Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
Publications > Journals > Journal of Exploratory Research in Pharmacology> Article Full Text
Review Article
OPEN ACCESS

Download PDF

Role of TRPV1 in Health and Disease

  • Sahar Majdi Jaffal* 
Journal of Exploratory Research in Pharmacology   2023;8(4):348-361

doi: 10.14218/JERP.2023.00013

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Jaffal SM. Role of TRPV1 in Health and Disease. J Explor Res Pharmacol. 2023;8(4):348-361. doi: 10.14218/JERP.2023.00013.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) channel is a non-selective cation channel that plays a pivotal role in pain transduction. However, more than a pain sensor, it is involved in an array of vital processes in different body systems. The findings of several studies illustrated that many disorders are associated with alterations in the function and/or expression of the TRPV1 channel. Accordingly, the TRPV1 channel has become an important target in numerous therapeutic interventions. Several TRPV1 antagonists are already in the market, however, there is a need for new drugs with fewer or no side effects. This review highlights the involvement of the TRPV1 channel in a plethora of physiological and pathological conditions and points to its importance as a therapeutic target.

Keywords

TRPV1, Expression, Function, Health, Disease, Target

Introduction

Transient receptor potential vanilloid 1 (TRPV1)

In 1997, TRPV1 receptor was cloned from the dorsal root ganglia (DRGs) neurons of rats.1 Since then, multiple studies have been conducted to elucidate the structure, mechanisms and roles of the TRPV1 channel in health and disease. The TRPV1 channel is a non-selective cation channel characterized by cation influx when activated1 with a very high calcium (Ca2+) permeability (PCa/PNa ∼ 10).1 Previous research highlights that several endogenous and exogenous stimuli activate the TRPV1 channel. More specifically, the channel is activated by noxious heat (>43 °C), anandamide, low extracellular pH, redox state, prostaglandins (PGs), nerve growth factor (NGF), substance P (SP), oxytocin, lysophosphatidic acid, 9, 13 and 20-hydroxyoctadecadienoic acid, linoleic acid as well as the highly selective agonists capsaicin and resiniferatoxin (RTX).1–3

TRPV1 structure

Figure 1 depicts TRPV1 structure. TRPV1 channel possesses a tetrameric structure with 6 transmembrane domains and pore-forming hydrophobic stretch linking segment 5 (S5) and S6.4 The channel has an unusual characteristic in which it has cytosolic intracellular C and N termini.5 Notably, a considerable amount of literature showed that the TRPV1 channel contains multiple phosphorylation sites whereby its activity can be regulated by various kinases, including protein kinase A (PKA), PKC, Ca2+/calmodulin dependent kinase II (CaMKII), sarcoma (Src) kinase, and the Ca2+-dependent phosphatase, calcineurin.6

Transient receptor potential vanilloid 1 (TRPV1) structure.
Fig. 1  Transient receptor potential vanilloid 1 (TRPV1) structure.

The TRPV1 channel possesses a tetrameric structure with 6 transmembrane domains and a pore-forming hydrophobic stretch linking segment 5 (S5) and S6. The channel has an unusual characteristic in which it has cytosolic intracellular C and N termini. When the TRPV1 channel is activated, sodium (Na+) and calcium (Ca2+) channels open leading to ion influx, initiation of depolarization, additional Ca2+ entry through voltage-gated Ca2+ channels, propagation of action potential into the central nervous system (CNS) and finally, different sensations. H+ refers to protons.

TRPV1 activation

There are several mechanisms for TRPV1 activation. In more detail, TRPV1 agonists (e.g. capsaicin and anandamide) activate the channel by direct binding while the non-agonist activators can induce sensitization for the channel through post-translational modifications, changing one or more of the following parameters: membrane potential, pH, temperature threshold, or trafficking to the plasma membrane.7,8 Overall, when the TRPV1 channel is activated, sodium (Na+) and Ca2+ channels open leading to ion influx, initiation of depolarization, additional Ca2+ entry through voltage-gated Ca2+ channels, propagation of action potential into the central nervous system (CNS) and finally, different sensations such as stinging, burning, itching or a feeling of warmth.9,10 Xin et al. (2005) reported the involvement of the TRPV1 channel in Ca2+ release from intracellular stores due to its expression in the endoplasmic reticulum (ER), sarcoplasmic reticulum and membrane.11 Accordingly, the TRPV1 channel contributes to the increase in Ca2+ concentration through four sources including the TRPV1 channel in the plasma membrane and ER; Ca2+-induced Ca2+ release and store-operated Ca2+ entry.12 On the other hand, Ferrini et al. (2007) reported that the administration of capsaicin to the spinal lamina II neurons causes SP release that excites inhibitory neurons in laminae I, III and IV, leading to an increase in the release of inhibitory neurotransmitters (e.g. gamma-amino butyric acid (GABA)/glycine) in mice.13 Thus, capsaicin enhances the inhibitory neurotransmission as a parallel alternative pathway to glutamate in the transfer of nociceptive signals.13

TRPV1 expression

It is well documented that the TRPV1 channel is highly expressed in DRGs, trigeminal ganglia (TGs) and the spinal cord.1 Also, it is found in the striatum, amygdala, thalamus, microglia, astrocytes and other regions in the CNS as well as non-neuronal tissues such as hair follicles, mast cells, smooth muscles, keratinocytes, liver, tongue, oral cavity, bladder, kidneys, lungs, spleen and cochlea.10,14 Related research shows that low levels of the TRPV1 channel are expressed in the entorhinal cortex, olfactory bulb, hippocampus, periaqueductal gray (PAG) and other regions.15 Moreover, the TRPV1 channel is widely present in multiple peripheral tissues/systems including the vasculature, gastrointestinal (GI) tract, urinary bladder, and immune system.16–18

TRPV1 in health

Appealing evidence shows that the TRPV1 channel plays key roles in thermosensation, oral sensation, proteasome activity, modulation of autophagy, energy homeostasis, muscle physiology, GI motility, and the release of inflammatory mediators as well as crosstalk between the immune system and sensory nervous system.1,18–24 In addition, the TRPV1 channel is involved in the modulation of synaptic transmission through pre- and post-synaptic mechanisms and microglia-to-neuron communication.10 To elaborate, the TRPV1 channel modulates glutamatergic and GABAergic transmission and causes changes in neuronal firing.25,26 Thus, it has a role in brain plasticity and development.10,27 Moreover, numerous studies have shown that the TRPV1 channel is implicated in the regulation of long-term potentiation of excitatory postsynaptic potentials in the hippocampus which is responsible for learning and memory.28

In the urinary bladder, the TRPV1 channel is involved in the micturition reflex, regulation of the contractility in muscle cells, blood flow and nerve excitability.17,29 In addition, the TRPV1 channel is involved in the regulation of vascular tone and blood pressure due to its wide expression in smooth muscle cells, perivascular nerves, and endothelial cells of the cardiac system.30 Moreover, previous studies point to the vasodilatory effect of the TRPV1 channel and its role in the stimulation of mucus secretion in the gut.31 In the stomach and duodenum, the TRPV1 channel takes part in the maintenance of tissue integrity in addition to its protective role against aggressive compounds.32 Also, the TRPV1 channel plays a role in the control of motor function in the GI tract.10 Also, the TRPV1 channel is a key component in the fertility outcome in men.33 In other contexts, it is increasingly recognized that the channel is a fundamental contributor to the healing of different wounds as reviewed by Bagood and Isseroff (2021) and other researchers.34 The TRPV1 channel acts as a mechanosensor in the lens and contributes to the regulation of water and ion transport to restore lens volume and maintain internal lens hydrostatic pressure gradient.35

Figure 2 shows body systems that have TRPV1 expression.

Body systems that have transient receptor potential vanilloid 1 (TRPV1) expression.
Fig. 2  Body systems that have transient receptor potential vanilloid 1 (TRPV1) expression.

GI, gastrointestinal; S, segment.

TRPV1 in disease

As the TRPV1 channel is implicated in several physiological processes, many disorders have been associated with alterations in the function and/or expression of the TRPV1 channel. Close attention is currently paid to the involvement of the TRPV1 channel in diseases, pointing to its importance as a promising therapeutic target. This review highlights up to date findings regarding the involvement of the TRPV1 channel in diseases.

TRPV1 and dysregulation of temperature

It is widely accepted that TRPV1 knockout mice show altered responses to heat.36,37 The animals exhibited little thermal hypersensitivity during inflammation and impairment in painful heat detection.37 In another study, it was revealed that the sensitivity to noxious heat was attenuated after silencing the TRPV1 gene by short hairpin ribonucleic acid.38 Other research implicated that the expression of the TRPV1 channel accounted for the activity of hypothalamus in thermoregulation.39 Importantly, the use of several TRPV1 antagonists was associated with side effects such as hyperthermia and accidental burns (e.g. AMG0347) or hypothermia (e.g. 1165901) as a further indication to the link between TRPV1 and thermoregulation.40,41

TRPV1 and pain

Many studies have depicted that the TRPV1 channel is expressed in sensory neurons.1 In more detail, the TRPV1 channel is expressed in the unmyelinated C-fibers and the myelinated Aδ-fibers.1 Thus, the TRPV1 channel is involved in the nociception of mechanical, thermal, and chemical stimuli during pain.42 In detail, it has been long recognized that the TRPV1 channel plays a fundamental role in inflammatory and neuropathic types of pain.43 By virtue of this fact, mice that lack the TRPV1 channel display a significant decrease in pain sensation.37 Additionally, emerging evidence shows that TRPV1 expression changes after nerve injury.44 In addition, it was revealed that the alterations in TRPV1 expression and function were major contributors to diabetes-induced variations in thermal pain.45 Furthermore, cumulative evidence confirms that the TRPV1 channel is implicated in inflammatory pain through the activation of kinases (e.g. PKA and PKC) and an increase in TRPV1 activity by many inflammatory mediators.46 Additionally, the TRPV1 channel is a major contributor to cases of neuropathic pain such as chemotherapy-induced peripheral neuropathy.47 In this regard, one study has shown that paclitaxel causes TRPV1 sensitization through the release of mast cell tryptase that causes activation for the protease-activated receptor 2 (PAR2) and other kinases.48 On the other hand, abundant evidence shows that the TRPV1 channel contributes to fibromyalgia which is a chronic pain disorder characterized by fatigue, widespread body pain, and mental health problems.49,50 Importantly, the TRPV1 channel, among other pain receptors, has been implicated in different types of pain during coronavirus disease 2019 (COVID-19) and after recovery (post-COVID-19).51,52

