The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...

receptor and the vanilloid receptor 1, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that, in humans, is encoded by the ''TRPV1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the

TRPV TRPV is a family of transient receptor potential cation channels (TRP channels) in animals. All TRPVs are highly calcium selective. TRP channels are a large group of ion channels consisting of six protein families, located mostly on the plasma ...

group of transient receptor potential family of

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

s. The function of TRPV1 is detection and regulation of

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

. In addition, TRPV1 provides a sensation of scalding heat and pain (

nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...

). In primary afferent

sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The ...

s, it cooperates with TRPA1 (a chemical irritant receptor) to mediate the detection of noxious environmental stimuli.

Function

TRPV1 is an element of or mechanism used by the mammalian

somatosensory system In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...

. It is a nonselective

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

channel that may be activated by a wide variety of

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogen ...

and

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than ; acidic conditions;

(the irritating compound in hot chili peppers); and

allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...

, the pungent compound in mustard and wasabi. The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-oleyl-dopamine, and

N-arachidonoyl-dopamine ''N''-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 rece ...

. TRPV1 receptors are found mainly in the nociceptive

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

of the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

, but they have also been described in many other tissues, including the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. TRPV1 is involved in the transmission and modulation of

pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...

(

), as well as the integration of diverse painful stimuli.

Sensitization

The sensitivity of TRPV1 to noxious stimuli, such as high temperatures, is not static. Upon tissue damage and the consequent

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

, a number of inflammatory mediators, such as various

prostaglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deri ...

and

bradykinin Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...

, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli ( hyperalgesia) or pain sensation in response to non-painful stimuli ( allodynia). Most sensitizing pro-inflammatory agents activate the

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

pathway. Phosphorylation of TRPV1 by

protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and ...

have been shown to play a role in sensitization of TRPV1. The cleavage of PIP2 by PLC-beta can result in disinhibition of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli.

Desensitization

Upon prolonged exposure to

, TRPV1 activity decreases, a phenomenon called ''desensitization''. Extracellular

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as phosphorylation by PKA and PKC, interaction with

calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...

, dephosphorylation by calcineurin, and the decrease of PIP₂, have been implicated in the regulation of desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

effect of capsaicin.

Clinical significance

Peripheral nervous system

As a result of its involvement in

, TRPV1 has been a target for the development of pain reducers ( analgesics). Three major strategies have been used:

TRPV1 Use

The TRPV1 receptor is useful to be able to measure how an organism can sense temperature change. In the lab the receptor may be removed from mice giving them the inability to detect differences in ambient temperature. In the pharmaceutical field this allows for the blocking of heat receptors giving patients with inflammatory disorders or severe burning pains a chance to heal without the pain. The lack of the TRPV1 receptor gives a glimpse into the developing brain as heat can kill most organisms in large enough doses, so this removal process shows researchers how the inability to sense heat may be detrimental to the survivability of an organism and then translate this to human heat disorders.

TRPV1 in immune cells

TRPV1 plays an important role not only in

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

es but also in immune cells. Activation of TRPV1 modulates immune response including the release of inflammatory

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...

s, and the ability to phagocytose. However, the role of TRPV1 in immune cells is not entirely understood and it is currently intensely studied. TRPV1 is not the only TRP channel expressed in immune cells. TRPA1, TRPM8 and TRPV4 are the most relevant TRP channels that are also studied in immune cells. The expression of TRPV1 was confirmed in the cells of innate immunity as well as the cells of adaptive immunity. TRPV1 can be found in

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. Th ...

s, T lymphocytes,

natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repre ...

s and

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

es. TRPV1 is said to be potentially very important in immune cell functioning as it senses higher temperature and lower pH, which can affect the immune cell performance.

TRPV1 and Adaptive Immunity

TRPV1 is an important membrane channel in

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s as it regulates the influx of calcium cations. TRPV1’s involvement is mainly in T cell receptor signalling ( TCR) signalling, T cell activation and TCR-mediated influx of calcium ions, but it is involved in T cell

production as well. Indeed, T cells with TRPV1 knockout show impaired calcium uptake after T cell activation via TCR, thus they show dysregulation in signalling pathways such as NF-κB and NFAT.

