Stimulation of TRPV1+ and / or TRPA1+ sensory nerves for prevention and treatment of diseases

Abstract

Provided is stimulation of TRPV1+ and / or TRPA1+ sensory nerves for the prevention and treatment of diseases. Particularly provided is use of a substance for stimulating TRPV1+ and / or TRPA1+ sensory nerves in the prevention or treatment of inflammatory diseases, dysautonomia, or adrenal insufficiency, and in inhibiting the generation of pro-inflammatory cytokines and promoting the generation of anti-inflammatory cytokines. A TRPV1 and / or TRPA1 ion channel agonist can significantly effectively inhibit the expression of numerous pro-inflammatory cytokines and significantly improve the expression of the anti-inflammatory cytokine IL10, significantly improving both the physiological state and the survival rate of mice with inflammation. Moreover, the agonist can adjust spleen function, significantly inhibit the expression of pro-inflammatory genes in the spleen, increase the generation of catecholamine, and promote the secretion of cortisol-like hormones. The agonist has wide clinical application value for the prevention and treatment of related diseases.

Description

Stimulating TRPV1+ and / or TRPA1+ sensory nerves to prevent and treat diseases

[0001] Cross-reference to Related Applications

[0002] This application claims priority to the Chinese patent application No. 202410538879.9, filed on April 30, 2024, and entitled "Stimulating TRPV1+ and / or TRPA1+ sensory nerves to prevent and treat diseases", the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of biological medicine, and relates to stimulating TRPV1+ and / or TRPA1+ sensory nerves to prevent and treat diseases, in particular to a method and a drug for stimulating TRPV1+ and / or TRPA1+ sensory nerves to regulate autonomic nervous system and organ function to treat visceral dysfunction, to regulate hormone and catecholamine secretion, and to prevent and treat inflammatory diseases caused by pro-inflammatory cytokines or pro-inflammatory cytokine cascades. BACKGROUND

[0004] Autonomic nervous (vegetative nervous) dysfunction, adrenal insufficiency, hormone and catecholamine secretion disorders can destroy the body's physiological homeostasis, cause physical discomfort and induce the occurrence of various diseases. Pathogen invasion, tissue damage, visceral dysfunction, autoimmune diseases, organ transplantation, immunotherapy and exposure to stimulating factors can cause inflammatory response, the immune system helps the body resist the invasion of pathogens, the ravages of abnormal cells in the body, and the repair of damaged tissues. However, immune system disorders lead to excessive and persistent inflammation, which will produce excessive pro-inflammatory cytokines and form a cytokine cascade, and if the inflammatory process is not blocked in time, it will eventually form a cytokine storm or an inflammatory storm. When the body's normal compensatory anti-inflammatory response capacity is exceeded, the immune system will not distinguish between friend and foe, and will mistakenly attack the body's own tissues and cells, causing widespread damage to various systems and tissues throughout the body, and in severe cases, can lead to multiple organ failure and even death. The incidence of sepsis or sepsis caused by pathogenic microorganisms or other pathogenic factors is high, with more than 10 million severe cases worldwide each year. Due to the occurrence of inflammatory storm in these two diseases, the disease is extremely dangerous and abnormal, and the mortality rate is as high as 30%~70%, which has exceeded that of myocardial infarction. The coronavirus SARS-CoV, MERS-CoV and SARS-CoV-2 that ravage the world also have a close relationship with cytokine storm. Cytokine storm will release pro-inflammatory substances into the lung microenvironment in a short period of time, causing severe damage to lung tissue. The concentration of pro-inflammatory cytokines in the plasma of severe patients is significantly higher than that of mild patients, indicating that the severity of symptoms is closely related to the high expression of cytokines. There is also a great risk of inducing an inflammatory storm for the immunotherapy and CAR-T cell therapy of cancer patients, which even endangers life safety. For the critically ill patients of the above diseases, on the one hand, antibiotics, antiviral drugs or surgery are needed to eliminate the source of the disease in time, and at the same time, the focus of special attention is how to effectively inhibit excessive inflammation. In addition, the harm of chronic inflammation and autoimmune diseases to the body's persistent damage cannot be ignored, often leading to various chronic diseases (such as diabetes, atherosclerosis, etc.) and cancer. Unfortunately, there are currently limited drugs and treatment methods available for inhibiting inflammation, and the efficacy is not satisfactory, and often causes serious side effects.

[0005] In addition to the immune system, the nervous system plays a crucial role in the regulation of inflammatory responses. The cross-talk between neurons and immune cells promotes the functional integration of the two systems, which is important for the regulation of immune functions and mobilization of various physiological functions, and is an indispensable part of maintaining homeostasis. TRPV1 belongs to the TRP (transient receptor potential) family of cation channels, and is an important chemosensitive and temperature-sensitive receptor, which plays an important role in sensing external environmental temperature and regulating body temperature. TRPV1 ion channels can be activated by various stimuli, such as capsaicin, heat (> 43℃), acidic pH (< 5.3) and endogenous substances. In addition, pro-inflammatory factors (such as histamine, prostaglandins and ATP) can bind to G protein-coupled receptors (GPCRs) and trigger the sensitization of TRPV1 ion channels through a phospholipase C (PLC) and protein kinase A (PKA)-dependent phosphorylation pathway. TRPV1+ nerves are widely distributed in the skin and many internal organs, and the cell bodies of TRPV1+ neurons are located in the trigeminal ganglion, dorsal root ganglion and jugular ganglion. TRPV1+ sensory nerves are responsible for transmitting nociceptive or thermal information from the body surface or internal tissues to the corresponding brain regions, thereby sensing external environmental stimuli and the physiological state of internal tissues.

[0006] TRPA1 ion channels are highly co-expressed with TRPV1, and are important chemosensitive and temperature-sensitive receptors, which are activated by covalent modification of the N-terminal cysteine residue. Low temperature, chemical stimulants, mechanical stimulation, endogenous inflammatory molecules, oxidative stress and hypoxia can activate TRPA1 ion channels. TRPA1+ nerves are widely distributed in the skin and many internal organs, and the cell bodies of TRPA1+ neurons are located in the trigeminal ganglion, dorsal root ganglion and jugular ganglion.

[0007] SUMMARY

[0008] The purpose of the present application is to provide a method and a drug for stimulating TRPV1+ and / or TRPA1+ sensory nerves to regulate autonomic nervous system and organ function, treating visceral dysfunction, regulating hormone and catecholamine secretion, and preventing and treating inflammatory diseases caused by pro-inflammatory cytokines or pro-inflammatory cytokine cascades. The technical problems to be solved by the present application are not limited to the technical subject described, and other technical subjects not mentioned herein can be clearly understood by those skilled in the art through the following description.

[0009] To achieve the above-mentioned purpose, the present application first provides the use of a substance stimulating TRPV1+ and / or TRPA1+ sensory nerves in the preparation of a product having any one of the following functions:

[0010] A1) preventing, treating or adjuvant treating inflammatory diseases;

[0011] A2) inhibits pro-inflammatory cytokine expression or inhibits pro-inflammatory cytokine cascade;

[0012] A3) promotes anti-inflammatory cytokine expression or production;

[0013] A4) prevents, treats or adjuvant treats autonomic nervous function disorder disease;

[0014] A5) promotes catecholamine secretion;

[0015] A6) prevents, treats or adjuvant treats adrenal insufficiency disease;

[0016] A7) promotes adrenal secretion of corticosteroids.

[0017] In the above uses, the substance that stimulates TRPV1+ and / or TRPA1+ sensory nerves can be a substance that activates TRPV1 and / or TRPA1 ion channels through chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, ultrasonic stimulation or infrared stimulation.

[0018] In the above uses, the substance that stimulates TRPV1+ and / or TRPA1+ sensory nerves can be a TRPV1 and / or TRPA1 ion channel agonist.

[0019] In the above uses, the TRPV1 and / or TRPA1 ion channel agonist can be any of the following:

[0020] B1) an agent or drug that activates TRPV1 and / or TRPA1 ion channels;

[0021] B2) an agent or drug that activates TRPV1+ and / or TRPA1+ sensory neurons;

[0022] B3) an agent or drug that promotes replication, transcription, translation, post-transcriptional modification and / or post-translational modification of TRPV1 and / or TRPA1 genes;

[0023] B4) an agent or drug that increases or up-regulates the content, activity and / or function of TRPV1 and / or TRPA1 proteins.

[0024] Further, the TRPV1 and / or TRPA1 ion channel agonist can be an agent or a drug for overexpressing a TRPV1 and / or TRPA1 gene (e.g., a recombinant vector for overexpressing a TRPV1 and / or TRPA1 gene). The overexpression can be achieved by regulation at the gene level (e.g., replication, transcription, translation, post-transcriptional modification, and / or post-translational modification of the gene) or by promoting or increasing the amount, activity, and / or function of the target protein at the protein level. The means of overexpression is not particularly limited, and numerous ways of achieving overexpression are well known to those skilled in the art. For example, the nucleic acid molecule to be overexpressed or the nucleic acid molecule encoding the TRPV1 and / or TRPA1 protein can be placed under the control of a strong promoter; the copy number of one or more genes encoding the TRPV1 and / or TRPA1 protein of the present application can be increased; or the strength of the ribosome binding site or Kozak sequence, the stability of the mRNA, the codon usage, etc. can be increased.