Since the TRPV1 channel is involved in the nociception of different stimuli, it is widely considered a promising target for pain control.42 Notably, despite the fact that the first exposure to TRPV1 activators causes pain, repeated exposure to these activators inhibits pain perception due to TRPV1 desensitization, thus representing a unique form of analgesia.9

TRPV1 and inflammation

It is well known that tissue injury is associated with inflammation and the release of multiple inflammatory mediators such as PGE2 NGF, and bradykinin as well as protons that are responsible for tissue acidosis indicating that there is interplay between the TRPV1 channel and inflammation.53 Many inflammatory mediators sensitize the TRPV1 channel by lowering its threshold leading to its activation at body temperature by several mechanisms that differ according to the types of nociceptors and inflammatory mediators.43,54 These mediators have significant effects on the TRPV1 channel. Also, growing evidence demonstrates that inflammation promotes the sensitized state of the TRPV1 channel through increased activity of PKC and PKA. Thereby, the TRPV1 channel is considered a key detector for brain inflammation and autoimmune encephalitis.27,55 Besides, the literature supports the fact that inflammation causes TRPV1 anterograde transport from the cell body to the periphery via the sciatic nerve.56 Evidently, inflammation-induced reactive oxygen species (ROS) increased the translation of TRPV1 mRNA and caused anterograde transport of the TRPV1 protein to the periphery.57 In this context, it has been found that the trafficking and expression of the TRPV1 channel change at the transcriptional, translational, and post-translational levels during nerve injury and inflammation.58 Moreover, there is growing evidence indicating that the recruitment of vesicular TRPV1 pools to the membrane and the surface insertion of the TRPV1 channel onto the surface of DRGs are complementary mechanisms required for the enhancement of TRPV1 functionality by some inflammatory mediators such as NGF, insulin-like growth factor 1 and adenosine triphosphate (ATP).54 Supporting this contention, earlier reports showed that numerous inflammatory mediators lower the threshold of TRPV1 activation via phosphorylation.4 Likewise, there is substantial evidence revealing that NGF produced after inflammation and/or tissue injury has an impact on a regulatory region located upstream of the TRPV1 gene and hence evokes TRPV1 expression in nociceptors, partly through transcription.59 Additionally, it was demonstrated that the administration of TRPV1 antagonists inhibits ovalbumin-induced coughing in guinea pigs, indicating that the TRPV1 channel plays a crucial role in inflammatory coughing.60 Additionally, Orliac et al. (2007) proposed that the effect of anandamide during endotoxic shock (a case of severe inflammatory response) was enhanced by TRPV1 overexpression in rats.61

TRPV1 and cancer

Research evidence has proved the involvement of the TRPV1 channel in tumorigenesis (cell proliferation, death, and metastasis) as the channel contributes to cell division.62,63 The effects and mechanisms of using various TRPV1 agonists/antagonists on different cancer cells were reviewed by Li et al. (2021).63 Accumulating knowledge shows that the anti-tumor potential of capsaicin is demonstrated in different cancer cell lines via one or more of the following mechanisms: suppressing angiogenesis, increasing apoptosis, changing different signaling pathways or inhibiting proliferation and motility of cells.63,64 The fact that TRPV1 activation leads to Ca2+ influx indicates that there is interplay between the TRPV1 channel and intracellular Ca2+ concentration, which is needed in many processes such as cell migration, cytotoxicity and ultimately cell death.65,66 In this regard, one study demonstrated that the administration of the TRPV1 agonist, RTX, induced cell death in pancreatic cancer cells.66 More precisely, it was revealed that the TRPV1 channel contributes to the proliferation of different human cancer cell lines and tumors such as osteosarcoma, colorectal cancer cells, dermal cancer cells, pancreatic cancer cells, urothelial cancer cells, renal cancer cells, hepatocellular carcinoma, nasopharyngeal carcinoma, breast carcinoma, neuroblastoma, and melanoma.63 Meanwhile, the channel has an impact on the apoptosis/necrosis of breast carcinoma, osteosarcoma, lung cancer cells, gastric cells, oral squamous cell carcinoma, nasopharyngeal carcinoma, uterine cervix cancer, endometrial cancer, cutaneous melanoma, cervical carcinoma and bladder cancer cells.63 Additionally, evidence suggests that the TRPV1 channel has a role, via different mechanisms, in cancer cell metastasis and invasiveness in different cells such as colorectal cancer cells, pancreatic cancer cells, urothelial cells, papillary thyroid carcinoma, dermal cancer cells, lung cancer cells, cervix adenocarcinoma, hepatoblastoma, nasopharyngeal carcinoma, neuroblastoma and melanoma.63 In addition, the TRPV1 channel plays a role in bone cancer due to its activation by tissue acidosis mediated by osteoclasts.67 In the oral cavity, TRPV1 expression was detected in the cell carcinoma of the human tongue.68 Also, in cultured DRGs, it was found that treating the animals with the anticancer drugs oxaliplatin and cisplatin caused upregulation for TRPV1 mRNA.69 Besides, a considerable body of work shows that the TRPV1 channel is implicated in several hematological malignancies due to its expression in macrophages, monocytes, and dendritic cells.70 Moreover, previous research has shown that there is a link between TRPV1 expression and the efficiency of chemotherapy as well as radiotherapy.63 Notably, caution has been raised in some studies regarding the association between the long term use of capsaicin and the emergence of cancer in animals.71

TRPV1 and psychiatric/neurological disorders

It is widely recognized that the TRPV1 channel is involved in several psychiatric and neurological disorders such as anxiety, conditioned fear, depression, drug-addiction disorders, epilepsy and Alzheimer’s disease.10,35,65,72 In more detail, earlier reports revealed that the TRPV1 channel was expressed in the hippocampus and cortex of patients who had epilepsy.73 Additionally, it was found that the administration of the TRPV1 antagonist capsazepine suppressed seizures in genetically epilepsy-prone animals.74 Remarkably, multiple studies have demonstrated that the TRPV1 channel promotes the migration of astrocytes and release of pro-inflammatory cytokines from astrocytes into the nearby neurons to maintain epileptogenesis.75 In the substantia nigra, it is evident that the activation of astrocytic TRPV1 prevents the degeneration of dopaminergic neurons in a model of Parkinson’s disease in rats.76 Furthermore, You et al. (2012) reported that TRPV1 knockout mice exhibited antidepressant behavior.77 Also, TRPV1 activation reversed memory impairment and hippocampal damage caused by the cytotoxic effects of Amyloid-β peptide.65 Additional lines of evidence documented the potential role for the TRPV1 channel in schizophrenia.78 Importantly, it merits consideration that the TRPV1 channel has been detected in brain areas that are involved in the control of stress such as the hippocampus, locus coeruleus, medial prefrontal cortex, hypothalamus, and dorsolateral periaqueductal gray (dlPAG).79 In this regard, the TRPV1 channel in dlPAG has been implicated in the attenuation of cannabidiol (CBD)-mediated anxiolysis.79

TRPV1 and disorders of the auditory system

In the study of Takumida et al. (2005), the authors documented that the TRPV1 channel was detected in the inner ear of guinea pigs; more specifically, in hair cells and supporting cells of the organ of Corti; spiral ganglia of the cochlea; and the vestibular end organs.80 Further, multiple studies showed that the cochlear expression of the TRPV1 channel was involved in drug-induced cochleotoxicity (hearing loss) during systemic inflammation.81 Additionally, TRPV1 expression was up-regulated in the vestibular and spiral ganglia in the inner ear of mice after kanamycin challenge.82 Besides, earlier studies shed new light on the role of the TRPV1 channel in cisplatin ototoxicity as its absence provided protection against hearing loss.83 In addition, a significant amount of research has shown that several cochlear stressors (e.g. noise and ototoxic drugs) affect the TRPV1 channel indicating the role of this channel in the regulation of cytoprotection and/or cell death pathways.83 Consistent with these findings, it was found that inhibiting inflammation or oxidative stress decreased TRPV1 expression, modulated the apoptotic and inflammatory signals and provided protection against cochlear damage and hearing loss.83

TRPV1 and disorders of the ocular system

It is well documented that the TRPV1 channel is expressed in different regions of the lens including the epithelium, outer cortex and inner cortex.35,84In vivo, TRPV1 absence was associated with impairment in the healing of the epithelium in debrided corneal defects in rodents.84 Furthermore, a considerable body of work has revealed that TRPV1 activation by mechanical injury causes cytoskeletal rearrangement, an increase in Ca2+ concentration, and enhances the migration of isolated retinal astrocytes.85 In ganglion cells, it has been published that the increase in intraocular pressure augments TRPV1 expression, which is involved in protecting ganglion cells from apoptosis.86 Additionally, the application of capsaicin to the corneal epithelium causes TRPV1 activation, an increase in intracellular Ca2+ concentration, the release of inflammatory mediators, and protection against infection by microorganisms.87

TRPV1 and anosmia/ageusia

People experience a burning sensation on their tongues when eating chili peppers. Thus, multiple studies have highlighted the involvement of the TRPV1 channel in taste perception.