TRPV1 and Innate Immunity

Regarding innate immunity, activation of TRPV1 by

has been shown to suppress the production of nitrite radical,

superoxide anion In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...

and

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...

s. Furthermore, administration of

, and subsequent activation of TRPV1, suppresses phagocytosis in

s. In a mouse model, TRPV1 affect

maturation and function, however, further studies are needed to clarify this effect in humans. In

s, the increase in cytosolic calcium cations leads to synthesis of

prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...

s. Activation of TRPV1 by

modulates

immune response due to the higher influx of calcium ions into the cell. TRPV1 is also considered a novel therapeutic agent in many inflammatory diseases. Multiple studies have proven that TRPV1 influences the outcome of several inflammatory diseases such as chronic

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

, esophageal inflammation,

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...

and

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Studies using TRPV1’s agonists and antagonists have shown that their administration indeed changes the course of inflammation. However, at this point, there is a lot of contradictive evidence about what type of response, pro-inflammatory or anti-inflammatory, TRPV1’s activation induces. Further research needs to be carried out. Meanwhile, it is important to highlight that TRPV1’s influence on inflammatory diseases is probably not limited to only immune cells as it is rather an interplay between immune cells,

s, and other cell types (epithelial cells etc.).

TRPV1 and Cancer

TRPV1 was found to be overexpressed in several types of

s, e.g.,

pancreatic cancer Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancr ...

and colon

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, o ...

. This suggest that certain types of

s might be more prone to cell death mediated by

-induced (and also other

vanilloid The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids. : A number of vani ...

-induced) cell death. Indeed, studies have shown inversed correlation of consumption of chili-based foods and all-cause mortality along with

s. This beneficial impact of the consumption of chili-based foods was attributed to capsaicinoid content. TRPV1 activation caused by its agonist

was shown to induce G0-G1 cell arrest and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

in leukemic cell lines, Adult T-Cell Leukaemia and

Multiple Myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...

. Capsaicin reduces the expression of anti-apoptotic protein

Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...

and it also promotes activation of p53, a tumour-suppressor protein known as a major regulator of cell death. This effect of

in both cases subsequently leads to above-mentioned

TRPV1 and Neuroinflammation

The interplay between

s and immune cells is a well-known phenomenon, therefore it is no surprise that TRPV1 plays its role in neuroinflammation, as it is expressed both in neurons and in immune cells. Significant importance should be paid to the confirmed expression of TRPV1 in

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

and

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s, cells found in close proximity to

s. The neuro-immune axis is the place of production of neuroinflammatory molecules and receptors that interplay between the two systems and ensure a complex response to external stimuli (or to the body’s own pathologies). Studying TRPV1’s involvement in neuroinflammation has a great therapeutical significance for the future. Cutaneus neurons expressing TRPV1 and

s were found to be located close to each other. Activation of TRPV1 channels in

s is associated with subsequent production of interleukin 23 (IL-23) by

s and further production of IL-17 by

s. These interleukins are important for host defence against pathogenic fungi (such as '' Candida albicans'') and bacteria (such as ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...

''), thus TRPV1’s activation can lead to better defence against these

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...

s, thanks to the neuro-immune axis. TRPV1 is said to contribute to

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

via its Ca²⁺-signalling, which leads to mitochondria-induced cell death. The TRPV1 channel also influences microglia-induced inflammation. Migration and

chemotaxis Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

and

s seems to be affected by TRPV1’s interaction with the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...

and Ca²⁺-signalling. TRPV1 is therefore involved in the neuro-immune axis via its function in

as well. TRPV1 was shown to have protective effect in neurologic disorders such as Huntington’s disease,

vascular dementia Vascular dementia (VaD) is dementia caused by problems in the supply of blood to the brain, typically a series of minor strokes, leading to worsening cognitive abilities, the decline occurring piecemeal. The term refers to a syndrome consisting ...

, and Parkinson’s disease. However, its precise function needs to be further explored.

Ligands

Antagonists

Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist

capsazepine Capsazepine is a synthetic antagonist of capsaicin. It is used as a biochemical tool in the study of TRPV ion channels. Pharmacology Capsazepine blocks the painful sensation of heat caused by capsaicin (the active ingredient of chilli pepper) w ...

and the non-competitive antagonist

ruthenium red The inorganic dye ammoniated ruthenium oxychloride, also known as ruthenium red, is used in histology to stain aldehyde fixed mucopolysaccharides. Ruthenium red (RR) has also been used as a pharmacological tool to study specific cellular mechanis ...