[0025] Further, the TRPV1 ion channel agonists include, but are not limited to, the following chemicals: capsaicin, capsiate, capsaicinoid, capsaicin-d3, dihydrocapsaicin, dihydrocapsiate, gingerol, allicin, allin, N-arachidonyldopamine (NADA), (R)-methanandamide (AM-356), evodiamine, cannabinoid, cannabidiol, vocacapsaicin (CA-008), vocacapsaicin hydrochloride, N-oleoyldopamine (OLDA), hydroxy-α-sanshool, nonivamide, paradol, protokylol, eugenol, camphor, clotrimazole, arvanil, N-arachidonoylvanillamine, anandamide, 2-aminoethoxydiphenyl borate (2APB), resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil, 6'-iodoresiniferatoxin (6'-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives, 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot peptides, vanillotoxins, piperine, N-[2-(3,[4-Dimethylbenzyl)-3-(neovaleroxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide (MSK195), N-[2-(3,4-dimethylbenzyl)-3-(neovaleroxy)propyl]-N'-(4-hydroxy-3-methoxybenzyl)thiourea (JYL 79), 2-aminoethoxydiphenyl borate (2-aminoethoxydiphenyl) Borate, Zingerone, 10-Shogaol, Oleylgingerol, Oleylshogaol, N-(4-tert-butylbenzyl)-N'-(4-hydroxy-3-methoxybenzyl)thiourea (SU200), Amylocaine, Articaine, Benzocaine, Bupivacaine, Carbocaine, Carticaine, Chlorpromazine Cocaine (chloroprocaine), cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), eticaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaineoxycaine, risocaine, ropivacaine, tetracaine, amethocaine, trimecaine, diallyl sulfides, alkylamides derived from sanshool, oxidized linoleic metabolites, black pepper compounds, tinyatoxin, AM404, MDR-652, MSP-3, OMDM-5, OMDM-6, CB1 / 2 agonist 4, SA13353.

[0026] Agonists of other receptors or ion channels expressed by TRPV1+ neurons can also activate TRPV1+ neurons, such as agonists of the TRPA1 ion channel and some cytokine receptors.

[0027] The TRPA1 ion channel agonists include, but are not limited to, the following chemicals: allyl-isothiocyanate (AITC), mustard oil, icilin, allicin, cannabidiol, gingerol, optovin, polygodial, resveratrol, diallyl disulfide, cinnamaldehyde, cinnamon oil, imiquimod, moringin, voacangine, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, methyl syringate, deuterated methyl syringate (methyl syringate-d6), 4-(Phenyldiazenyl)benzoic acid, (E)-4-Oxo-2-nonenal (4-ONE), 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine,Meprylcaine (Oracaine), Metabutoxycaine, Piperocaine, Prilocaine, Procaine (Novocaine), Proparacaine, Propoxycaine, Risocaine, Ropivacaine, Tetracaine (Amethocaine), Trimecaine, Fenarnate, Nicotine, Diallyl sulfides nifedipine, Nimodipine, Nicardipine, Nitrendipine, L-type calcium channel agaonist BayK 8644, Hepoxilins A3 and B3, 12S-Hydroperoxy-5Z, 8Z, 10E, 14Z-eicosatetraenoic acid, 4, 5-Epoxyeicosatrienoic acid, Supercimlamaldehyde, microRNA-711, microRNA-let-7b, ASP7663, AS1269574, PF-4840154, JT010.

[0028] In the above uses, the TRPV1 ion channel agonist can be a capsaicin or capsaicinoid.

[0029] The capsaicinoids include capsaicin analogs and derivatives thereof, are known to the skilled person and are commercially available.

[0030] Further, the capsaicinoids include, but are not limited to, norbixin, homocapsaicin, dihydrocapsaicin, nor dihydrocapsaicin (nordihydrocapsaicin), homodihydrocapsaicin, nonivamide (pungentamide), octanoyl vanillylamide, decanoyl vanillylamide and zucapsaicin (cis-capsaicin, Civamide).

[0031] The present application also provides the use of TRPV1 and / or TRPA1 ion channels as a target in any of the following:

[0032] C1 ) in the manufacture of a product for preventing, treating or adjuvant treating an inflammatory disease;

[0033] C2) in the manufacture of a product for inhibiting pro-inflammatory cytokine expression or inhibiting a pro-inflammatory cytokine cascade;

[0034] C3) in the manufacture of a product for promoting anti-inflammatory cytokine expression or production;

[0035] C4) in the manufacture of a product for preventing, treating or adjuvant treating an autonomic nervous function disorder disease;

[0036] C5) in the manufacture of a product for promoting catecholamine secretion;

[0037] C6) in the manufacture of a product for preventing, treating or adjuvant treating an adrenal insufficiency disease;

[0038] C7) in the manufacture of a product for promoting adrenal secretion of corticosteroids;

[0039] C8) in the development, design or screening of a candidate drug and / or a therapeutic method for treating and / or preventing an inflammatory disease due to a pro-inflammatory cytokine or a pro-inflammatory cytokine cascade;

[0040] C9) in the development, design or screening of a candidate drug and / or a therapeutic method for treating and / or preventing an autonomic nervous function disorder disease and a disease due to insufficient catecholamine secretion;

[0041] C10) in the development, design or screening of a candidate drug and / or a therapeutic method for treating and / or preventing an adrenal insufficiency disease.

[0042] The present application also provides a pharmaceutical composition comprising a TRPV1 ion channel agonist and / or a TRPA1 ion channel agonist of any of the present application, and one or more pharmaceutically acceptable carriers.

[0043] Further, the pharmaceutical composition has at least one of the following uses:

[0044] D1 ) preventing, treating or adjuvant treating an inflammatory disease;

[0045] D2) inhibiting pro-inflammatory cytokine expression or inhibiting a pro-inflammatory cytokine cascade;

[0046] D3) promoting anti-inflammatory cytokine expression or production;

[0047] D4) preventing, treating or co-treating an autonomic nervous function disorder disease;

[0048] D5) promoting catecholamine secretion;

[0049] D6) preventing, treating or co-treating an adrenal insufficiency disease;

[0050] D7) promoting adrenal secretion of corticosteroids.

[0051] The pharmaceutically acceptable carrier is selected from the group consisting of diluents, excipients, fillers, binders, humectants, disintegrants, preservatives, stabilizers, absorption promoters, adsorptive carriers, surfactants, lubricants, nebulizing agents, suspending agents, plasticizers and dispersants.

[0052] In the above uses, the pro-inflammatory cytokine can be TNFa, IL6, IL1a, IL1P, IL1f9, IL1rl1, IL1rn, IL2, IL12b, IL13, IL15, IL16, IL20rb, IL27, TNFSF15, TNFSF18, TNFRSF12a, TNFRSF19, CD40, CSF2, CSF3, LIF, TIMP1, TSLP, FAS, OSMR, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL12, CCL17, CCL19, CCL20, CCL22, CCL27, CCR6, CXCL1, CXCL5, CXCL10, CXCL11, CX3CL1, XCL1, IFNa1, IFNa2, IFNa4, IFNa5, IFNa9, IFNab, IFNb1, IFNg, IFIH1, IFIT1, IFIT1bl1, IFIT2, IFIT3, IFIT3b, IFI27l2b, IFI47, IFI204, IFI205, IFI207, IFI211, IRF4 and / or IRF6.

[0053] In the above uses, the anti-inflammatory cytokine can be IL10.

[0054] The corticosteroid described herein can be corticosterone.

[0055] The catecholamine described herein can be dopamine, norepinephrine and / or epinephrine.

[0056] The present application also provides a method for screening a candidate drug for treating and / or preventing an inflammatory disease caused by a proinflammatory cytokine or a proinflammatory cytokine cascade, the method comprising: screening a drug to be screened with TRPV1 and / or TRPA1 ion channels as a target, and selecting a drug capable of activating TRPV1 and / or TRPA1 ion channels, or up-regulating TRPV1 and / or TRPA1 gene and / or TRPV1 and / or TRPA1 protein level as the candidate drug.

[0057] The products described herein can include reagents, agents, drugs, pharmaceutical compositions, therapeutic kits, and the like.

[0058] The present application also provides the use of a substance stimulating TRPV1+ and / or TRPA1+ sensory nerves in any one of:

[0059] E1) preventing, treating or adjuvant treating an inflammatory disease;

[0060] E2) inhibiting proinflammatory cytokine expression or inhibiting a proinflammatory cytokine cascade;

[0061] E3) promoting anti-inflammatory cytokine expression or production;

[0062] E4) preventing, treating or adjuvant treating an autonomic nervous function disorder disease;

[0063] E5) promoting catecholamine secretion;

[0064] E6) preventing, treating or adjuvant treating an adrenal insufficiency disease;

[0065] E7) promoting adrenal secretion of corticosteroids.