Remarkably, the TRPV1 channel is expressed in neurons innervating the oral cavity.88,89 There are several pieces of evidence indicating that the TRPV1 channel responds to a number of substances (e.g. allicin, capsaicin, alcohol and gingerol) and modifies salt stimuli.90 Also, appealing evidence shows that a TRPV1 channel variant is expressed in the epithelial cells and taste buds of the tongue.89 Besides, it has been reported that TRPV1 polymorphisms are linked to alterations in the sensitivity to the taste of salts.91 Notably, earlier research mentions that capsaicin can decrease sucrose preference and inhibit voltage-dependent Na+ channels in taste cells in TRPV1 knockout mice.91 In this context, Hu et al. (2016) reported that the TRPV1 channel was involved in rimonabant-induced olfactory discrimination deficit and that the impaired olfactory discrimination was rescued by the TRPV1 antagonist capsazepine.92 Further, the TRPV1 channel seems to be linked to the anosmia/ageusia symptoms in COVID-19 patients.51,52

TRPV1 and infections

Several reports demonstrated that the TRPV1 channel plays important roles in bacterial, fungal and viral infections.51,52,93–95 In more detail, Maruyama et al. (2017) reported that the topical Candida albicans skin infection stimulated the release of calcitonin gene-related peptide (CGRP) in a TRPV1 dependent manner during bone infection.93 Another study showed the beneficial effects of TRPV1 ablation on inducing immunosuppression against Streptococcus pyogenes in the skin.94 Likewise, the TRPV1 channel has been implicated in the anti-inflammatory and immunosuppressive responses in animals infected with Staphyloccocus aureus in the skin and lung.95,96 In a model of sepsis (cecal ligation and puncture), it was revealed that the animals that are deficient in the TRPV1 channel suffered from severe symptoms such as decreased phagocytosis in macrophages, increased apoptosis of peritoneal mononuclear cells, increased levels of inflammatory mediators, decreased levels of ROS, and reduced bacterial clearance.21 In fact, the link between the TRPV1 channel, Ca2+ concentration and ROS provides evidence for the involvement of the TRPV1 channel in viral infections.97 More precisely, an accumulation of knowledge showed that Ca2+ entry into the cells is of key importance to the viral lifecycle at several steps including its entry, replication, assembly, and release.98 Further, it has been reported that there is interplay between the increase in intracellular Ca2+ and ROS levels in mitochondria, which is crucial for the lifecycle of many viruses.99

As shown from previous studies, the TRPV1 channel is one of the receptors that provide favorable environments for viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).51,52 The wide expression of the TRPV1 channel in tissues that were frequently infected by SARS-CoV-2 suggests that the channel plays a crucial role in COVID-19, one of the world’s worst pandemics in the current century. In the review of Jaffal and Abbas (2021), the authors summarized the studies that demonstrated a correlation between the TRPV1 channel and several symptoms of COVID-19 including fever, pain, myalgia, inflammation, cough, headache, pulmonary edema, anosmia, ageusia, as well as problems of the GI and cardiovascular systems.51 Also, the TRPV1 channel can be implicated in other manifestations of COVID-19 disease such as anxiety as well as visual, renal, and hepatic problems.51Figure 3 shows a representation of a SARS-CoV-2-induced cytokine storm,52 which is considered the leading cause of death in COVID-19 patients. The activation of the TRPV1 channel in the peripheral nervous system (PNS) and CNS contributes to Ca2+ influx and the release of neuropeptides that induce liberation of more inflammatory mediators. These mediators cause sensitization of more TRPV1 channels, among others leading to excessive stimulation and providing a favorable environment for SARS-Cov-2. In summary, the inflammatory cytokine storm produces a loop of amplified release of mediators at different levels leading to more adverse outcomes.

Representative sketch for the cytokine storm in Coronavirus disease 2019 (COVID-19) and the involvement of the transient receptor potential vanilloid 1 (TRPV1) channel (Modified from Jaffal, 2021).
Fig. 3  Representative sketch for the cytokine storm in Coronavirus disease 2019 (COVID-19) and the involvement of the transient receptor potential vanilloid 1 (TRPV1) channel (Modified from Jaffal, 2021).52

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) can cross the blood brain barrier (BBB) and cause more devastating effects. During COVID-19, the activation of the TRPV1 channel in the peripheral nervous system (PNS) and central nervous system (CNS) contributes to calcium (Ca2+) influx and the release of neuropeptides that induce the liberation of more inflammatory mediators. These mediators cause sensitization of more TRPV1 channels, among others leading to excessive stimulation and providing a favorable environment for SARS-Cov-2. DRGs, dorsal root ganglia.

TRPV1 and disorders of the reproductive system

It is well known that the TRPV1 channel is expressed in the head, midpiece, and tail of sperm and is involved in the regulation of acrosomal reaction and sperm capacitation.33,100 As such, there is correlation between TRPV1 expression and the fecundity potential of sperm.33 In this context, earlier reports have shown that the TRPV1 channel is downregulated in the spermatozoa of idiopathic infertile men, subfertile men, and normozoospermic infertile males.33 Further, in TRPV1 knockout mice, it was found that the testes of mice were more susceptible to oxidative stress, testicular damage, and dysfunctional sperm development.101 It was also found that vulvodynia (a condition of pain in the opening of vagina) is linked to more epithelial innervation when accompanied by more TRPV1 expression in vulva.102 Besides this, the TRPV1 channel contributes to the sensory symptoms experienced by patients who suffer from hyperalgesia, allodynia, and a burning sensation in the vulvar vestibulus region.102

TRPV1 and disorders of the respiratory system

A remarkable amount of literature demonstrates that the TRPV1 channel is expressed in several regions in the upper and lower respiratory tracts such as the vascular endothelial cells, submucosal gland cells, smooth muscle cells, cholinergic neurons, inflammatory cells, laryngeal epithelial cells, blood vessels, fibroblast cells, T cells, and the airway epithelium.103,104 Also, the TRPV1 channel is expressed in neurons of the vagal nerve that innervate the airways.38 Moreover, previous studies highlighted that TRPV1 antagonism decreased airway hyperresponsiveness in guinea pigs and exerted anti-tussive effects in a capsaicin-induced cough model of guinea pigs.105,106 In line with the involvement of the TRPV1 channel in respiratory disorders, it was found that TRPV1 expression increased in patients suffering from chronic obstructive pulmonary disease (COPD) and chronic cough.107,108 In addition, the TRPV1 channel was critical for the effect of NGF (when administered via inhalation or intracerebroventricular (ICV) injection) in enhancing cough and airway obstruction in guinea pigs.109,110 Moreover, accumulated data suggest that the activation of the TRPV1 channel on respiratory effector cells can lead to tracheal mucosal edema, bronchoconstriction, protein secretion and inflammatory cell chemotaxis.109,111 Interestingly, earlier reports have shown a relationship between TRPV1 single nucleotide polymorphisms (SNPs) and protective effects against wheezing in patients who suffer from asthma.112 Additionally, a recent study documented the increase in TRPV1 expression in rhinovirus that contributes to asthma exacerbations.113 In this regard, several studies have shown that capsaicin nasal spray is useful in the treatment of idiopathic rhinitis.114

TRPV1 and obesity

Previous reports have demonstrated that the TRPV1 channel is expressed in adipocytes and plays a key role in the regulation of metabolic processes that are related to obesity.115,116 Capsaicin promotes weight loss by increasing the sympathetic nervous system activity, decreasing appetite as well as increasing energy expenditure, fat oxidation, insulin and leptin resistance.117,118 Furthermore, capsaicin improves endurance capacity and energy metabolism in skeletal muscles.119

The findings of a recent meta-analysis of clinical trials showed that the daily consumption of capsiate (a non-pungent vanilloid) or capsaicin increased thermogenesis and decreased appetite, and can thus be useful in weight management.120 Further, it has been published that dietary capsaicin and capsinoids increase energy expenditure and thermogenesis mediated by an increase in brown adipose cells and a decrease in white adipogenesis.115 It is evident that the administration of low-dose dietary capsaicin improved insulin sensitivity, increased fat oxidation, decreased body fat and improved the functions of liver.116 Despite that, there are conflicting results about the role of the TRPV1 channel in weight management due to the risk of developing myocardial infarction.121 Of note, the effects of capsaicin depend on the administered dose and duration of its application. Further research is needed in this regard.

TRPV1 and disorders of the GI tract

In the GI tract, the TRPV1 channel is expressed in the afferent neurons (vagal and spinal) in the esophagus, jejunum, stomach, rectum, colon as well as the small intestine.16,119,122 In fact, accumulated evidence supports the findings that TRPV1-labeled nerve fibers are distributed in each layer of the GI tract including submucosa, mucosa, muscle, and myenteric plexus.123 Thus, the TRPV1 channel is implicated in the cases of irritable bowel syndrome (IBS), neurogenic pancreatitis, and ileus.123 It is well established that CGRP released after TRPV1 activation in primary nociceptive nerves leads to a strong inhibitory effect on gastric acid induced irritation.124 Additionally, many substances (e.g. tachykinins) are released when the TRPV1 channel is activated causing gastric motility and acceleration for gastric emptying.125 Furthermore, it has been illustrated that ulcer formation in rats is suppressed by the injection of low dose capsaicin and that the perfusion of capsaicin into the stomach of rats can inhibit gastric mucosal injury.126,127 Evidently, several studies have been published about the effects of capsaicin on reducing the symptoms of functional dyspepsia caused by duodenal and gastric dysfunction, reducing upper abdominal symptoms as well as increasing GI dysfunction, leading to IBS-related symptoms.19 Interestingly, TRPV1 expression increased in a rat model of chronic pancreatitis and in patients of ulcerative colitis and Crohn’s disease.128,129 Further, it is increasingly apparent that the channel is involved in gastric pain hypersensitivity and gastroesophageal reflux disease.123 Moreover, it was revealed that capsaicin could improve liver function in a mouse model of hepatic failure.130 The fact that TRPV1 expression has been found to increase in oesophagitis, colonic inflammation, acute haemorrhoidal disease, and distal colitis is further evidence of the involvement of the TRPV1 channel in the disorders of the GI tract.8

TRPV1 and disorders of the cardiovascular system

Previous studies have confirmed that the TRPV1 channel is densely expressed in the sensory neurons that innervate the ventricles, endothelial cells, epicardial surface of the heart, myocardium, cardiomyocytes, the adventitia of the ascending aorta, aortic arch, and the vascular smooth muscle cells.131 Moreover, TRPV1 expression is detected in large arteries, aorta and carotid arteries.132 Following this, other studies have shown that the TRPV1 channel plays a role in sensing blood pressure fluctuations.133 Furthermore, it has been found that TRPV1 activation mediates the hypotensive action and is implicated in myogenic vasoconstriction in the Bayliss reflex in the resistance arteries.10,134 In this regard, previous studies showed that the administration of capsaicin increased coronary flow and decreased left ventricular end diastolic pressure and infarct size in wild type mice.135 In addition, it has been found that TRPV1 activation can alleviate atherosclerosis induced by a high-fat diet in mice through cellular cholesterol cleavage.136 Specifically, dietary capsaicin decreased atherosclerosis by regulating lipid metabolism and decreasing endothelial dysfunction.136,137 According to Harper et al. (2010), TRPV1 receptors that exist on platelets can promote inflammatory mediators leading to platelet activation and the formation of atherosclerosis.138 The TRPV1 channel, being expressed in the perivascular nerves, also plays a crucial role in cardioprotection by stimulating the release of potent neuropeptides such as CGRP and SP that cause vasodilation or vasoconstriction.138–140 Moreover, it has been documented that there is association between decreased expression of the TRPV1 channel in metabolic syndrome and increased ischemic reperfusion injury in isolated mice hearts.141 Further, emerging evidence indicates that the TRPV1 channel mediates relaxation of smooth muscle cells in the endothelium.142 However, previous studies have implicated that high consumption of capsaicin can cause myocardial infarction and vasospasm.143 In this regard, Song et al. (2017) documented that TRPV1 activation is responsible for the contraction of smooth muscle cells in pulmonary artery, vasoconstriction and the pathogenesis of idiopathic pulmonary arterial hypertension.144

