capsaicin in itch.
4.7. Capsaicin in Gastric Disorders
Sensory neurons are responsible for maintenance of gastric integrity [
251
]. Therefore, the
gastroprotective effects of capsaicin lie in the modulation of the sensory neurons, since chemical
ablation of these neurons mitigates capsaicin protective effects [
252
254
]. Daily treatment with
400
µ
g of capsaicin, three times a day, reduces ethanol- and indomethacin-induced gastric mucosal
damage in healthy human subjects [
255
]. In terms of animal models, treatment with capsaicin also
reduces indomethacin-induced microbleeding [
255
]. Corroborating, intragastric administration of
capsaicin in rats and dogs attenuates aspirin-, indomethacin- and ethanol-induced gastric damage [
251
],
and enhances gastric protection by stimulating capsaicin-sensitive sensory neurons. This effect
was demonstrated using
51
Cr-EDTA clearance technique, which evaluates epithelial integrity by
mucosal blood-to-lumen permeability [
254
]. The gastroprotective mechanism of capsaicin is due to the
activation of TRPV1 at gastric sensory neurons which stimulates the release of CGRP and NO [
251
,
255
]
since co-treatment of capsaicin and L-nitro-arginine methyl ester (L-NAME, a NOS inhibitor) reduces
capsaicin effectiveness in mice [256].
Helicobacter pylori (H. pylori) is one of the main causative agents of gastric ulcer, and its presence
correlates with use of NSAIDs [
257
]. Capsaicin reduces H. pylori-induced gastric ulcer by reducing
IL-8 production. In addition, capsaicin also reduces H. pylori-induced NF-
κ
B activity evaluated by
luciferase activity for p65 subunit and nuclear translocation by confocal immunofluorescence in gastric
epithelial cells [
258
]. Moreover, it is noteworthy that capsaicin per se possess bactericidal activity and
inhibits H. pylori growth
in vitro
which may contribute to its protective effect [
259
]. Thus, the medical
premise that consumption of chili peppers may be prejudicial to the host is not entirely true. In fact,
epidemiologic studies with 103 patients with peptic ulcer in China [
260
], and 190 in India [
261
] suggest
that consumption of chili peppers is inversely proportional to the incidence of peptic ulcer pointing
out to the gastroprotective effects of capsaicin.
Molecules 2016,21, 844 17 of 33
4.8. Capsaicin in Urological Disorders
Capsaicin has been studied as an alternative therapy for the relief of the symptoms of neurogenic
bladder, a urological disorder that seriously affects the quality of life of patients [
262
]. Neurogenic
bladder is often present in patients with multiple sclerosis, spinal cord injury, and other neurological
pathologies. Neurogenic detrusor overactive (NDO) and detrusor hyperreflexia are dysfunctions that
characterize neurogenic bladder and lead to urgency and increase in urinary frequency, and in many
cases, incontinence [
262
,
263
]. Overactive bladder is a clinical condition that resembles neurogenic
bladder [
264
], however, its etiology is not associated with neurological or urogenital diseases [
265
,
266
].
The first possibility of clinical use of capsaicin in the treatment of urinary tract disorders was
demonstrated using intravesical injection of a 100 mL of 1 mM (30 mg) solution of capsaicin (dissolved
in alcohol and saline) in patients with multiple sclerosis that presented bladder detrusor hyperreflexia.
The same dose has been used successfully in several studies of patients with neurogenic detrusor
over activity after spinal cord injury or neurogenic bladder [
267
270
]. The use of alcohol as a solvent
can cause irritation and become a limiting factor in the use of capsaicin, causing pelvic pain in more
than 50% of patients as reviewed before [
271
]. The efficacy of an alternative dilution of capsaicin in
a glucidic solution to treat patients with neurogenic detrusor over activity was also demonstrated.
However, this dilution has not been able to avoid pain reported by treatment with capsaicin [272].
Capsaicin also seems to have a protective effect against bladder disorders. An animal study
demonstrated that the pretreatment with capsaicin (125 mg/kg, s.c.) was able to prevent spinal cord
injury-induced hyperreflexia of the detrusor in rats. A boost treatment 4-5 days after spinal injury
maintained the effect of capsaicin [273].
The effect of capsaicin or RTX is related to the action on TRPV1 receptors in the urinary tract,
not only in sensory fibers that innervate these structures, but also in urothelial cells [
274
,
275
].
In vitro
studies with bladder urothelial cells from non-neurogenic overactive bladder patients showed that
expression and activation of TRPV1, as well as capsaicin-sensitivity are increased in comparison with
healthy volunteers [
276
,
277
]. Capsaicin targeting of TRPV1 receptors in the C-fibers leads to the
activation followed by desensitization, being responsible for the beneficial effect of capsaicin on the
bladder activity, but also by the initial pain sensation due to their use [262].