[0066] The present application also provides a method for preventing or treating a disease, the method comprising stimulating TRPV1+ and / or TRPA1+ sensory nerves of a subject or patient.

[0067] In the above method, the disease includes an inflammatory disease, an autonomic nervous function disorder disease or an adrenal insufficiency disease.

[0068] In the above method, the method comprises administering to the subject or patient a TRPV1 ion channel agonist and / or a TRPA1 ion channel agonist described herein, or a pharmaceutical composition described herein.

[0069] The patient described herein can be a patient suffering from an inflammatory disease, an autonomic nervous function disorder disease or an adrenal insufficiency disease.

[0070] In the above method, the administration method includes intramuscular injection, intramuscular injection, subcutaneous injection, intradermal injection, transdermal injection, intravenous injection, arterial injection, intraperitoneal injection, intraperitoneal injection, microneedle injection, mucosal administration, oral administration, oral and nasal cavity spray, inhalation, skin application, in vivo implantation and in vitro device administration.

[0071] In the above method, the administration site includes the abdominal cavity, the whole body skin, the subcutaneous tissue, the muscle, the nape of the neck, the waist and back, and the abdomen.

[0072] Further, the amount of administration can be a therapeutically effective amount. The therapeutically effective amount can refer to the amount of the drug (i) to treat or prevent a particular disease, condition or disorder; (ii) to alleviate, ameliorate or eliminate one or more symptoms of a particular disease, condition or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder described herein. The therapeutically effective amount can be determined by testing in known in vitro or in vivo (e.g. animal model) systems.

[0073] In the above method, the stimulation includes chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, electrical signal stimulation, ultrasound stimulation and infrared stimulation.

[0074] The temperature stimulation can include hot compress, heat therapy, etc. The temperature stimulation can be a heat stimulation greater than or equal to 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0075] The present application also provides a method for inhibiting the expression of proinflammatory cytokines, which comprises stimulating the TRPV1+ and / or TRPA1+ sensory nerves of a subject or patient.

[0076] Further, the pro-inflammatory cytokine is selected from the group consisting of TNFa, IL6, IL1a, IL1P, IL1f9, IL1rl1, IL1rn, IL2, IL12b, IL13, IL15, IL16, IL20rb, IL27, TNFSF15, TNFSF18, TNFRSF12a, TNFRSF19, CD40, CSF2, CSF3, LIF, TIMP1, TSLP, FAS, OSMR, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL12, CCL17, CCL19, CCL20, CCL22, CCL27, CCR6, CXCL1, CXCL5, CXCL10, CXCL11, CX3CL1, XCL1, IFNa1, IFNa2, IFNa4, IFNa5, IFNa9, IFNab, IFNb1, IFNg, IFIH1, IFIT1, IFIT1bl1, IFIT2, IFIT3, IFIT3b, IFI27l2b, IFI47, IFI204, IFI205, IFI207, IFI211, IRF4, and IRF6.

[0077] The present application also provides a method of promoting anti-inflammatory cytokine expression, the method comprising stimulating TRPV1+ and / or TRPA1+ sensory nerves of a subject or patient.

[0078] Further, the anti-inflammatory cytokine is IL10.

[0079] The stimulation of TRPV1+ and / or TRPA1+ sensory nerves of a subject or patient described herein can be activating TRPV1 and / or TRPA1 ion channels or activating TRPV1+ and / or TRPA1+ sensory neurons by chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, electrical signal stimulation, ultrasound stimulation, or infrared stimulation.

[0080] The "TRPV1+ sensory nerve" described herein can refer to a sensory nerve or sensory neuron expressing TRPV1, i.e. a TRPV1-positive sensory nerve fiber or a TRPV1-positive sensory neuron. The TRPV1+ sensory nerve includes TRPV1+ peripheral somatic sensory nerves, TRPV1+ internal tissue somatic sensory nerves, and TRPV1+ vagal sensory nerves throughout the body.

[0081] The "TRPA1+ sensory nerve" described herein can refer to a sensory nerve or sensory neuron expressing TRPA1, i.e. a TRPA1-positive sensory nerve fiber or a TRPA1-positive sensory neuron. The TRPA1+ sensory nerve includes TRPA1+ peripheral somatic sensory nerves, TRPA1+ internal tissue somatic sensory nerves, and TRPA1+ vagal sensory nerves throughout the body.

[0082] As used herein, "treatment" includes preventative and therapeutic treatment. "Preventative treatment" refers to preventing, inhibiting or reducing the occurrence of a disorder before it manifests. "Therapeutic treatment" refers to treating a subject already suffering from a relevant disease.

[0083] Stimulating TRPV1+ and / or TRPA1+ sensory nerves is effective in treating inflammatory diseases and modulating visceral functions in body sites including but not limited to the following: abdominal cavity, whole body skin, subcutaneous tissue and muscle, especially the nape of the neck, the waist and back, and the abdomen, etc. Suitable modes of administration include: TRPV1+ and / or TRPA1+ nerve agonists by intradermal, transdermal, subcutaneous, intramuscular, intraperitoneal injection and oral administration, skin application of cream or gel, spray, in vivo implant or ex vivo carrying device, and electrical signal stimulation, hot compress, electrical stimulation, ultrasonic stimulation, infrared stimulation, etc.

[0084] The expression "inflammatory disease" is used herein in the broadest sense to include all diseases and pathological conditions associated with systemic or local inflammatory responses, including both acute and chronic inflammatory diseases.