TRPV1 and diabetes

A considerable body of work shows that nerve fibers that express the TRPV1 channel innervate Langerhans islets in the pancreas.145 Also, previous research has confirmed an alteration in the activity and/or expression of the TRPV1 channel in insulin resistance.118 In the long-term diabetic microenvironment, earlier studies demonstrated that TRPV1 desensitization in DRGs decreased TRPV1 activity and contributed to peripheral diabetic neuropathy.146 Furthermore, the injection of capsaicin attenuated hyperglycaemia in Zucker diabetic fatty animals which is a model of human type 2 diabetes mellitus.145 In this sense, TRPV1 knockout mice exhibited impairment in glucose metabolism manifested by a decrease in glucose-induced insulin secretion.147 Importantly, it has been found that the TRPV1 channel is a modulator for clock gene oscillations in black adipose tissue (BAT) and is involved in the regulation of hepatic functions and glucose metabolism.148,149 Besides, earlier studies revealed that hepatic glycogen storage was compromised in TRPV1 knockout mice due to impairment in glucose homeostasis.149 Further, it was shown that the livers of TRPV1 knockout mice exhibited changes in proteomics and a decrease in glycogen storage in addition to an enhancement in glycogenolysis, gluconeogenesis, and the levels of inflammatory parameters.149

TRPV1 and disorders of the cutaneous system

The burning feeling of capsaicin in the skin was discovered by Hogyes in 1878 before the discovery of the TRPV1 channel.33 Since then, several studies have been conducted to unravel the effects and mechanisms of the TRPV1 channel on different systems including the cutaneous system. In the skin, it is evident that the TRPV1 channel presents in epidermal keratinocytes, mast cells, epithelial cells of hair follicles, blood vessels, eccrine sweat glands, keratinocytes, nociceptors, immune cells, sebocytes, fibroblasts, and melanocytes.33,150 Interestingly, it has been documented that TRPV1 positive nociceptors in hair follicles play a role in the proliferation and migration of stem cells to improve healing.151 Many people have used capsaicin to treat psoriasis, atopic dermatitis, and allergic contact dermatitis.152–154 Also, the channel plays an important role in the healing of wounds in different models such as incision wounds, tape striping, burn wounds, corneal wounds and ultraviolet B wounds.33 Therapeutically, it has been found that honokiol (a natural compound extracted from magnolia plants) is effective in treating third degree burns by decreasing the mRNA and protein expression of TRPV1.155 Moreover, in one study, mice lacking the TRPV1 gene showed reduction in histamine-induced scratching and itching sensation compared to wild-type mice.156 Regarding hair growth, Bodo et al. (2005) suggested that the TRPV1 channel can influence human hair growth and that TRPV1-based therapy can be used for the treatment of hirsutism (unwanted hair growth), effluvium, and alopecia (hair loss).157

TRPV1 and headache

Several studies have unraveled the role of the TRPV1 channel in migraines. It is well known that one of the factors that contribute to migraines is the release of neuropeptides through the activation of trigeminal afferents in the cranial vasculature (trigeminovascular system).158 Due to the expression of the TRPV1 channel in TGs and dural nerves, it is well documented that this channel is implicated in headache and migraine mechanisms.159 In this regard, previous studies have shown that the anti-migraine drug sumatriptan alleviates headache in a TRPV1 dependent manner.159 Other pieces of research elucidated the mechanisms of botulinum toxin A (BoNTA) in treating chronic migraine. The studies shed new light on the inhibition of TRPV1 trafficking to the plasma membrane in TGs and the decrease in capsaicin-induced pain after BoNTA treatment.160,161 Moreover, many studies used TRPV1 agonists and antagonists to probe meningeal afferents and reported the effectiveness of TRPV1 agonists, rather than antagonists, in treating migraines.162,163 In this regard, the repeated administration of intranasal capsaicin to chronic migraine patients resulted in 50–80% amelioration of migraine attack due to TRPV1 desensitization.163 Likewise, it was found that the use of an intranasal TRPV1 agonist (civamide) decreased the frequency of headache attacks in 72.7% of patients and caused absence of pain in 33% of patients.164 Importantly, it has been revealed that neurogenic vascular effects of the TRPV1 channel are implicated in migraine pathophysiology through CGRP release and dural vasodilation.158 Widely popular, pro-inflammatory mediators stimulate trigeminal nociceptors possibly via the TRPV1 channel highlighting the role of the TRPV1 channel in migraines and the role of non-steroidal anti-inflammatory drugs (NSAIDs) in treating them.165,166 Of relevance, it was found that the transient receptor potential ankyrin 1 (TRPA1) channel requires co-activation of the TRPV1 channel to initiate afferent signaling from the meninges and that ethanol triggers migraine attacks through release of CGRP in a TRPV1-dependent manner.167–169

TRPV1 and disorders of the urinary system

In the urinary tract, the TRPV1 channel is expressed in sensory nerve fibers, smooth muscles and the urothelium.169 Importantly, the expression of the TRPV1 channel has been correlated with the severity of inflammation in interstitial cystitis or bladder pain syndrome.170 According to clinical studies, capsaicin is recommended for the treatment of neurogenic bladder hyperreflexia as it causes a decrease in bladder capacity, pressure threshold for micturition and the patients’ desire to void.17 Also, the TRPV1 channel is expressed in the renal pelvis and contributes to the maintenance of diuresis, natriuresis, water and Na+ homeostasis.171 Additionally, previous findings have shown that the TRPV1 channel responds to many chemicals (e.g. allicin, alcohol, capsaicin, and gingerol) that are known to modify salt stimuli.172 In this context, capsaicin has been effective in treating incontinence in people suffering from dysfunctional micturition reflex.40 Additionally, recent preclinical data revealed that TRPV1 activators improved the outcome of ischemic acute kidney injury.173

TRPV1 and disorders of the muscular system

It is well established that the TRPV1 channel is expressed in muscle afferents and is involved in muscle nociception and muscle pain conditions.8 Moreover, TRPV1 mutations are associated with muscle disorders such as exertional heat stroke and malignant hyperthermia.24 Additionally, several studies have shown that TRPV1 activation leads to Ca2+ release, membrane excitability, neurotransmitter release, and muscle contraction.174 Supporting this contention, it has been revealed that the upregulation of nitric oxide and peroxynitrite in overloaded muscle activates the TRPV1 channel.175 Also, TRPV1 knockout mice exhibited stronger muscles with improvement in neuromuscular function compared to wildtype counterparts.24 In frogs, it was documented that TRPV1 activation decreased the tension of fast skeletal muscle fibers causing a change in muscle activity.176

TRPV1 and disorders of the skeletal system

It has been long recognized that capsaicin attenuates key parameters that are responsible for symptoms of adjuvant arthritis.177 Also, there is mounting evidence that the TRPV1 channel is involved in bone remodeling and bone diseases such as osteoporosis which is characterized by a decrease in bone density, increase in bone resorption, and fragile bones.178,179 In this context, Alexander et al. (2013) reported the up-regulation of the TRPV1 channel in osteoclasts obtained from osteoporotic patients.178 In addition, it was found that TRPV1 genetic deletion, inhibition, or desensitization in mice decreased the activity of osteoclasts in vitro and inhibited ovariectomy-induced bone loss as well as osteoporosis in vivo.179 Moreover, previous studies documented that capsazepine inhibited the differentiation of osteoclasts and osteoblasts in vitro as well as ovariectomy-induced bone loss in vivo.180 Accordingly, it is strongly suggested that the TRPV1 channel is involved in several bone problems.

Pharmacological agents that interact with the TRPV1 channel

As the TRPV1 channel is involved in multiple biological and pathological processes, several pharmacological agents that target this channel have been synthesized and it is increasingly recognized that there are multiple endogenous and exogenous agonists for the TRPV1 channel.181 Capsaicin is an exogenous TRPV1 agonist extracted from the plant Capsicum annuum L.182 The agonistic action of capsaicin has been exploited therapeutically by synthesizing patches that include high doses of capsaicin, leading to TRPV1 desensitization.143 Remarkably, accumulating knowledge illustrates that capsaicin creams and patches attenuate pain due to TRPV1 desensitization on local cutaneous nociceptors and a loss of responsiveness to many sensory stimuli.9 Accordingly, capsaicin (8% patch; Qutenza™) was approved by the United States Food and Drug Administration in 2009 for the treatment of postherpetic neuralgia-induced neuropathic pain.143 Also, it has been revealed that capsaicin, formulated as a topical cream or a transdermal patch, is effective for the management of pain in minor muscle strains or cramps and joint pain.143 On the other hand, many endogenous agonists (also called endovanilloids) for the TRPV1 channel have been identified including anandamide, N-oleoylethanolamine, N-Arachidonoyl-dopamine, N-oleoyl dopamine, lysophosphatidic acid, 20-hydroxyeicosatetraenoic acid, AM-404, hydroperoxyeicosatetraenoic acids [5-(S), 8-(S), 12-(S) and 15-(S)], hepoxilins A3, ATP, ammonia, polyamines (e.g. spermine, spermidine, putrescine), linoleic acid, in addition to 9, 13 and 20-hydroxyoctadecadienoic acid.181 TRPV1 antagonists are classified into competitive or non-competitive antagonists according to their binding sites.181,182 Capsazepine is the first reported competitive TRPV1 antagonist that blocks capsaicin-or RTX-induced channel activation. Other examples include JYL-1421, A-425619, BCTC, JNJ-1720, SB-705498, SB-366791, AMG-9810, MK2295 and AMG-2674.181,182 Examples of non-competitive antagonists are ruthenium red, RRRRWW-NH2, methoctramine, AG-489, AG-505, DD-161515, and DD-191515.181 In another context, TRPV1 antagonists can be classified according to their effects on body temperature. In more detail, the antagonists can increase, decrease, or un-change body temperature. Some antagonists (e.g. AMG-0347 and AMG-517) can cause hyperthermia, which is a drawback, while hypothermia can be caused by other antagonists such as A-1165901. Meanwhile, one group of antagonists do not change body temperature (thermoneutral antagonists).182

Future directions

There is no doubt that the TRPV1 channel is an important therapeutic target and that the pharmacological modulators of the TRPV1 channel can be potential drug targets for several disorders. The fact that there are drawbacks for several TRPV1 antagonists that are available in the market strengthens the need to discover novel TRPV1 modulators.181,182

TRPV1 modulation has been implicated in the anti-nociceptive effect of several medicinal plants, a finding that was proved by molecular docking studies.183–185 In accordance with this idea, Abbas, (2020) reviewed 137 natural ingredients that affect TRPV1 activity in different in vivo and in vitro assays.186 On the other hand, it has been long recognized that several toxins or venoms extracted from snakes, frogs, bees, spiders, scorpions, and marine organisms can act as TRPV1 modulators.1,7,51 Continuing the search for novel compounds that can be exploited therapeutically and target the TRPV1 channel without adverse effects is of vital importance.