. These agents could be useful when applied systemically. Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing

from inflammatory and neuropathic pain models in rats. This provides evidence that TRPV1 is

's sole receptor In humans, drugs acting at TRPV1 receptors could be used to treat

neuropathic Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...

pain associated with

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

, or

amputation Amputation is the removal of a limb by trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on indi ...

, as well as pain associated with the inflammatory response of damaged tissue, such as in

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...

. These drugs can affect body temperature (

hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extrem ...

) which is a challenge to therapeutic application. For example, a transient temperature gain (~1 °C for a duration of approximately 40 minutes, reverting to baseline by 40 minutes) was measured in rats with the application of TRPV1 antagonist AMG-9810. The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing a mild increase in body temperature (

), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature by telling the body to "cool itself down". Without these signals, the body overheats. Likewise, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature. Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance. Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance. In 2008, AMG-517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the causation of hyperthermia (~38.3 °C mean increase which was most intense on day 1 but was attenuated on days 2–7. Another molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported. As we increase understanding of modality specific agonism of TRPV1 it seems that next generation therapeutics targeting TRPV1 have the potential to side-step hyperthermia. Moreover, for at least two indications or approaches this may be a secondary issue. Where the therapeutic approach (e.g., in analgesia) is agonist-mediated desensitization then the hyperthermic effects of antagonists may not be relevant. Secondarily in applications such as TRPV1 antagonism for the treatment of severe conditions such as heart failure, then there may be an acceptable trade-off with mild hyperthermia, although no hyperthermia was observed in rodent models of heart failure treated with BCTC, SB-366791 or AMG-9810. Post translational modification of TRPV1 protein by its

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

is critical for its functionality. Reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.

Agonists

TRPV1 is activated by numerous agonists from natural sources. Agonists such as

and resiniferatoxin activate TRPV1 and, upon prolonged application, cause TRPV1 activity to decrease (desensitization), leading to alleviation of pain via the subsequent decrease in the TRPV1 mediated release of inflammatory molecules following exposures to noxious stimuli. Agonists can be applied locally to the painful area in various forms, generally as a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials. Eight percent capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin. Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.

Cannabinoid ligands

Cannabinoid

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

include: * Cannabidiol (CBD) -

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

* Cannabigerol (CBG) - agonist * Tetrahydrocannabivarin (THCV) - agonist * Cannabigerovarin (CBGV) - agonist

N-Acyl amides

N-Acyl Amides that activate cannabimimetic receptors include: * Anandamide (AEA) * N-Arachidonoyl dopamine * N-Oleoyl dopamine * N-Arachidonoyl taurine * N-Docosahexaenoyl ethanolamine * N-Docosahexaenoyl GABA * N-Docosahexaenoyl aspartic acid * N-Docosahexaenoyl glycine * N-Docosahexaenoyl serine * N-Arachidonoyl GABA * N-Linoleyl GABA

Fatty acid metabolites

Certain metabolites of polyunsaturated fatty acids have been shown to stimulate cells in a TRPV1-dependent fashion. The metabolites of

linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. ...

, including 13(''S'')-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE), 13(''R'')-hydroxy-9Z,11E-octadecadienoic acid (13(''R'')-HODE, 9(''S'')-hydroxy-10(E),12(Z)-octadecadienoic acid (9(''S'')-HODE), 9(''R'')-hydroxy-10(E),12(Z)-octadecadienoic acid (9(''R'')-HODE), and their respective keto analogs, 13-oxoODE and 9-oxoODE (see 13-HODE and 9-HODE sections on Direct actions), activate peripheral and central mouse pain sensing neurons. Reports disagree on the potencies of these metabolites with, for example, the most potent one, 9(''S'')-HODE, requiring at least 10 micromoles/liter. or a more physiological concentration of 10 nanomoles/liter to activate TRPV1 in rodent neurons. The TRPV1-dependency of these metabolites' activities appears to reflect their direct interaction with TPRV1. Although relatively weak agonists of TRPV1 in comparison to anandamide, these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents and to cause injury to airway epithelial cells and thereby to contribute to

disease in mice and therefore possibly humans. Certain

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''ara ...

metabolites, including 20-hydroxy-5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (see

20-Hydroxyeicosatetraenoic acid 20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regu ...