[0085] Non-limiting examples of conditions treatable using the present application include autonomic (neurogenic) disorders, adrenal insufficiency, cortisol dysregulation, catecholamine dysregulation, sepsis, septicemia, septic shock, endotoxic shock, cytokine-induced toxicity, acute severe inflammation, chronic refractory inflammation, organ ischemia-reperfusion injury, organ necrosis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, immune responses associated with cytokine and T-lymphocyte-mediated acute and delayed hypersensitivity, allergic diseases, reperfusion injury of myocardium or other tissues, cardiovascular ischemia, ischemic reperfusion disorders, meningitis, encephalitis, Ramsay-Hunt encephalitis, limbic and / or brainstem encephalitis, cerebral infarction, cerebral embolism, cerebral ischemia, acute purulent meningitis or other central nervous system inflammatory diseases, neuritis, neuralgia, hyperalgesia, polyradiculitis, spinal cord injury, paralysis, rheumatoid spondylitis, central nervous system inflammatory diseases, allergic neuritis, systemic lupus erythematosus, arthritis, acute arthritis, rheumatoid arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, spondyloarthropathy, and juvenile onset rheumatoid arthritis, osteoarthritis, chronic progressive arthritis, deforming arthritis, serum-negative spondyloarthropathy, chronic primary polyarthritis, reactive arthritis, and ankylosing spondylitis, rheumatic diseases, sclerosis, systemic sclerosis, multiple sclerosis, optic multiple sclerosis of the spinal cord, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, progressive systemic sclerosis, atherosclerosis, arteriosclerosis, diffuse sclerosis, and ataxic sclerosis, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, diseases associated with eosinophils, such as hypereosinophilia, pulmonary infiltration hypereosinophilia, hypereosinophilia-myalgia syndrome, Loeffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary hypereosinophilia, granulocyte transfusion associated syndrome, stiff person or stiff person syndrome, encephalomyelitis, allergic encephalomyelitis, experimental allergic encephalomyelitis, transverse myelitis, myasthenia gravis, thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome, and sensory neuropathy, multifocal motor neuropathy, opticospinal encephalomyelitis, polyneuropathy, chronic neuropathy, IgM polyneuropathy, IgM-mediated neuropathy, peripheral neuropathy, ion channelopathies such as epilepsy, migraine, periodic paralysis, and central nervous system channelopathies, autism, presenile dementia, demyelinating diseases, Alzheimer's disease, diseases involving T cell infiltration, leukocyte adhesion deficiency, diseases involving leukocyte diapedesis, allograft rejection, graft-versus-host disease, respiratory distress syndrome, influenza, influenza virus infection, coronavirus infection,Respiratory syncytial virus infection, Adenovirus infection, Parainfluenza virus infection, Hepatitis B virus infection, Hepatitis C virus infection, Metapneumovirus infection, Cytomegalovirus infection, Smallpox infection, Herpes virus infection, Disseminated bacteremia, Dengue fever, Candidiasis, Human immunodeficiency virus (HIV) infection, Echovirus infection, Parvovirus infection, Rubella virus infection, Post-vaccination syndrome, Congenital rubella infection, Epstein-Barr virus infection, Mumps, Post-streptococcal nephritis, Malaria, Filariasis, Amoebiasis, Leprosy, Leishmaniasis, Trypanosomiasis, Schistosomiasis, Ascariasis, Aspergillosis, Sampson's syndrome, Kaplan's syndrome, Parasitic disease, such as leishmaniasis, Burns, Blistering disease, Asthma, Pharyngitis, Thyroiditis, Autoimmune thyroiditis, Chronic thyroiditis, Subacute thyroiditis, Hashimoto's disease, Primary hypothyroidism, Hypoparathyroidism, Autoimmune thyroid disease, Idiopathic hypothyroidism, Hyperthyroidism, Allergic and atopic rhinitis, Bronchitis, Bronchiolitis, Pneumonia, Lymphoid interstitial pneumonitis, Obliterative bronchiolitis (non-transplant), Pulmonary emphysema, Pulmonary dust disease, Pulmonary fibrosis, Alveolitis, Bird fancier's lung, Chronic hypersensitivity pneumonitis, Farmer's lung, Alveolitis, Bronchitis, Chronic obstructive airway disease, Silicosis, Pulmonary cirrhosis, Interstitial lung disease, Transfusion reaction disease, Myointimal fibrosis, Diffuse interstitial pulmonary fibrosis, Interstitial pulmonary fibrosis, Idiopathic pulmonary fibrosis, Pleuritis, Autoimmune myocarditis, Pericarditis, Myocarditis, Dilated cardiomyopathy, Endocarditis, Myocardial ischemia, Cardiac arrhythmia, Post-infarction syndrome, Post-cardiotomy syndrome, Cardiomyopathy, Valvulitis, Thrombotic obliteration of the blood vessels, Chorioretinitis, Arteriosclerotic disease, Idiopathic nephrotic syndrome, Minimal change nephropathy, Crohn's disease, Diabetic aortopathy, Nephropyelitis, Arteriolitis, Peptic ulcer, Pancreatitis, Acquired splenic atrophy, Nodular periarteritis, Angiitis, Arteritis, Thrombotic phlebitis, Vasculitis disease, Giant cell (Takayasu's) arteritis, Midpiece angiitis, Allergic granulomatous angiitis, Benign lymphocytic angiitis, Alport's syndrome, Polyarteritis nodosa, Microscopic polyarteritis, Central nervous system angiitis, Necrotizing, Cutaneous, Hypersensitivity angiitis, Systemic necrotizing angiitis, ANCA-associated vasculitis, De Quervain's thyroiditis, Thyrotoxicosis, Allergic granulomatous angiitis or syndrome, Temporal arteritis, Abdominal disease, Appendicitis, Gastric atrophy, Autoimmune atrophic gastritis, Peptic ulcer, Gastric ulcer, Duodenal ulcer, Peritonitis, Pancreatitis, Ulcerative colitis, Pseudomembranous colitis, Acute colitis, Ischemic colitis, Cholangitis, Cholecystitis, Nephrotic syndrome, Inflammation of the pancreatic islets, Hepatitis, Crohn's disease, Enteritis, Inflammatory bowel disease, Allergic enteritis, Crohn's disease, Colitis, Ulcerative colitis, Collagenous colitis,chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, autoimmune liver disease, non-alcoholic fatty liver disease, Guillain-Barre syndrome, primary biliary cirrhosis, autoimmune orchitis and oophoritis, epididymitis, vaginitis, prostatitis, urethritis, sinusitis, dermatitis, dermatomyositis, primary sclerosing cholangitis, episcleritis, total or partial uveitis, iritis, choroiditis, uveitis, anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, superantigen uveitis, posterior uveitis, autoimmune uveitis, Goodpasture's syndrome, glomerulonephritis, idiopathic membranous glomerulonephritis or idiopathic membranous nephropathy, membranous or membranoproliferative glomerulonephritis, rapidly progressive glomerulonephritis, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, immune complex nephritis, antibody-mediated nephritis, adrenalitis, diabetic nephropathy, glomerulosclerosis, vasculitic nephritis, nephrosis, granulomatous orchitis, leukocyte adhesion deficiency, juvenile onset (Type I) diabetes mellitus, childhood insulin-dependent diabetes mellitus, adult onset diabetes mellitus (Type II diabetes mellitus), autoimmune diabetes mellitus, idiopathic diabetes insipidus, tuberculosis, sarcoidosis, granulomatosis, lymphomatoid granulomatosis, Wegener's granulomatosis, granulocytopenia, polymyalgia rheumatica, Kawasaki disease, aplastic anemia, autoimmune aplastic anemia, Coombs-positive anemia, congenital pure red cell anemia, hemolytic anemia or immune hemolytic anemia, including autoimmune hemolytic anemia, pernicious anemia, Addison's disease, pure red cell anemia or aplasia, Factor VIII deficiency, hemophilia, autoimmune blood disorders, hypotension, vascular dysfunction, vasodilation, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, Behcet's disease or disease, Castleman's syndrome, Raynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigus, pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigoid, bullous pemphigoid, autoimmune polyendocrine disease, Reiter's disease or syndrome, thrombocytopenia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, autoimmune hemolysis, Berger's disease, cryoglobulinemia, polyglandular syndromes, paraneoplastic syndromes, including paraneoplastic syndromes of the nervous system, such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, Sjogren's syndrome, linear IgA dermatosis, celiac disease, celiac sprue, recalcitrant aphthous, idiopathic aphthous, cryoglobulinemia, amyotrophic lateral sclerosis, coronary artery disease, ataxia-telangiectasia, autoimmune ear disease such as autoimmune inner ear disease, autoimmune hearing loss, opsoclonus myoclonus syndrome, polychondritis, pulmonary alveolar proteinosis, amyloidosis, episcleritis, non-cancerous lymphocytosis, primary lymphocytosis, including monoclonal B-cell lymphocytosis,Selective benign monoclonal gammopathy or monoclonal gammopathy of unknown significance, paraneoplastic syndrome, muscle disease, inflammatory myopathy, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, CREST syndrome, autoimmune infertility in men and women, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent miscarriage, erythema multiforme, Cushing's syndrome, cystic fibrosis, focal segmental glomerulosclerosis, sudden hearing loss, blindness, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, endocrine opthalmopathy, uveo-retinitis, ocular and orbital inflammatory disease, diabetic retinopathy, chorioretinal inflammation, scleritis, episcleritis, endophthalmitis, autoimmune retinal disease, erythema elevatum diutinum, eosinophilic fasciitis, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, Shulman's syndrome, Felty's syndrome, ciliary body inflammation, endocrine ophthalmopathy, hypersensitivity endophthalmitis, sympathetic ophthalmia, Henoch-Schonlein purpura, Evan's syndrome, autoimmune gonadal failure, Sydenham chorea, peripheral myelopathy, giant cell polymyalgia, aphthosis, aphthous stomatitis, spermatogenesis deficiency, infertility due to anti-sperm antibodies, Dupuytren's contracture, leprosy erythema nodosum, idiopathic facial paralysis, chronic fatigue syndrome, rheumatic fever, Harman-Rich disease, sensorineural hearing loss, paroxysmal hemoglobinuria, hypogonadism, leukopenia, infectious mononucleosis, primary idiopathic myxedema, skin disease with acute inflammatory component, pyoderma gangrenosum, non-malignant thymoma, vitiligo, SCID and Barmah Forest virus related diseases, acquired immune deficiency syndrome (AIDS), toxic shock syndrome, food poisoning, pyoderma gangrenosum, erythema nodosum, anti-glomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathy, primary myxedema, sympathetic ophthalmia, mixed connective tissue disease, polyendocrine failure, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism, acquired epidermolysis bullosa, hemochromatosis, nephrotic syndrome, primary sclerosing cholangitis, ethmoid, frontal, maxillary or sphenoid sinusitis, bronchopulmonary aspergillosis, aspergilloma or granuloma containing eosinophils, endometriosis, polyendocrine autoimmune disease, sclerosing cholangitis, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, autoimmune diseases associated with collagen diseases and allergic hypersensitivity disorders.