Conclusions

Since its cloning in 1997, research on the TRPV1 channel has grown rapidly. Several reports have documented the role of the TRPV1 channel in many biological and pathological conditions. Accordingly, attention has been directed towards the development of effective drugs that target the TRPV1 channel to treat different diseases. This review provides knowledge on the functions of the TRPV1 channel in health and diseases and highlights its importance as a target in pharmaceutical industries.

Abbreviations

ATP: 

adenosine triphosphate

BAT: 

black adipose tissue

BoNTA: 

botulinum toxin a

Ca2+: 

calcium

CaMKII: 

calmodulin dependent kinase II

CBD: 

cannabidiol

CGRP: 

calcitonin gene-related peptide

CNS: 

central nervous system

COPD: 

chronic obstructive pulmonary disease

COVID-19: 

coronavirus disease 2019

dlPAG: 

dorsolateral periaqueductal gray

DRGs: 

dorsal root ganglia

ER: 

endoplasmic reticulum

GABA: 

gamma- amino butyric acid

GI: 

gastrointestinal

IBS: 

irritable bowel syndrome

ICV: 

intracerebroventricular

Na+: 

sodium

NGF: 

nerve growth factor

NSAIDs: 

non-steroidal anti-inflammatory drugs

PAG: 

periaqueductal gray

PAR2: 

protease-activated receptor 2

PGs: 

prostaglandins

PKA: 

protein kinase A

PNS: 

peripheral nervous system

ROS: 

reactive oxygen species

RTX: 

resiniferatoxin

S5: 

segment 5

SARS-CoV-2: 

severe acute respiratory syndrome coronavirus 2

SNPs: 

single nucleotide polymorphisms

SP: 

substance P

Src: 

sarcoma

TGs: 

trigeminal ganglia

TRPA1: 

transient receptor potential ankyrin 1

TRPV1: 

transient receptor potential vanilloid 1

Declarations

Acknowledgement

The author acknowledges the architect Maram Jaffal for her professional creation of the illustrations in this review.

Funding

None.

Conflict of interest

None.

Authors’ contributions

SMJ is the sole author of the work.