) and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',12''S'',14''Z''-eicosatetraenoic acid (12(S)-HpETE), 12(''S'')-hydroxy-5''Z'',8''Z'',10''E'',12''S'',14''Z''-eicosatetraenoic acid (12(''S'')-HETE (see 12-HETE),

hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid ...

A3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) likewise activate TRPV1 and may thereby contribute to tactile hyperalgesia and allodynia (see Hepoxilin#Pain perception). Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite,

Prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...

, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716), has been associated with

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volum ...

-induced cough in humans. Resolvin E1 (RvE1), RvD2 (see resolvins), neuroprotectin D1 (NPD1), and maresin 1 (Mar1) are metabolites of the omega 3 fatty acids, eicosapentaenoic acid (for RvE1) or docosahexaenoic acid (for RvD2, NPD1, and Mar1). These metabolites are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV1, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on the neurons or nearby

s. CMKLR1,

GPR32 G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors. Gene The ''GPR32'' was initially identified and defined by mo ...

FPR2 N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the ''FPR2'' gene and is activated to regulate cell function ...

, and

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

s have been proposed to be the receptors through which these SPMs operate to

down-regulate In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...

TRPV1 and thereby pain perception.

Fatty acid conjugates

N-Arachidonoyl dopamine, an endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC₅₀ of approximately of 50 nM. N-Oleyl-dopamine, another endogenous agonist, binds to human VR1 with an Ki of 36 Nm. Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors. AM404—an

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...

(also known as acetaminophen) —that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist. The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors. TRPV1 colocalizes with CB1 receptors and CB2 receptors in sensory and

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

s respectively, and other plant-cannabinoids like CBN, CBG, CBC,

THCV Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very different effects from THC. ...

, and CBDV are also agonists of this

. There is also evidence that non cannabinoid components of the Cannabis secondary metabolome such as

myrcene Myrcene, or β-myrcene, is a monoterpene. A colorless oil, it occurs widely in essential oils. It is produced mainly semi-synthetically from ''Myrcia'', from which it gets its name. It is an intermediate in the production of several fragrances. � ...

activate TRPV1.

Vitamin D metabolites

Vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...

metabolites, calcifediol (25-hydroxy vitamin D or 25OHD) and calcitriol (1,25-hydroxy vitamin D or 1,25OHD), act as endogenous ligands of TRPV1.

Central nervous system

TRPV1 is also expressed at high levels in the

and has been proposed as a target for treatment not only of pain but also for other conditions such as

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

. Furthermore, TRPV1 appears to mediate long-term synaptic depression (LTD) in the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...

. LTD has been linked to a decrease in the ability to make new memories, unlike its opposite long-term potentiation (LTP), which aids in memory formation. A dynamic pattern of LTD and LTP occurring at many synapses provides a code for memory formation. Long-term depression and subsequent pruning of synapses with reduced activity is an important aspect of memory formation. In rat brain slices, activation of TRPV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD. In the brainstem (solitary tract nucleus), TRPV1 controls the asynchronous and spontaneous release of glutamate from unmyelinated cranial visceral afferents - release processes that are active at normal temperatures and hence quite distinct from TRPV1 responses in painful heat. Hence, there may be therapeutic potential in modulating TRPV1 in the central nervous system, perhaps as a treatment for epilepsy (TRPV1 is already a target in the peripheral nervous system for pain relief).

Interactions

TRPV1 has been shown to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with: * CALM1, * SNAPAP, and * SYT9. * CBD * AEA * NPR1 * PKG

Discovery

The

dorsal root ganglion A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...

(DRG)

s of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin. The research group of David Julius, therefore, created a

cDNA library A cDNA library is a combination of cloned cDNA (complementary DNA) fragments inserted into a collection of host cells, which constitute some portion of the transcriptome of the organism and are stored as a " library". cDNA is produced from fully ...

of genes expressed in

neurons, expressed the clones in HEK 293 cells, and looked for cells that respond to capsaicin with calcium influx (which HEK-293 normally not do). After several rounds of screening and dividing the library, a single clone encoding the TRPV1 channel was finally identified in 1997. It was the first TRPV channel to be identified. Julius was awarded the 2021 Nobel prize in Physiology or Medicine for his discovery.

References

External links

* * * Th
Endocannabinoidome
The World of Endocannabinoids and Related Mediators Book • 2014 {{Transient receptor potential channel modulators Ion channels