[0086] The present application constructs a systemic inflammation mouse model by injecting LPS (lipopolysaccharide, a component of cell wall of gram-negative bacteria), finds that stimulating TRPV1+ sensory nerves in different parts of the mouse body can reduce the expression of various cytokines (such as TNF-α, IL-6 and IL1β) to different degrees, and among them, subcutaneous injection of capsaicin on the back of the neck is the most effective anti-inflammatory method (Figure 1). The anti-inflammatory effect of stimulating TRPV1+ sensory nerves depends on the dose of capsaicin. Transdermal stimulation of TRPV1+ skin sensory nerves using capsaicin cream can effectively inhibit cytokine expression, which shows that direct stimulation of TRPV1+ sensory nerves in the skin can effectively resist inflammation (Figure 2). By detecting the expression of 31 cytokines through Luminex protein multi-factor analysis, it is found that stimulating TRPV1+ sensory nerves can inhibit the expression of many pro-inflammatory cytokines and chemokines, and increase the expression of anti-inflammatory cytokines (IL10). In trpv1 knockout mice, capsaicin pretreatment cannot produce anti-inflammatory effect, so capsaicin is anti-inflammatory by specifically stimulating TRPV1+ sensory nerves (Figure 3). Stimulation of TRPV1+ skin sensory nerves by heat of about 50°C significantly inhibits the expression of many pro-inflammatory cytokines, chemokines and interferons, and increases the expression of anti-inflammatory cytokine IL10. Cold stimulation of about 0°C only inhibits the expression of TNFα and CCL3. Therefore, heat treatment similar to moxibustion stimulates TRPV1+ skin sensory nerves to effectively resist inflammation (Figure 4). In the case of lethal systemic inflammation, stimulating TRPV1+ sensory nerves can significantly improve the survival rate of inflammatory mice and improve their physiological state (Figure 5). Through pre-resection surgery of the spleen and reserpine drug pretreatment experiments, the present application reveals that stimulating TRPV1+ sensory nerves can regulate the function of the spleen by activating the sympathetic nerves to resist inflammation (Figure 6). By using transcriptome sequencing to detect the expression of spleen genes, it is found that stimulating TRPV1+ sensory nerves significantly affects the expression of spleen genes, especially the expression of pro-inflammatory genes, and functional analysis shows that the differentially expressed genes are mainly enriched in inflammation-related signaling pathways (Figure 7). By dynamically monitoring the changes in serum catecholamine concentration in mice and subdiaphragmatic vagotomy surgery and hexamethonium bromide pretreatment, it is found that stimulating TRPV1+ somatic sensation can activate the vagus-adrenal axis to increase the production of catecholamines. In trpv1 knockout mice, injection of capsaicin cannot promote the expression of three catecholamines (Figure 8). In addition, stimulating TRPV1+ sensory nerves can activate the hypothalamus-pituitary-adrenal reflex arc to promote the secretion of cortisol hormones. In trpv1 knockout mice, the expression of corticosterone in mice injected with capsaicin does not rise (Figure 9). Stimulating TRPA1+ sensory nerves in different parts of the mouse body can reduce the expression of various cytokines (such as TNF-α and IL-6) to different degrees (Figure 10).The AITC pre-treatment cannot produce anti-inflammatory effect in the TRPA1 knockout mice, thus the AITC is anti-inflammatory by stimulating TRPA1+ sensory nerves specifically (Figure 11). In the case of lethal systemic inflammation, stimulating TRPA1+ sensory nerves can improve the survival rate and physiological state of the inflammatory mice (Figure 12). By dynamically monitoring the change of catecholamine serum concentration in mice, it is found that stimulating TRPA1+ sensory nerves can increase the production of catecholamines (Figure 13). Stimulating TRPA1+ sensory nerves can activate the hypothalamic-pituitary-adrenal reflex arc to promote the secretion of cortisol hormones (Figure 14).

[0087] In summary, stimulating TRPV1+ and / or TRPA1+ peripheral sensory nerves can regulate the somatosensory nerve-autonomic nerve-immune system reflex arc to synergistically inhibit the production of pro-inflammatory cytokines, while activating the vagus nerve-adrenal axis to increase the production of catecholamines, and activating the hypothalamic-pituitary-adrenal reflex arc to promote the secretion of cortisol hormones. Therefore, sensory nerves not only can perceive changes in the external environment and the state of internal tissues, but also can regulate visceral function and physiological state of the body through sensory nerve-autonomic nerve reflex arc, sensory nerve-hormone reflex arc, and nerve-immune interaction mechanism. The research of the present application suggests that temperature stimulation, chemical stimulation, mechanical stimulation, tissue damage or pathogen infection of the body surface activate the peripheral sensory nervous system to instantaneously or continuously interfere with visceral function and break the homeostasis of the body, which can lead to physical discomfort and disease in severe cases. Accordingly, appropriate preventive measures can be taken to prevent physiological disorders of the body.

[0088] The present application is based on the following findings of the inventor: an important physiological mechanism is disclosed, stimulating sensory nerves can regulate visceral function and physiological state of the body, which can be used to regulate the homeostasis of the body and prevent and treat diseases. The present application utilizes this important physiological mechanism, and discloses a method and drug for treating visceral dysfunction, regulating hormone and catecholamine secretion, effectively reducing the production of pro-inflammatory cytokines to inhibit inflammation, regulating the physiological state of the body, and preventing and treating inflammatory diseases caused by pro-inflammatory cytokines or pro-inflammatory cytokine cascade, by activating TRPV1+ and / or TRPA1+ sensory nerves to regulate the autonomic nervous system and organ function.

[0089] Therefore, the present application provides a new use of a substance stimulating TRPV1+ and / or TRPA1+ sensory nerves (such as a substance activating TRPV1 and / or TRPA1 ion channels by chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, ultrasonic stimulation or infrared stimulation) in preventing, treating or adjuvant treating inflammatory diseases, autonomic nervous functional disorder diseases and adrenal insufficiency diseases. The present application has not been conceived in the prior art to use TRPV1 and / or TRPA1 ion channel agonists as a target to prevent or treat inflammatory diseases, autonomic nervous functional disorder diseases and adrenal insufficiency diseases. Unexpectedly, the present inventors have proved by experiments that TRPV1 ion channel agonists (such as capsaicin or a hot stimulating substance) can significantly and effectively inhibit the expression of a plurality of pro-inflammatory cytokines and significantly increase the expression of anti-inflammatory cytokine IL10, not only significantly improving the physiological state of inflammatory mice, but also significantly improving the survival rate of inflammatory mice. Meanwhile, TRPV1 and / or TRPA1 ion channel agonists can also regulate the function of the spleen, significantly inhibit the expression of pro-inflammatory genes in the spleen, increase the production of catecholamines (dopamine, norepinephrine and epinephrine) and promote the secretion of cortisol hormones. The present application can also be used for screening candidate drugs for treating and / or preventing inflammatory diseases, autonomic nervous functional disorder diseases and adrenal insufficiency diseases caused by pro-inflammatory cytokines or pro-inflammatory cytokine cascades, developing new disease treatment methods and therapeutic drugs. The present application has wide clinical application value for preventing and treating related diseases. BRIEF DESCRIPTION OF DRAWINGS

[0090] Fig. 1 is a schematic diagram of the anti-inflammatory effect of stimulating TRPV1+ sensory nerves in different parts of the mouse body.

[0091] Fig. 2 is a schematic diagram of the anti-inflammatory effect of stimulating TRPV1+ sensory nerves depending on the dose of capsaicin, and stimulating TRPV1+ cutaneous sensory nerves can effectively inhibit the expression of cytokines.

[0092] Fig. 3 is a schematic diagram of stimulating TRPV1+ sensory nerves to inhibit the expression of a plurality of cytokines and chemokines, and this anti-inflammatory response depends on TRPV1+ sensory nerves.

[0093] Fig. 4 is a schematic diagram of effectively inhibiting the expression of a plurality of pro-inflammatory cytokines and chemokines by stimulating the TRPV1 ion channel.

[0094] Fig. 5 is a schematic diagram of stimulating TRPV1+ sensory nerves to improve the survival rate and physiological state of inflammatory mice.

[0095] Fig. 6 is a schematic diagram of stimulating TRPV1+ sensory nerves to regulate the function of the spleen by activating sympathetic nerves to further resist inflammation.

[0096] Figure 7 is a schematic diagram showing that stimulation of TRPV1+ sensory nerves significantly suppresses pro-inflammatory gene expression in the spleen as shown by transcriptome sequencing of the spleen.

[0097] Figure 8 is a schematic diagram showing that stimulation of TRPV1+ sensory nerves can activate the vagus-adrenal axis to increase catecholamine production.

[0098] Figure 9 is a schematic diagram showing that stimulation of TRPV1+ sensory nerves can activate the hypothalamic-pituitary-adrenal reflex arc to promote corticosteroid secretion.

[0099] Figure 10 is a schematic diagram showing that stimulation of TRPA1+ sensory nerves at different parts of the mouse body has different anti-inflammatory effects.

[0100] Figure 11 is a schematic diagram showing that AITC pre-treatment cannot produce anti-inflammatory effects in trpa1 knockout mice.

[0101] Figure 12 is a schematic diagram showing that stimulation of TRPA1+ sensory nerves can improve survival rate and physiological status of inflamed mice.

[0102] Figure 13 is a schematic diagram showing that stimulation of TRPA1+ sensory nerves can induce catecholamine production.

[0103] Figure 14 is a schematic diagram showing that stimulation of TRPA1+ sensory nerves can activate the hypothalamic-pituitary-adrenal reflex arc to promote corticosteroid secretion. Embodiments of the present application

[0104] The present application will be further described in conjunction with the specific embodiments, and the examples given are only to illustrate the present application, and are not intended to limit the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not in any way constitute a limitation on the present application.

[0105] In the following examples, the experimental methods are conventional methods, and are performed according to the techniques or conditions described in the literature in the art or according to the product instructions, unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained commercially, unless otherwise specified.

[0106] The biological materials and reagents involved in the following examples are as follows:

[0107] 1. Animals

[0108] C57BL / 6J mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Trpv1- / - (KO CMP-193034-Trpv1) mice (hereinafter referred to as trpv1 knockout mice) were purchased from SJAIO Biological Technology Co., Ltd. Trpa1- / - (KO CMP-277328-Trpa1) mice (hereinafter referred to as trpa1 knockout mice) were purchased from SJAIO Biological Technology Co., Ltd. All animals were raised in a standard barrier environment, and mice could freely ingest standard mouse feed and drinking water. All animal experiments were performed according to the experimental protocols approved by the Animal Ethics Committee of Beijing Institute of Biotechnology.