References

  1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389(6653):816-824 View Article PubMed/NCBI
  2. Alawi K, Keeble J. The paradoxical role of the transient receptor potential vanilloid 1 receptor in inflammation. Pharmacol Ther 2010;125(2):181-195 View Article PubMed/NCBI
  3. Alsalem M, Wong A, Millns P, Arya PH, Chan MS, Bennett A, et al. The contribution of the endogenous TRPV1 ligands 9-HODE and 13-HODE to nociceptive processing and their role in peripheral inflammatory pain mechanisms. Br J Pharmacol 2013;168(8):1961-1974 View Article PubMed/NCBI
  4. Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch 2005;451(1):143-150 View Article PubMed/NCBI
  5. Salzer I, Ray S, Schicker K, Boehm S. Nociceptor Signalling through ion Channel Regulation via GPCRs. Int J Mol Sci 2019;20(10):2488 View Article PubMed/NCBI
  6. Suh YG, Oh U. Activation and activators of TRPV1 and their pharmaceutical implication. Curr Pharm Des 2005;11(21):2687-2698 View Article PubMed/NCBI
  7. Julius D. TRP channels and pain. Annu Rev Cell Dev Biol 2013;29:355-384 View Article PubMed/NCBI
  8. White JP, Urban L, Nagy I. TRPV1 function in health and disease. Curr Pharm Biotechnol 2011;12(1):130-144 View Article PubMed/NCBI
  9. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011;107(4):490-502 View Article PubMed/NCBI
  10. Storozhuk MV, Moroz OF, Zholos AV. Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems. Biomed Res Int 2019;2019:5806321 View Article PubMed/NCBI
  11. Xin H, Tanaka H, Yamaguchi M, Takemori S, Nakamura A, Kohama K. Vanilloid receptor expressed in the sarcoplasmic reticulum of rat skeletal muscle. Biochem Biophys Res Commun 2005;332(3):756-762 View Article PubMed/NCBI
  12. Kárai LJ, Russell JT, Iadarola MJ, Oláh Z. Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+ release in sensory neurons. J Biol Chem 2004;279(16):16377-16387 View Article PubMed/NCBI
  13. Ferrini F, Salio C, Vergnano AM, Merighi A. Vanilloid receptor-1 (TRPV1)-dependent activation of inhibitory neurotransmission in spinal substantia gelatinosa neurons of mouse. Pain 2007;129(1-2):195-209 View Article PubMed/NCBI
  14. Dinh QT, Groneberg DA, Peiser C, Mingomataj E, Joachim RA, Witt C, et al. Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung. Respir Physiol Neurobiol 2004;144(1):15-24 View Article PubMed/NCBI
  15. Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, et al. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 2011;31(13):5067-5077 View Article PubMed/NCBI
  16. Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol 2004;560(Pt ;3):867-881 View Article PubMed/NCBI
  17. Maggi CA. Ciba Foundation Symposium 151 ‐ Neurobiology of Incontinence. John Wiley & Sons, Ltd; 1990, 77-90 View Article PubMed/NCBI
  18. Li YR, Gupta P. Immune aspects of the bi-directional neuroimmune facilitator TRPV1. Mol Biol Rep 2019;46(1):1499-1510 View Article PubMed/NCBI
  19. Du Q, Liao Q, Chen C, Yang X, Xie R, Xu J. The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System. Front Physiol 2019;10:1064 View Article PubMed/NCBI
  20. Tominaga M. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007 View Article PubMed/NCBI
  21. Fernandes ES, Liang L, Smillie SJ, Kaiser F, Purcell R, Rivett DW, et al. TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. J Immunol 2012;188(11):5741-5751 View Article PubMed/NCBI
  22. Amantini C, Farfariello V, Cardinali C, Morelli MB, Marinelli O, Nabissi M, et al. The TRPV1 ion channel regulates thymocyte differentiation by modulating autophagy and proteasome activity. Oncotarget 2017;8(53):90766-90780 View Article PubMed/NCBI
  23. Christie S, Wittert GA, Li H, Page AJ. Involvement of TRPV1 Channels in Energy Homeostasis. Front Endocrinol (Lausanne) 2018;9:420 View Article PubMed/NCBI
  24. Lafoux A, Lotteau S, Huchet C, Ducreux S. The Contractile Phenotype of Skeletal Muscle in TRPV1 Knockout Mice is Gender-Specific and Exercise-Dependent. Life (Basel) 2020;10(10):233 View Article PubMed/NCBI
  25. Li DP, Chen SR, Pan HL. VR1 receptor activation induces glutamate release and postsynaptic firing in the paraventricular nucleus. J Neurophysiol 2004;92(3):1807-1816 View Article PubMed/NCBI
  26. Drebot II, Storozhuk MV, Kostyuk PG. An unexpected effect of capsaicin on spontaneous GABA-ergic IPSCS in hippocampal cell cultures. Neurophysiology 2006;38(4):308-311 View Article PubMed/NCBI
  27. Marrone MC, Morabito A, Giustizieri M, Chiurchiù V, Leuti A, Mattioli M, et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat Commun 2017;8:15292 View Article PubMed/NCBI
  28. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F, et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 2007;27(4):832-839 View Article PubMed/NCBI
  29. Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002;5(9):856-860 View Article PubMed/NCBI
  30. Baylie RL, Brayden JE. TRPV channels and vascular function. Acta Physiol (Oxf) 2011;203(1):99-116 View Article PubMed/NCBI
  31. Holzer P. Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther 2011;131(1):142-170 View Article PubMed/NCBI
  32. Geppetti P, Trevisani M. Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function. Br J Pharmacol 2004;141(8):1313-1320 View Article PubMed/NCBI
  33. Swain N, Samanta L, Goswami C, Kar S, Majhi RK, Kumar S, et al. TRPV1 channel in spermatozoa is a molecular target for ROS-mediated sperm dysfunction and differentially expressed in both natural and ART pregnancy failure. Front Cell Dev Biol 2022;10:867057 View Article PubMed/NCBI
  34. Bagood MD, Isseroff RR. TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing. Int J Mol Sci 2021;22(11):6135 View Article PubMed/NCBI
  35. Nakazawa Y, Donaldson PJ, Petrova RS. Verification and spatial mapping of TRPV1 and TRPV4 expression in the embryonic and adult mouse lens. Exp Eye Res 2019;186:107707 View Article PubMed/NCBI
  36. Mishra SK, Tisel SM, Orestes P, Bhangoo SK, Hoon MA. TRPV1-lineage neurons are required for thermal sensation. EMBO J 2011;30(3):582-593 View Article PubMed/NCBI
  37. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000;288(5464):306-313 View Article PubMed/NCBI
  38. Christoph T, Bahrenberg G, De Vry J, Englberger W, Erdmann VA, Frech M, et al. Investigation of TRPV1 loss-of-function phenotypes in transgenic shRNA expressing and knockout mice. Mol Cell Neurosci 2008;37(3):579-589 View Article PubMed/NCBI
  39. Voronova IP, Tuzhikova AA, Kozyreva TV. Thermosensitive TRP channels gene expression in hypothalamus of normal rats and rats adapted to cold (In Russian). Ross Fiziol Zh Im I M Sechenova 2012;98(9):1101-1110 View Article PubMed/NCBI
  40. Nilius B, Szallasi A. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev 2014;66(3):676-814 View Article PubMed/NCBI
  41. Garami A, Pakai E, McDonald HA, Reilly RM, Gomtsyan A, Corrigan JJ, et al. TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development. Acta Physiol (Oxf) 2018;223(3):e13038 View Article PubMed/NCBI
  42. Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol 2008;1(3):255-269 View Article PubMed/NCBI
  43. Caterina MH, Gold MS, Meyer RA. The neurobiology of pain (Molecular and Cellular Neurobiology). New York: Oxford University Press; 2005, 1-35 View Article PubMed/NCBI
  44. Fukuoka T, Tokunaga A, Tachibana T, Dai Y, Yamanaka H, Noguchi K. VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain 2002;99(1-2):111-120 View Article PubMed/NCBI
  45. Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS. Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 2008;4:9 View Article PubMed/NCBI
  46. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, et al. Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 2005;1:3 View Article PubMed/NCBI
  47. Nassini R, Benemei S, Fusi C, Trevisan G, Materazzi S. Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy. Open Pain J 2013;6:127-136 View Article PubMed/NCBI
  48. Chen Y, Yang C, Wang ZJ. Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 2011;193:440-451 View Article PubMed/NCBI
  49. Fischer SPM, Brusco I, Brum ES, Fialho MFP, Camponogara C, Scussel R, et al. Involvement of TRPV1 and the efficacy of α-spinasterol on experimental fibromyalgia symptoms in mice. Neurochem Int 2020;134:104673 View Article PubMed/NCBI
  50. Hsiao IH, Lin YW. Electroacupuncture Reduces Fibromyalgia Pain by Attenuating the HMGB1, S100B, and TRPV1 Signalling Pathways in the Mouse Brain. Evid Based Complement Alternat Med 2022;2022:2242074 View Article PubMed/NCBI
  51. Jaffal SM, Abbas MA. TRP channels in COVID-19 disease: Potential targets for prevention and treatment. Chem Biol Interact 2021;345:109567 View Article PubMed/NCBI
  52. Jaffal SM. Moscova: Eliva Press; 2021 View Article PubMed/NCBI
  53. Gilligan JP, Lovato SJ, Erion MD, Jeng AY. Modulation of carrageenan-induced hind paw edema by substance P. Inflammation. 1994;18(3):285-292 View Article PubMed/NCBI
  54. Camprubí-Robles M, Planells-Cases R, Ferrer-Montiel A. Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors. FASEB J 2009;23(11):3722-3733 View Article PubMed/NCBI
  55. Paltser G, Liu XJ, Yantha J, Winer S, Tsui H, Wu P, et al. TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis. Mol Med 2013;19(1):149-159 View Article PubMed/NCBI
  56. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin 2007;45(2):27-37 View Article PubMed/NCBI
  57. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002;36(1):57-68 View Article PubMed/NCBI
  58. Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 2009;8(1):55-68 View Article PubMed/NCBI
  59. Xue Q, Jong B, Chen T, Schumacher MA. Transcription of rat TRPV1 utilizes a dual promoter system that is positively regulated by nerve growth factor. J Neurochem 2007;101(1):212-222 View Article PubMed/NCBI
  60. McLeod RL, Fernandez X, Correll CC, Phelps TP, Jia Y, Wang X, et al. TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs. Cough 2006;2:10 View Article PubMed/NCBI
  61. Orliac ML, Peroni RN, Abramoff T, Neuman I, Podesta EJ, Adler-Graschinsky E. Increases in vanilloid TRPV1 receptor protein and CGRP content during endotoxemia in rats. Eur J Pharmacol 2007;566(1-3):145-152 View Article PubMed/NCBI
  62. Kelleher FC, Fennelly D, Rafferty M. Common critical pathways in embryogenesis and cancer. Acta Oncol 2006;45(4):375-388 View Article PubMed/NCBI
  63. Li L, Chen C, Chiang C, Xiao T, Chen Y, Zhao Y, et al. The Impact of TRPV1 on Cancer Pathogenesis and Therapy: A Systematic Review. Int J Biol Sci 2021;17(8):2034-2049 View Article PubMed/NCBI
  64. Chen M, Xiao C, Jiang W, Yang W, Qin Q, Tan Q, et al. Capsaicin Inhibits Proliferation and Induces Apoptosis in Breast Cancer by Down-Regulating FBI-1-Mediated NF-κB Pathway. Drug Des Devel Ther 2021;15:125-140 View Article PubMed/NCBI
  65. Balleza-Tapia H, Crux S, Andrade-Talavera Y, Dolz-Gaiton P, Papadia D, Chen G, et al. TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro. Elife 2018;7:e37703 View Article PubMed/NCBI
  66. Hartel M, di Mola FF, Selvaggi F, Mascetta G, Wente MN, Felix K, et al. Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut 2006;55(4):519-528 View Article PubMed/NCBI
  67. Ghilardi JR, Röhrich H, Lindsay TH, Sevcik MA, Schwei MJ, Kubota K, et al. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 2005;25(12):3126-3131 View Article PubMed/NCBI
  68. Marincsák R, Tóth BI, Czifra G, Márton I, Rédl P, Tar I, et al. Increased expression of TRPV1 in squamous cell carcinoma of the human tongue. Oral Dis 2009;15(5):328-335 View Article PubMed/NCBI