The use of both capsaicin and RTX is still not a routine clinical practice and can become
an alternative treatment for patients who do not respond to conventional therapy with oral
antimuscarinics, especially those with neurogenic bladder. However, both molecules present the
disadvantage of repeated intravesical applications and the initial discomfort that may discourage the
patient adherence to treatment [262].
5. Clinically Available Capsaicin Pharmaceutical Formulations
Among the therapeutic uses of capsaicin in the clinic, the most common is for the management
of pain. Low-concentration creams, lotions, and patches containing capsaicin (0.025%–0.1% wt/wt)
intended for daily topical application have been available in most countries since the early 1980s. These
topical formulations are usually self-administered medications and often without the requirement of a
prescription [
278
]. Clinical studies have revealed that three to five topical skin applications per day for
periods of two to six weeks have modest beneficial effects against various pain syndromes, including
post-herpetic neuralgia, diabetic neuropathy, and chronic musculoskeletal pain [
279
,
280
]. Another
topical capsaicin formulation available is the high concentration patch containing 8% capsaicin, which
is widely used to treat post-herpetic neuralgia, HIV neuropathy, and other conditions with neuropathic
pain symptoms [
281
,
282
]. The capsaicin 8% patch rapidly delivers capsaicin into the skin while
minimizing unwanted systemic effects, and it is already approved for treatment of neuropathic pain in
Europe and USA (only post-herpetic neuralgia) [
116
]. Robust clinical data demonstrate the efficacy
of 8% patch in the treatment of neuropathic pain [
116
,
283
,
284
]. Of note, in a study with patients
with neuropathic pain in Scotland [
283
], and another involving 629 patients of 22 countries and
regions [
284
], suggest that the 8% patch presents similar efficacy to pregabalin, no differences in time
Molecules 2016,21, 844 18 of 33
to response between treatments, and therefore, represents a promising alternative for the treatment of
neuropathic pain [
283
,
284
]. The administration of this formulation requires a single application for
30 or 60 min under the supervision of a health-care professional, which reduces potential variability in
administration and a lack of patient compliance, in addition to avoiding environmental exposure of
patients to capsaicin [278,281,282].
Pharmaceutical formulations for per oral administration of capsaicin are available in the form
of capsules containing chili peppers [
140
]. The therapeutic dose for per oral administration of
capsaicin has not been established, however, the generally recommended daily dose stated on labels of
commercially available capsules is 1350–4000 mg of capsicum with 0.25% capsaicin. This range of dose
has been shown to increase energy expenditure, fat oxidation, thermogenesis, and decrease appetite
in humans [
130
], although both lower (0.4–2 mg) and higher (135–150 mg) doses are also effective in
promoting these effects [
135
,
160
,
285
]. Other pharmaceutical formulations containing capsaicin are
capsicum nasal sprays and homeopathic preparation of Capsicum annum and Eucalyptol nasal sprays.
These formulations have been used to treat nonallergic rhinitis and the symptoms associated with
this condition [
286
,
287
]. Although a therapeutic dose has not been established yet, a previous study
has shown that 4 µg/puff of capsicum, three times a day for three consecutive days, is efficacious for
non-allergic, non-infectious perennial rhinitis [287].
6. Conclusions and Future Perspectives
Capsaicin and food-containing capsaicin have been together with humans over thousands of years,
but only more recently that our understanding of how capsaicin affects our organism has significantly
advanced. Capsaicin has been essential to our understanding of physiological and pathological
processes as well as the relevance of TRPV1 channels. Figure 5summarizes the pharmacological actions
of capsaicin reviewed herein. Capsaicin importance is corroborated by the varied pharmaceutical
formulations available and clinical applications, such as the capsaicin 8% patch to treat neuropathic
pain. Despite being an old molecule, capsaicin is still a hot topic in scientific community and presents a
wide horizon of potential therapeutic uses. Therefore, new pharmaceutical formulations, development
of new analogs, or targeting the capsaicin-activated receptor TRPV1 are promising pharmacological
approaches in the following years.
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.
Molecules 2016,21, 844 19 of 33
Acknowledgments:
This work was supported by grants from Coordenadoria de Aperfeiçoamento de Pessoal
de Nível Superior (CAPES, Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq,
Brazil), Ministério da Ciência, Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Ensino Superior
(SETI)/Fundação Araucária and Governo do Estado do Paraná (Brazil).
Conflicts of Interest: The authors declare no conflict of interest.
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