[0109] 2. Biological reagents

[0110] Allyl isothiocyanate (AITC) (36682), LPS (L2630), Reserpine (83580), and Hexamethonium bromide (H0879) were purchased from Sigma-Aldrich. Capsaicin (A3278) was purchased from Apexbio. Capsaicin cream (Shuxiao) was produced by Puwai Pharmaceutical. Parameter Corticosterone Assay kit (KGE009), IL-1β (MLB00C), and IL-6 (M6000B) ELISA kits were purchased from R&D systems. TNFα (EK282 / 4-96) ELISA kit was purchased from Union Biomed. Bio-Plex Pro Mouse Chemokine Panel 31-Plex (12009159) was purchased from Bio-Rad. 3-CAT ELISA kit (BA E-5600R) was purchased from LDN.

[0111] The solvents involved in the following examples are all physiological saline.

[0112] Example 1, Comparison of anti-inflammatory effects of stimulating TRPV1+ sensory nerves in different parts of the mouse body

[0113] 6-8 week old male C57BL / 6J mice were injected intraperitoneally with 8 mg / kg LPS (endotoxin) to establish a systemic inflammation mouse model. Thirty minutes before LPS injection, mice were injected intraperitoneally, subcutaneously in the abdomen, subcutaneously in the nape of the neck or subcutaneously in the lumbar back with 4 mg / kg capsaicin (a TRPV1 ion channel agonist) or 0.25 mg / kg capsaicin via the tail vein to establish CAP-LPS experimental groups, and a solvent (saline) + LPS control group. Blood samples were collected at 1.5 hours and 6 hours after LPS injection, and the blood samples were left at room temperature for 2 hours before centrifugation at 2000 g for 20 minutes to collect serum, which was stored at -80°C before use. The expression levels of cytokines TNFα, IL6 and IL1β in serum were detected by TNFα, IL6 or IL1β ELISA kits according to the manufacturer's instructions.

[0114] The results are shown in Figure 1. Capsaicin treatment at different sites can effectively inhibit the expression of TNFα. Subcutaneous injection of capsaicin in the nape of the neck can inhibit the expression of IL6 at 1.5 hours and 6 hours, while subcutaneous injection of capsaicin in the abdomen can only suppress the production of IL6 at 1.5 hours, and injection of capsaicin at other sites cannot affect the expression of IL6. The expression level of IL1β is very low and cannot be detected at 1.5 hours after LPS injection, and the expression of IL1β is significantly increased at 6 hours, and only subcutaneous injection of capsaicin in the nape of the neck or lumbar back can effectively inhibit the production of IL1β. Therefore, stimulating TRPV1+ sensory nerves at different parts of the body can reduce the expression of cytokines to varying degrees, and subcutaneous injection of capsaicin in the nape of the neck is the most effective anti-inflammatory method.

[0115] Example 2, Effect of capsaicin dose on anti-inflammatory effect of stimulating TRPV1+ sensory nerves

[0116] Without LPS, 4 mg / kg capsaicin was injected subcutaneously in the nape of the neck at 1.5 hours and 6 hours. Thirty minutes before LPS injection, 1 mg / kg capsaicin, 4 mg / kg capsaicin or capsaicin cream was applied to the skin of the nape of the neck of the shaved mice. Blood samples were collected at 1.5 hours and 6 hours after LPS injection, and the blood samples were left at room temperature for 2 hours before centrifugation at 2000 g for 20 minutes to collect serum, which was stored at -80°C before use. The expression levels of cytokines TNFα and IL6 in serum were detected by TNFα or IL6 ELISA kits according to the manufacturer's instructions.

[0117] Results are shown in Figure 2. Without LPS injection, 4 mg / kg capsaicin only produced basal levels of cytokine expression. Subcutaneous injection of 1 mg / kg capsaicin in the nape of the neck resulted in a 55.3% decrease in TNFa expression, while 4 mg / kg capsaicin resulted in a 70.1% decrease in TNFa expression. IL6 expression was decreased by 1 mg / kg capsaicin. 4 mg / kg capsaicin resulted in a 92% decrease in IL6 expression at 1.5 hours and a 72.4% decrease at 6 hours. Transdermal stimulation of TRPV1+ cutaneous sensory nerves by capsaicin cream effectively suppressed cytokine expression. This demonstrates that direct stimulation of TRPV1+ sensory nerves in the skin is effective in anti-inflammation. The above results show that the anti-inflammatory effect of stimulating TRPV1+ sensory nerves is dependent on the dose of capsaicin, and when the dose of capsaicin is greater than or equal to 1 mg / kg, the expression levels of cytokines TNFa and IL6 can be reduced, and when the dose of capsaicin is greater than or equal to 4 mg / kg, the effect of inhibiting cytokines is better, and transdermal stimulation of TRPV1+ cutaneous sensory nerves can effectively suppress cytokine expression.

[0118] Example 3, Stimulation of TRPV1+ sensory nerves in the nape suppresses the expression of many cytokines and chemokines

[0119] Without LPS, blood was taken 1.5 hours after subcutaneous injection of solvent (saline) or 4 mg / kg capsaicin in the nape. 30 minutes before LPS injection, 4 mg / kg capsaicin was subcutaneously injected in the nape of the mouse to establish the CAP-LPS experimental group, and a solvent+LPS control group was set. In trpv1 knockout mice, 4 mg / kg capsaicin was subcutaneously injected in the nape 30 minutes before intraperitoneal injection of LPS as the CAP-LPS experimental group, and a solvent+LPS control group was set. Blood was taken 1.5 hours after LPS injection, and the blood sample was placed at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. According to the manufacturer's instructions, the expression of 31 cytokines was detected by Bio-Plex Pro Mouse Chemokine Panel 31-Plex kit through Luminex protein multi-factor analysis.

[0120] Results are shown in Figure 3. Without LPS injection, subcutaneous injection of capsaicin at the back of the neck of mice only suppressed the basal expression of IL6. LPS injection led to the up-regulation of 13 pro-inflammatory cytokines and chemokines, while pre-injection of capsaicin at the back of the neck significantly suppressed the expression of these 13 cytokines and chemokines, and elevated the expression of anti-inflammatory cytokine IL10. In trpv1 knock-out mice, capsaicin pre-treatment failed to produce anti-inflammatory effect, thus capsaicin is anti-inflammatory through specifically stimulating TRPV1+ sensory nerves. The above results indicate that stimulating TRPV1+ sensory nerves at the back of the neck can suppress the expression of a number of cytokines and chemokines, and that this anti-inflammatory response is dependent on TRPV1+ sensory nerves.

[0121] Example 4, Heat stimulation of TRPV1 ion channel at the back of the neck

[0122] After shaving the back of the neck of C57BL / 6J mice, the skin at the back of the neck was contacted with heat stimulation (warm pack at about 50°C, similar to moxa-stimulation) or cold stimulation (ice pack at about 0°C) for 15 minutes, and then LPS was injected intraperitoneally after another 15 minutes. Un-treated LPS control group, 50°C-LPS experimental group and 0°C-LPS experimental group were set up respectively. Blood samples were collected 1.5 hours after LPS injection, and the blood samples were left at room temperature for 2 hours, and then centrifuged at 2000g for 20 minutes to collect serum, which was stored at -80°C before use. The expression of 31 cytokines was detected by Bio-Plex Pro Mouse Chemokine Panel 31-Plex kit through Luminex protein multi-factor analysis according to the manufacturer's instructions.

[0123] Results are shown in Figure 4. TRPV1 ion channel can be activated by temperature >43°C. Heat stimulation at about 50°C significantly suppressed the expression of a number of pro-inflammatory cytokines, chemokines and interferons, and elevated the expression of anti-inflammatory cytokine IL10. Cold stimulation at about 0°C only suppressed the expression of TNFa and CCL3. Thus, heat stimulation of TRPV1+ skin sensory nerves through moxa-stimulation can effectively suppress the expression of a number of pro-inflammatory cytokines and chemokines.