  69. Anand U, Otto WR, Anand P. Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons. Mol Pain 2010;6:82 View Article PubMed/NCBI
  70. Omari SA, Adams MJ, Geraghty DP. TRPV1 Channels in Immune Cells and Hematological Malignancies. Adv Pharmacol 2017;79:173-198 View Article PubMed/NCBI
  71. Toth B, Gannett P. Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice. In Vivo 1992;6(1):59-63 View Article PubMed/NCBI
  72. Edwards JG. TRPV1 in the central nervous system: synaptic plasticity, function, and pharmacological implications. Prog Drug Res 2014;68:77-104 View Article PubMed/NCBI
  73. Bhaskaran MD, Smith BN. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy. Exp Neurol 2010;223(2):529-536 View Article PubMed/NCBI
  74. Cho SJ, Vaca MA, Miranda CJ, N’Gouemo P. Inhibition of transient potential receptor vanilloid type 1 suppresses seizure susceptibility in the genetically epilepsy-prone rat. CNS Neurosci Ther 2018;24(1):18-28 View Article PubMed/NCBI
  75. Wang X, Yang XL, Kong WL, Zeng ML, Shao L, Jiang GT, et al. TRPV1 translocated to astrocytic membrane to promote migration and inflammatory infiltration thus promotes epilepsy after hypoxic ischemia in immature brain. J Neuroinflammation 2019;16(1):214 View Article PubMed/NCBI
  76. Nam JH, Park ES, Won SY, Lee YA, Kim KI, Jeong JY, et al. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF. Brain 2015;138(Pt 12):3610-3622 View Article PubMed/NCBI
  77. You IJ, Jung YH, Kim MJ, Kwon SH, Hong SI, Lee SY, et al. Alterations in the emotional and memory behavioral phenotypes of transient receptor potential vanilloid type 1-deficient mice are mediated by changes in expression of 5-HT1A, GABA(A), and NMDA receptors. Neuropharmacology 2012;62(2):1034-1043 View Article PubMed/NCBI
  78. Chahl LA. TRP’s: links to schizophrenia?. Biochim Biophys Acta 2007;1772(8):968-977 View Article PubMed/NCBI
  79. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(8):1517-1521 View Article PubMed/NCBI
  80. Takumida M, Kubo N, Ohtani M, Suzuka Y, Anniko M. Transient receptor potential channels in the inner ear: presence of transient receptor potential channel subfamily 1 and 4 in the guinea pig inner ear. Acta Otolaryngol 2005;125(9):929-934 View Article PubMed/NCBI
  81. Jiang M, Li H, Johnson A, Karasawa T, Zhang Y, Meier WB, et al. Inflammation up-regulates cochlear expression of TRPV1 to potentiate drug-induced hearing loss. Sci Adv 2019;5(7):eaaw1836 View Article PubMed/NCBI
  82. Kitahara T, Li HS, Balaban CD. Changes in transient receptor potential cation channel superfamily V (TRPV) mRNA expression in the mouse inner ear ganglia after kanamycin challenge. Hear Res 2005;201(1-2):132-144 View Article PubMed/NCBI
  83. Ramkumar V, Sheth S, Dhukhwa A, Al Aameri R, Rybak L, Mukherjea D. Transient Receptor Potential Channels and Auditory Functions. Antioxid Redox Signal 2022;36(16-18):1158-1170 View Article PubMed/NCBI
  84. Sumioka T, Okada Y, Reinach PS, Shirai K, Miyajima M, Yamanaka O, et al. Impairment of corneal epithelial wound healing in a TRPV1-deficient mouse. Invest Ophthalmol Vis Sci 2014;55(5):3295-3302 View Article PubMed/NCBI
  85. Ho KW, Lambert WS, Calkins DJ. Activation of the TRPV1 cation channel contributes to stress-induced astrocyte migration. Glia 2014;62(9):1435-1451 View Article PubMed/NCBI
  86. Sappington RM, Sidorova T, Ward NJ, Chakravarthy R, Ho KW, Calkins DJ. Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress. Channels (Austin) 2015;9(2):102-113 View Article PubMed/NCBI
  87. Zhang F, Yang H, Wang Z, Mergler S, Liu H, Kawakita T, et al. Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling. J Cell Physiol 2007;213(3):730-739 View Article PubMed/NCBI
  88. Lyall V, Heck GL, Vinnikova AK, Ghosh S, Phan TH, Alam RI, et al. The mammalian amiloride-insensitive non-specific salt taste receptor is a vanilloid receptor-1 variant. J Physiol 2004;558(Pt 1):147-159 View Article PubMed/NCBI
  89. Simon SA, Gutierrez R. Neurobiology of TRP Channels. CRC Press; 2017 View Article PubMed/NCBI
  90. Aroke EN, Powell-Roach KL, Jaime-Lara RB, Tesfaye M, Roy A, Jackson P, et al. Taste the Pain: The Role of TRP Channels in Pain and Taste Perception. Int J Mol Sci 2020;21(16):5929 View Article PubMed/NCBI
  91. Costa RM, Liu L, Nicolelis MA, Simon SA. Gustatory effects of capsaicin that are independent of TRPV1 receptors. Chem Senses 2005;30(Suppl 1):i198-i200 View Article PubMed/NCBI
  92. Hu SS. Involvement of TRPV1 in the Olfactory Bulb in Rimonabant-Induced Olfactory Discrimination Deficit. Chin J Physiol 2016;59(1):21-32 View Article PubMed/NCBI
  93. Maruyama K, Takayama Y, Kondo T, Ishibashi KI, Sahoo BR, Kanemaru H, et al. Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis. Cell Rep 2017;19(13):2730-2742 View Article PubMed/NCBI
  94. Pinho-Ribeiro FA, Baddal B, Haarsma R, O’Seaghdha M, Yang NJ, Blake KJ, et al. Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection. Cell 2018;173(5):1083-1097.e22 View Article PubMed/NCBI
  95. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013;501(7465):52-57 View Article PubMed/NCBI
  96. Baral P, Umans BD, Li L, Wallrapp A, Bist M, Kirschbaum T, et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat Med 2018;24(4):417-426 View Article PubMed/NCBI
  97. Jia Y, Lee LY. Role of TRPV receptors in respiratory diseases. Biochim Biophys Acta 2007;1772(8):915-927 View Article PubMed/NCBI
  98. Jayaseelan VP, Paramasivam A. Repurposing calcium channel blockers as antiviral drugs. J Cell Commun Signal 2020;14(4):467-468 View Article PubMed/NCBI
  99. Hyser JM, Estes MK. Pathophysiological Consequences of Calcium-Conducting Viroporins. Annu Rev Virol 2015;2(1):473-496 View Article PubMed/NCBI
  100. Bernabò N, Pistilli MG, Mattioli M, Barboni B. Role of TRPV1 channels in boar spermatozoa acquisition of fertilizing ability. Mol Cell Endocrinol 2010;323(2):224-231 View Article PubMed/NCBI
  101. Mizrak SC, van Dissel-Emiliani FM. Transient receptor potential vanilloid receptor-1 confers heat resistance to male germ cells. Fertil Steril 2008;90(4):1290-1293 View Article PubMed/NCBI
  102. Tympanidis P, Casula MA, Yiangou Y, Terenghi G, Dowd P, Anand P. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur J Pain 2004;8(2):129-133 View Article PubMed/NCBI
  103. Song WJ, Morice AH. Cough Hypersensitivity Syndrome: A Few More Steps Forward. Allergy Asthma Immunol Res 2017;9(5):394-402 View Article PubMed/NCBI
  104. Watanabe N, Horie S, Michael GJ, Keir S, Spina D, Page CP, et al. Immunohistochemical co-localization of transient receptor potential vanilloid (TRPV)1 and sensory neuropeptides in the guinea-pig respiratory system. Neuroscience 2006;141(3):1533-1543 View Article PubMed/NCBI
  105. Adcock JJ. TRPV1 receptors in sensitisation of cough and pain reflexes. Pulm Pharmacol Ther 2009;22(2):65-70 View Article PubMed/NCBI
  106. El-Hashim AZ, Jaffal SM. Cough reflex hypersensitivity: A role for neurotrophins. Exp Lung Res 2017;43(2):93-108 View Article PubMed/NCBI
  107. Baxter M, Eltom S, Dekkak B, Yew-Booth L, Dubuis ED, Maher SA, et al. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 2014;69(12):1080-1089 View Article PubMed/NCBI
  108. Mitchell JE, Campbell AP, New NE, Sadofsky LR, Kastelik JA, Mulrennan SA, et al. Expression and characterization of the intracellular vanilloid receptor (TRPV1) in bronchi from patients with chronic cough. Exp Lung Res 2005;31(3):295-306 View Article PubMed/NCBI
  109. El-Hashim AZ, Jaffal SM. Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms. Thorax 2009;64(9):791-797 View Article PubMed/NCBI
  110. El-Hashim AZ, Jaffal SM, Al-Rashidi FT, Luqmani YA, Akhtar S. Nerve growth factor enhances cough via a central mechanism of action. Pharmacol Res 2013;74:68-77 View Article PubMed/NCBI
  111. Brozmanova M, Mazurova L, Ru F, Tatar M, Kollarik M. Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs. Eur J Pharmacol 2012;689(1-3):211-218 View Article PubMed/NCBI
  112. Cantero-Recasens G, Gonzalez JR, Fandos C, Duran-Tauleria E, Smit LA, Kauffmann F, et al. Loss of function of transient receptor potential vanilloid 1 (TRPV1) genetic variant is associated with lower risk of active childhood asthma. J Biol Chem 2010;285(36):27532-27535 View Article PubMed/NCBI
  113. Abdullah H, Heaney LG, Cosby SL, McGarvey LP. Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax 2014;69(1):46-54 View Article PubMed/NCBI
  114. Van Gerven L, Steelant B, Cools L, Callebaut I, Backaert W, de Hoon J, et al. Low-dose capsaicin (0.01 mM) nasal spray is equally effective as the current standard treatment for idiopathic rhinitis: A randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2021;147(1):397-400.e4 View Article PubMed/NCBI
  115. Saito M, Yoneshiro T. Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol 2013;24(1):71-77 View Article PubMed/NCBI
  116. Panchal SK, Bliss E, Brown L. Capsaicin in Metabolic Syndrome. Nutrients 2018;10(5):630 View Article PubMed/NCBI
  117. Yoshioka M, Lim K, Kikuzato S, Kiyonaga A, Tanaka H, Shindo M, et al. Effects of red-pepper diet on the energy metabolism in men. J Nutr Sci Vitaminol (Tokyo) 1995;41(6):647-656 View Article PubMed/NCBI
  118. Lee E, Jung DY, Kim JH, Patel PR, Hu X, Lee Y, et al. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J 2015;29(8):3182-3192 View Article PubMed/NCBI
  119. Shuba YM. Beyond Neuronal Heat Sensing: Diversity of TRPV1 Heat-Capsaicin Receptor-Channel Functions. Front Cell Neurosci 2020;14:612480 View Article PubMed/NCBI
  120. Ludy MJ, Moore GE, Mattes RD. The effects of capsaicin and capsiate on energy balance: critical review and meta-analyses of studies in humans. Chem Senses 2012;37(2):103-121 View Article PubMed/NCBI
  121. Sogut O, Kaya H, Gokdemir MT, Sezen Y. Acute myocardial infarction and coronary vasospasm associated with the ingestion of cayenne pepper pills in a 25-year-old male. Int J Emerg Med 2012;5:5 View Article PubMed/NCBI
  122. Matsumoto K, Tashima K, Horie S. Localization of TRPV1 Channels and Contractile Effect of Capsaicin in Mouse Isolated Lower Gastrointestinal Tract: Higher Abundance and Sensitivity of TRPV1 Channels in Rectum and Distal Colon Than in Transverse and Proximal Colon. Gastroenterology 2008;134(4):A-159 View Article PubMed/NCBI
  123. Yu X, Yu M, Liu Y, Yu S. TRP channel functions in the gastrointestinal tract. Semin Immunopathol 2016;38(3):385-396 View Article PubMed/NCBI
  124. Negro A, Lionetto L, Simmaco M, Martelletti P. CGRP receptor antagonists: an expanding drug class for acute migraine?. Expert Opin Investig Drugs 2012;21(6):807-818 View Article PubMed/NCBI
  125. de Man JG, Boeckx S, Anguille S, de Winter BY, de Schepper HU, Herman AG, et al. Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors. Neurogastroenterol Motil 2008;20(5):546-556 View Article PubMed/NCBI
  126. Szolcsányi J, Barthó L. Capsaicin-sensitive afferents and their role in gastroprotection: an update. J Physiol Paris 2001;95(1-6):181-188 View Article PubMed/NCBI
  127. Horie S, Yamamoto H, Michael GJ, Uchida M, Belai A, Watanabe K, et al. Protective role of vanilloid receptor type 1 in HCl-induced gastric mucosal lesions in rats. Scand J Gastroenterol 2004;39(4):303-312 View Article PubMed/NCBI
  128. Xu GY, Winston JH, Shenoy M, Yin H, Pendyala S, Pasricha PJ. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 2007;133(4):1282-1292 View Article PubMed/NCBI