[0124] Example 5, Stimulating TRPV1+ sensory nerves at the back of the neck can improve survival rate and physiological status of inflammatory mice

[0125] 9-11 week old male mice were injected intraperitoneally with 8 mg / kg LPS to establish a systemic inflammation mouse model. 30 minutes before LPS injection, 4 mg / kg capsaicin was injected subcutaneously on the back of neck of C57BL / 6J mice to establish the CAP-LPS experimental group (n=25), and a solvent+LPS control group (n=19) was set up. 30 minutes before LPS injection, 4 mg / kg capsaicin was injected subcutaneously on the back of neck of trpv1 knockout mice to establish the CAP-LPS experimental group (n=17), and a solvent+LPS control group (n=13) was set up. The physiological state of the mice was detected every 12 hours before and after LPS injection. According to the body temperature, body weight, fur color and active state, etc., the inflammation mice were comprehensively judged whether to reach the death standard, and euthanized in time. The mice reached any one of the following standards to be judged as dead: 1 body temperature (body temperature <32℃ was judged as dead); 2 body weight (20% decrease in body weight was judged as dead); 3 total score of clinical symptoms (total score reached 2 points was judged as dead), including 4 kinds of clinical symptoms each scored in three grades (0, 1, 2), a eye secretion (excessive secretion causing eye closure 0 points, excessive secretion 1 point, no secretion 2 points), b diarrhea (severe 0 points, loose stool 1 point, normal 2 points), c fur color (dull, dull and lack of grooming hair 0 points, dull and lack of grooming hair 1 point, shiny hair 2 points), d active state (drowsy and mild stimulation only to lift the head 0 points, not active and mild stimulation only to move less than two steps 1 point, normal 2 points), and the total score of four items was 8 points for the normal physiological state of the mice. The mice were comprehensively judged whether to reach the premature termination of the experiment standard, and euthanized in time, and the death time of the mice was recorded. The 14th day after injection was taken as the survival experiment termination point, and all experimental mice were euthanized.

[0126] The results are shown in Figure 5. The survival rate of the inflammation mice in the control group was only 7%, while the survival rate of the inflammation mice injected with capsaicin in the experimental group was as high as 60%. We continuously observed the experimental mice for 2 weeks, and all the surviving mice recovered in weight after 1 week of the experiment, and no further deaths occurred, indicating that stimulating TRPV1+ sensory nerves can continuously protect mice against inflammation attacks. In addition, the body temperature change of the inflammation mice injected with capsaicin in the experimental group was significantly better than that of the control mice. In trpv1 knockout mice, the survival rate and body temperature change of the trpv1 knockout inflammation mice injected with capsaicin in the experimental group were not different from those of the control mice.

[0127] Example 6, stimulating TRPV1+ sensory nerves regulates spleen function through activating sympathetic nerves to resist inflammation

[0128] Splenectomy: Mice were operated under isoflurane anesthesia. After laparotomy, the stomach was gently moved to expose the spleen. The blood vessels connecting the spleen were ligated with nylon surgical suture, and then the spleen was removed. The abdominal cavity was sutured and analgesics were injected subcutaneously. Three days after the operation, the relevant experiments were performed. Thirty minutes before LPS injection, 4 mg / kg capsaicin was injected subcutaneously on the nape of the neck of the splenectomized mice to establish the CAP-LPS experimental group, and a solvent+LPS control group was set up.

[0129] Reserpine treatment experiment (Reserpine is a peripheral sympathetic nerve inhibitor used to block peripheral sympathetic nerves; Martinez-Olivares, R., Villanueva, I., Racotta, R. & M. Depletion and recovery of catecholamines in several organs of rats treated with reserpine. Autonomic Neuroscience 128, 64-69 (2006)), 10 mg / kg Reserpine was injected intraperitoneally into mice, and 24 hours after injection, subsequent experiments were performed. Thirty minutes before LPS injection, 4 mg / kg capsaicin was injected subcutaneously on the nape of the neck of the Reserpine-treated mice to establish the CAP-LPS experimental group, and a solvent+LPS control group was set up.

[0130] Blood was collected 1.5 hours after LPS injection, and the blood sample was left at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored at -80°C before use. According to the manufacturer's instructions, the expression levels of TNFα and IL6 in serum were detected by TNFα or IL6 ELISA kit, respectively.

[0131] The results are shown in Figure 6. Capsaicin treatment after splenectomy cannot induce an anti-inflammatory response. Reserpine inhibits the release of norepinephrine in the peripheral sympathetic nerve endings and suppresses the transmission of sympathetic nerve signals. After blocking the peripheral sympathetic nerves with Reserpine, capsaicin treatment cannot produce an anti-inflammatory effect.

[0132] Example 7, Stimulation of TRPV1+ sensory nerves significantly inhibits the expression of spleen pro-inflammatory genes

[0133] Spleens were harvested 1 hour after subcutaneous injection of solvent or 4 mg / kg capsaicin in the nape of the neck without LPS. To establish the CAP-LPS group, 4 mg / kg capsaicin was injected subcutaneously in the nape of the neck 30 minutes before LPS injection, and a solvent+LPS control group was set up. Spleens were harvested 1 hour after LPS injection. Transcriptional sequencing and related data analysis services were provided by Beijing Bimake Biological Technology Co., Ltd.

[0134] The results are shown in Figure 7. Stimulation of TRPV1+ sensory nerves significantly affected the expression of spleen genes, particularly the expression of pro-inflammatory genes (including: Tnf, Il6, Ifng, etc.), both in the inflammatory state and in normal physiological conditions. Functional analysis showed that the differentially expressed genes were mainly enriched in inflammation-related signaling pathways.

[0135] Example 8, Stimulation of TRPV1+ somatosensory nerves can activate the vagus nerve-adrenal axis to increase catecholamine production

[0136] Wild-type and trpv1 knockout mice were injected subcutaneously in the nape of the neck with 4 mg / kg capsaicin to establish the experimental group, and a solvent control group was set up. Blood was taken at different time points.

[0137] Subdiaphragmatic vagotomy surgery: Mice were operated on under isoflurane anesthesia. After opening the abdomen, the stomach was gently moved aside to expose the esophagus, and the anterior and posterior subdiaphragmatic vagus nerves were identified and cut. The abdominal cavity was sutured, and analgesics were injected subcutaneously. Three days after surgery, the relevant experiments were performed. In mice with subdiaphragmatic vagotomy, physiological saline solvent or 4 mg / kg capsaicin was injected subcutaneously in the nape of the neck to establish a solvent control group and an experimental group. Blood was taken 40 minutes later.

[0138] Hexamethonium bromide (HEX) treatment: Mice were injected intraperitoneally with 10 mg / kg HEX. Thirty minutes after injection, physiological saline solvent or 4 mg / kg capsaicin was injected subcutaneously in the nape of the neck of the mice to establish a solvent control group and an experimental group. Blood was taken 40 minutes later.

[0139] The blood samples were placed at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect the serum, which was stored at -80°C before use. The 3-CAT ELISA kit was used to detect the concentration of catecholamines in the serum according to the manufacturer's instructions.

[0140] Results are shown in Figure 8. Injection of capsaicin increased the expression levels of dopamine, norepinephrine and epinephrine in the serum of wild type mice. In trpv1 knockout mice, injection of capsaicin did not promote the expression of the three catecholamines. HEX treatment can block the acetylcholine secreted by the vagus nerve terminal from binding to the nicotinic acetylcholine receptor, thereby blocking vagus nerve signaling (Ilcol, Y.O., Cansev, M., Yilmaz, M.S., Hamurtekin, E., Ulus, I.H. Peripheral administration of CDP-choline and its cholinergic metabolites increases serum insulin: muscarinic and nicotinic acetylcholine receptors are both involved in their actions. Neuroscience Letters. 431(1): 71-76 (2008)). In mice with subdiaphragmatic vagotomy or HEX pretreated mice, injection of capsaicin did not promote the expression of dopamine and norepinephrine. Therefore, stimulating TRPV1+ sensory nerves increases the production of catecholamines by activating the vagus nerve-adrenal axis.

[0141] Example 9, Stimulation of TRPV1+ sensory nerves can activate the hypothalamus-pituitary-adrenal reflex arc to promote the secretion of corticosteroids

[0142] After subcutaneous injection of solvent or 4 mg / kg capsaicin on the nape of wild type and trpv1 knockout mice, blood samples were taken at different time points, respectively. The blood samples were placed at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. According to the manufacturer's instructions, the concentration of corticosterone in the serum was detected using the Parameter Corticosterone Assay kit.

[0143] Results are shown in Figure 9. Fifteen minutes after injection of capsaicin, the concentration of corticosterone in the serum of wild type mice increased by 7 times, and then gradually decreased, and 3 hours later it had dropped to the background level. In trpv1 knockout mice, the expression of corticosterone in mice injected with capsaicin did not increase.

[0144] Example 10, Comparison of anti-inflammatory effects of stimulating TRPA1+ sensory nerves in different parts of the mouse body

[0145] 6-8 week old male C57BL / 6J mice were injected intraperitoneally with 8 mg / kg LPS (endotoxin) to establish a systemic inflammation mouse model. 30 minutes before LPS injection, 50 mg / kg AITC (TRPA1 ion channel agonist) was injected intraperitoneally, subcutaneously in the abdomen, subcutaneously in the nape of the neck or subcutaneously in the lumbar back of the mice, respectively, or 12.5 mg / kg AITC was injected via the tail vein to establish AITC-LPS experimental groups, and a solvent (normal saline) + LPS control group was set up. Blood samples were collected 1.5 hours after LPS injection, and the blood samples were left at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. The expression levels of cytokines TNFα and IL6 in serum were detected by TNFα or IL6 ELISA kits according to the manufacturer's instructions.

[0146] The results are shown in Figure 10. AITC treatment intraperitoneally and subcutaneously at various sites can effectively inhibit the expression of TNFα. AITC injection intraperitoneally, subcutaneously in the abdomen and subcutaneously in the nape of the neck can inhibit the expression of IL6, so stimulating TRPA1+ sensory nerves at intraperitoneal and subcutaneous sites can effectively inhibit the expression of cytokines.