  129. Luo C, Wang Z, Mu J, Zhu M, Zhen Y, Zhang H. Upregulation of the transient receptor potential vanilloid 1 in colonic epithelium of patients with active inflammatory bowel disease. Int J Clin Exp Pathol 2017;10(11):11335-11344 View Article PubMed/NCBI
  130. Avraham Y, Zolotarev O, Grigoriadis NC, Poutahidis T, Magen I, Vorobiav L, et al. Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice. Am J Gastroenterol 2008;103(12):3047-3056 View Article PubMed/NCBI
  131. Szabados T, Gömöri K, Pálvölgyi L, Görbe A, Baczkó I, Helyes Z, et al. Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies. Int J Mol Sci 2020;21(12):4472 View Article PubMed/NCBI
  132. Tóth A, Czikora A, Pásztor ET, Dienes B, Bai P, Csernoch L, et al. Vanilloid receptor-1 (TRPV1) expression and function in the vasculature of the rat. J Histochem Cytochem 2014;62(2):129-144 View Article PubMed/NCBI
  133. Sun H, Li DP, Chen SR, Hittelman WN, Pan HL. Sensing of blood pressure increase by transient receptor potential vanilloid 1 receptors on baroreceptors. J Pharmacol Exp Ther 2009;331(3):851-859 View Article PubMed/NCBI
  134. Scotland RS, Chauhan S, Davis C, De Felipe C, Hunt S, Kabir J, et al. Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction. Circ Res 2004;95(10):1027-1034 View Article PubMed/NCBI
  135. Zhong B, Ma S, Wang DH. Protective Effects of TRPV1 Activation Against Cardiac Ischemia/ Reperfusion Injury is Blunted by Diet-Induced Obesity. Cardiovasc Hematol Disord Drug Targets 2020;20(2):122-130 View Article PubMed/NCBI
  136. Ma L, Zhong J, Zhao Z, Luo Z, Ma S, Sun J, et al. Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc Res 2011;92(3):504-513 View Article PubMed/NCBI
  137. Xiong S, Wang P, Ma L, Gao P, Gong L, Li L, et al. Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1-Mediated Protein Kinase A/Uncoupling Protein 2 Pathway. Hypertension 2016;67(2):451-460 View Article PubMed/NCBI
  138. Harper AG, Brownlow SL, Sage SO. A role for TRPV1 in agonist-evoked activation of human platelets. J Thromb Haemost 2009;7(2):330-338 View Article PubMed/NCBI
  139. Gazzieri D, Trevisani M, Tarantini F, Bechi P, Masotti G, Gensini GF, et al. Ethanol dilates coronary arteries and increases coronary flow via transient receptor potential vanilloid 1 and calcitonin gene-related peptide. Cardiovasc Res 2006;70(3):589-599 View Article PubMed/NCBI
  140. Lo CCW, Moosavi SM, Bubb KJ. The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension. Front Physiol 2018;9:1167 View Article PubMed/NCBI
  141. Wei Z, Wang L, Han J, Song J, Yao L, Shao L, et al. Decreased expression of transient receptor potential vanilloid 1 impaires the postischemic recovery of diabetic mouse hearts. Circ J 2009;73(6):1127-1132 View Article PubMed/NCBI
  142. Wang Y, Cui L, Xu H, Liu S, Zhu F, Yan F, et al. TRPV1 agonism inhibits endothelial cell inflammation via activation of eNOS/NO pathway. Atherosclerosis 2017;260:13-19 View Article PubMed/NCBI
  143. Munjuluri S, Wilkerson DA, Sooch G, Chen X, White FA, Obukhov AG. Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation. Cells 2021;11(1):18 View Article PubMed/NCBI
  144. Song S, Ayon RJ, Yamamura A, Yamamura H, Dash S, Babicheva A, et al. Capsaicin-induced Ca(2+) signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. Am J Physiol Lung Cell Mol Physiol 2017;312(3):L309-L325 View Article PubMed/NCBI
  145. Gram DX, Ahrén B, Nagy I, Olsen UB, Brand CL, Sundler F, et al. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur J Neurosci 2007;25(1):213-223 View Article PubMed/NCBI
  146. Chen X, Duan Y, Riley AM, Welch MA, White FA, Grant MB, et al. Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons. Molecules 2019;24(4):775 View Article PubMed/NCBI
  147. Zhong B, Ma S, Wang DH. TRPV1 Mediates Glucose-induced Insulin Secretion Through Releasing Neuropeptides. In Vivo 2019;33(5):1431-1437 View Article PubMed/NCBI
  148. Moraes MN, Mezzalira N, de Assis LV, Menaker M, Guler A, Castrucci AM. TRPV1 participates in the activation of clock molecular machinery in the brown adipose tissue in response to light-dark cycle. Biochim Biophys Acta Mol Cell Res 2017;1864(2):324-335 View Article PubMed/NCBI
  149. Lacerda JT, Gomes PRL, Zanetti G, Mezzalira N, Lima OG, de Assis LVM, et al. Lack of TRPV1 Channel Modulates Mouse Gene Expression and Liver Proteome with Glucose Metabolism Changes. Int J Mol Sci 2022;23(13):7014 View Article PubMed/NCBI
  150. Ständer S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol 2004;13(3):129-139 View Article PubMed/NCBI
  151. Martínez-Martínez E, Galván-Hernández CI, Toscano-Márquez B, Gutiérrez-Ospina G. Modulatory role of sensory innervation on hair follicle stem cell progeny during wound healing of the rat skin. PLoS One 2012;7(5):e36421 View Article PubMed/NCBI
  152. Bernstein JE, Parish LC, Rapaport M, Rosenbaum MM, Roenigk HH. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15(3):504-507 View Article PubMed/NCBI
  153. Lee JH, Choi CS, Bae IH, Choi JK, Park YH, Park M. A novel, topical, nonsteroidal, TRPV1 antagonist, PAC-14028 cream improves skin barrier function and exerts anti-inflammatory action through modulating epidermal differentiation markers and suppressing Th2 cytokines in atopic dermatitis. J Dermatol Sci 2018;91(2):184-194 View Article PubMed/NCBI
  154. Feng J, Yang P, Mack MR, Dryn D, Luo J, Gong X, et al. Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nat Commun 2017;8(1):980 View Article PubMed/NCBI
  155. Khalid S, Khan A, Shal B, Ali H, Kim YS, Khan S. Suppression of TRPV1 and P2Y nociceptors by honokiol isolated from Magnolia officinalis in 3(rd) degree burn mice by inhibiting inflammatory mediators. Biomed Pharmacother 2019;114:108777 View Article PubMed/NCBI
  156. Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007;27(9):2331-2337 View Article PubMed/NCBI
  157. Bodó E, Bíró T, Telek A, Czifra G, Griger Z, Tóth IB, et al. A ‘hot’ new twist to hair biology - involvement of vanilloid receptor-1 signaling in human hair growth control. Exp Dermatol 2008;13(9):581-581 View Article PubMed/NCBI
  158. Akerman S, Kaube H, Goadsby PJ. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol 2004;142(8):1354-1360 View Article PubMed/NCBI
  159. Evans MS, Cheng X, Jeffry JA, Disney KE, Premkumar LS. Sumatriptan inhibits TRPV1 channels in trigeminal neurons. Headache 2012;52(5):773-784 View Article PubMed/NCBI
  160. Shimizu T, Shibata M, Toriumi H, Iwashita T, Funakubo M, Sato H, et al. Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A. Neurobiol Dis 2012;48(3):367-378 View Article PubMed/NCBI
  161. Luvisetto S, Vacca V, Cianchetti C. Analgesic effects of botulinum neurotoxin type A in a model of allyl isothiocyanate- and capsaicin-induced pain in mice. Toxicon 2015;94:23-28 View Article PubMed/NCBI
  162. Chizh B, Palmer J, Lai R, Guillard F, Bullman J, Baines A, et al. A randomised, two-period cross-over study to investigate the efficacy of the trpv1 antagonist SB-705498 in acute migraine. Eur J Pain 2009;13(S1):S202a-S202 View Article PubMed/NCBI
  163. Fusco BM, Barzoi G, Agrò F. Repeated intranasal capsaicin applications to treat chronic migraine. Br J Anaesth 2003;90(6):812 View Article PubMed/NCBI
  164. Diamond S, Freitag F, Phillips SB, Bernstein JE, Saper JR. Intranasal civamide for the acute treatment of migraine headache. Cephalalgia 2000;20(6):597-602 View Article PubMed/NCBI
  165. Markowitz S, Moskowitz MA. Vascular head pain: a neurobiologist’s approach. Funct Neurol 1986;1(4):351-356 View Article PubMed/NCBI
  166. Simonetti M, Fabbro A, D’Arco M, Zweyer M, Nistri A, Giniatullin R, et al. Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Mol Pain 2006;2:11 View Article PubMed/NCBI
  167. Denner AC, Vogler B, Messlinger K, De Col R. Role of transient receptor potential ankyrin 1 receptors in rodent models of meningeal nociception - Experiments in vitro. Eur J Pain 2017;21(5):843-854 View Article PubMed/NCBI
  168. Nicoletti P, Trevisani M, Manconi M, Gatti R, De Siena G, Zagli G, et al. Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig. Cephalalgia 2008;28(1):9-17 View Article PubMed/NCBI
  169. Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedebergs Arch Pharmacol 2006;373(4):287-299 View Article PubMed/NCBI
  170. Liu BL, Yang F, Zhan HL, Feng ZY, Zhang ZG, Li WB, et al. Increased severity of inflammation correlates with elevated expression of TRPV1 nerve fibers and nerve growth factor on interstitial cystitis/bladder pain syndrome. Urol Int 2014;92(2):202-208 View Article PubMed/NCBI
  171. Kassmann M, Harteneck C, Zhu Z, Nürnberg B, Tepel M, Gollasch M. Transient receptor potential vanilloid 1 (TRPV1), TRPV4, and the kidney. Acta Physiol (Oxf) 2013;207(3):546-564 View Article PubMed/NCBI
  172. Zhu Y, Xie C, Wang DH. TRPV1-mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. Am J Nephrol 2007;27(5):530-537 View Article PubMed/NCBI
  173. Roper SD. TRPs in taste and chemesthesis. Handb Exp Pharmacol 2014;223:827-871 View Article PubMed/NCBI
  174. Jordt SE, Ehrlich BE. TRP channels in disease. Subcell Biochem 2007;45:253-271 View Article PubMed/NCBI
  175. Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2006;2(11):596-607 View Article PubMed/NCBI
  176. Trujillo X, Ortiz-Mesina M, Uribe T, Castro E, Montoya-Pérez R, Urzúa Z, et al. Capsaicin and N-arachidonoyl-dopamine (NADA) decrease tension by activating both cannabinoid and vanilloid receptors in fast skeletal muscle fibers of the frog. J Membr Biol 2015;248(1):31-38 View Article PubMed/NCBI
  177. Colpaert FC, Donnerer J, Lembeck F. Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. Life Sci 1983;32(16):1827-1834 View Article PubMed/NCBI
  178. Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The Concise Guide to PHARMACOLOGY 2013/14: transporters. Br J Pharmacol 2013;170(8):1706-1796 View Article PubMed/NCBI
  179. Rossi F, Bellini G, Torella M, Tortora C, Manzo I, Giordano C, et al. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice. Br J Pharmacol 2014;171(10):2621-2630 View Article PubMed/NCBI
  180. Idris AI, Landao-Bassonga E, Ralston SH. The TRPV1 ion channel antagonist capsazepine inhibits osteoclast and osteoblast differentiation in vitro and ovariectomy induced bone loss in vivo. Bone 2010;46(4):1089-1099 View Article PubMed/NCBI
  181. Brito R, Sheth S, Mukherjea D, Rybak LP, Ramkumar V. TRPV1: A Potential Drug Target for Treating Various Diseases. Cells 2014;3(2):517-545 View Article PubMed/NCBI
  182. Koivisto AP, Belvisi MG, Gaudet R, Szallasi A. Advances in TRP channel drug discovery: from target validation to clinical studies. Nat Rev Drug Discov 2022;21(1):41-59 View Article PubMed/NCBI
  183. Vriens J, Nilius B, Vennekens R. Herbal compounds and toxins modulating TRP channels. Curr Neuropharmacol 2008;6(1):79-96 View Article PubMed/NCBI
  184. Jaffal SM, Al-Najjar BO, Abbas MA. Ononis spinosa alleviated capsaicin-induced mechanical allodynia in a rat model through transient receptor potential vanilloid 1 modulation. Korean J Pain 2021;34(3):262-270 View Article PubMed/NCBI
  185. Jaffal S, Oran S, Alsalem M, Al-Najjar B. Effect of Arbutus andrachne L. methanolic leaf extract on TRPV1 function: Experimental and molecular docking studies. J Appl Pharm Sci 2022;12(10):69-77 View Article PubMed/NCBI
  186. Abbas MA. Modulation of TRPV1 channel function by natural products in the treatment of pain. Chem Biol Interact 2020;330:109178 View Article PubMed/NCBI

Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2587576
  • Visits today : 5571