[0147] Example 11, AITC pretreatment cannot produce anti-inflammatory effect in trpa1 knockout mice

[0148] In trpa1 knockout mice, 50 mg / kg AITC was injected intraperitoneally, and 30 minutes later, LPS was injected intraperitoneally as an AITC experimental group, and a solvent control group was set up. Blood samples were collected 1.5 hours after LPS injection, and the blood samples were left at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. The expression levels of cytokines TNFα and IL6 in serum were detected by TNFα or IL6 ELISA kits according to the manufacturer's instructions.

[0149] The results are shown in Figure 11. AITC pretreatment cannot produce anti-inflammatory effect in trpa1 knockout mice, so AITC is anti-inflammatory by specifically stimulating TRPA1+ sensory nerves.

[0150] Example 12, stimulating TRPA1+ sensory nerves can improve the survival rate and physiological state of inflammatory mice

[0151] 9-11 week old male mice were injected intraperitoneally with 8 mg / kg LPS to establish a systemic inflammation mouse model. 30 minutes before LPS injection, C57BL / 6J mice were injected intraperitoneally with 50 mg / kg AITC to establish the AITC-LPS experimental group (n=15), and a solvent+LPS control group (n=14) was set up. 30 minutes before LPS injection, trpa1 knockout mice were injected intraperitoneally with 50 mg / kg AITC to establish the AITC-LPS experimental group (n=17), and a solvent+LPS control group (n=10) was set up. The physiological state of the mice was detected every 12 hours before and after LPS injection. The inflammation mice were judged to reach the death standard according to the body temperature, body weight, fur color and active state, and euthanized in time. The mice were judged to die when any of the following 1 item standards was reached: 1 body temperature (body temperature <32℃ was judged to die); 2 body weight (20% body weight loss was judged to die); 3 total score of clinical symptoms (total score reached 2 points was judged to die), including 4 kinds of clinical symptoms each scored in three grades (0, 1, 2), a eye secretion (excessive secretion causing eye closure 0 points, excessive secretion 1 point, no secretion 2 points), b diarrhea (severe 0 points, loose stool 1 point, normal 2 points), c fur color (dull, dull and lack of grooming hair 0 points, dull and lack of grooming hair 1 point, shiny hair 2 points), d active state (drowsy and mild stimulation only to lift the head 0 points, not active and mild stimulation only to move less than two steps 1 point, normal 2 points), and the total score of four items was 8 points for a normal physiological state of the mice. The mice were judged to reach the premature termination of the experiment standard in combination, euthanized in time, and the death time of the mice was recorded. The 14th day after the injection was taken as the survival experiment termination point, and all experimental mice were euthanized.

[0152] The results are shown in Figure 12. The survival rate of the inflammation mice in the control group was only 7%, while the survival rate of the inflammation mice injected with AITC in the experimental group was significantly improved, reaching 40%. We continuously observed the experimental mice for 2 weeks, and all the surviving mice recovered in weight after 1 week of the experiment, and no more deaths occurred, indicating that stimulating TRPA1+ sensory nerves can continuously protect mice against inflammation attacks. In addition, the body temperature change of the inflammation mice injected with AITC in the experimental group was significantly better than that of the control mice. In trpa1 knockout mice, the survival rate and body temperature change of the trpa1 knockout inflammation mice injected with AITC in the experimental group were not different from those of the control mice.

[0153] Example 13, stimulating TRPA1+ sensory nerves can induce catecholamine production

[0154] The wild-type mice were injected intraperitoneally with 50 mg / kg AITC to establish the experimental group, and a solvent control group was set up. Blood samples were taken at different time points. The blood samples were placed at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. The catecholamine concentration in the serum was detected using a 3-CAT ELISA kit according to the manufacturer's instructions.

[0155] The results are shown in Figure 13. Stimulation of TRPA1+ sensory nerves increased the expression levels of dopamine, norepinephrine and epinephrine in the serum of mice.

[0156] Example 14. Stimulation of TRPA1+ sensory nerves can activate the hypothalamic-pituitary-adrenal reflex arc to promote the secretion of cortisol

[0157] The wild-type mice were injected intraperitoneally with 50 mg / kg AITC, and blood samples were taken at different time points. The blood samples were placed at room temperature for 2 hours, then centrifuged at 2000g for 20 minutes to collect serum, which was stored in a -80°C refrigerator before use. The concentration of corticosterone in the serum was detected using a Parameter Corticosterone Assay kit according to the manufacturer's instructions.

[0158] The results are shown in Figure 14. The concentration of corticosterone in the serum of wild-type mice increased nearly 8-fold 15 minutes after injection of AITC, and then gradually decreased.

[0159] The above has been described in detail. For those skilled in the art, without departing from the purpose and scope of the present application, and without unnecessary experiments, the present application can be implemented in a wide range of equivalent parameters, concentrations and conditions. Although the present application gives a special example, it should be understood that further improvements can be made to the present application. In general, according to the principle of the present application, this application intends to include any changes, uses or improvements of the present application, including changes made by conventional techniques known in the art, which are outside the scope disclosed in this application. Some basic features can be applied within the scope of the following attached claims. Industrial applicability

[0160] The present application provides a new use of a substance stimulating TRPV1+ and / or TRPA1+ sensory nerves (such as a substance activating TRPV1 and / or TRPA1 ion channels through chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, ultrasonic stimulation or infrared stimulation) in preventing, treating or adjuvant treating inflammatory diseases, autonomic nervous function disorder diseases and adrenal insufficiency diseases. The inventors of the present application have proved through experiments that a TRPV1 ion channel agonist (such as capsaicin or a hot stimulant) and / or a TRPA1 ion channel agonist (such as AITC) can significantly and effectively inhibit the expression of a plurality of pro-inflammatory cytokines, not only significantly improve the physiological state of an inflammatory mouse, but also significantly improve the survival rate of the inflammatory mouse; meanwhile, the TRPV1 and / or TRPA1 ion channel agonist can also regulate the function of a spleen, significantly inhibit the expression of pro-inflammatory genes of the spleen, increase the production of catecholamines (dopamine, norepinephrine and epinephrine) and promote the secretion of cortisol hormones. The present application can also be used for screening a candidate drug for treating and / or preventing inflammatory diseases, autonomic nervous function disorder diseases and adrenal insufficiency diseases caused by pro-inflammatory cytokines or a pro-inflammatory cytokine cascade, developing a new disease treatment method and a treatment drug. The present application has a wide clinical application value for preventing and treating related diseases.

Claims

1. Use of a substance that stimulates TRPV1+ and / or TRPA1+ sensory nerves in the manufacture of a product having any one of the following functions: A1) preventing, treating or co-treating an inflammatory disease; A2) inhibiting pro-inflammatory cytokine expression or inhibiting a pro-inflammatory cytokine cascade; A3) promoting anti-inflammatory cytokine expression or production; A4) preventing, treating or co-treating an autonomic nervous system disorder disease; A5) promoting catecholamine secretion; A6) preventing, treating or co-treating an adrenal insufficiency disease; A7) promoting adrenal secretion of corticosteroids.

2. Use according to claim 1, characterized in that, The substance that stimulates TRPV1+ and / or TRPA1+ sensory nerves is a substance that activates the TRPV1 and / or TRPA1 ion channel by chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, ultrasound stimulation or infrared stimulation.

3. Use according to claim 1 or 2, characterized in that, The substance that stimulates TRPV1+ and / or TRPA1+ sensory nerves is a TRPV1 and / or TRPA1 ion channel agonist.

4. Use according to any one of claims 1 to 3, characterized in that, The TRPV1 and / or TRPA1 ion channel agonist is any one of the following: B1) an agent or drug that activates the TRPV1 and / or TRPA1 ion channel; B2) an agent or drug that activates TRPV1+ and / or TRPA1+ sensory neurons; B3) an agent or drug that promotes replication, transcription, translation, post-translational modification and / or post-translational modification of the TRPV1 and / or TRPA1 gene; B4) an agent or drug that increases or upregulates the content, activity and / or function of the TRPV1 and / or TRPA1 protein.

5. Use according to claim 3 or 4, characterized in that, The TRPV1 and / or TRPA1 ion channel agonist is a capsaicin or capsaicinoid.

6. Use of the TRPV1 and / or TRPA1 ion channel as a target in any one of the following: C1) in the manufacture of a product for preventing, treating or co-treating an inflammatory disease; C2) in the manufacture of a product for inhibiting pro-inflammatory cytokine expression or inhibiting a pro-inflammatory cytokine cascade; C3) in the manufacture of a product for promoting anti-inflammatory cytokine expression or production; C4) in the manufacture of a product for preventing, treating or co-treating an autonomic nervous system disorder disease; C5) in the manufacture of a product for promoting catecholamine secretion; C6) in the manufacture of a product for preventing, treating or co-treating an adrenal insufficiency disease; C7) in the manufacture of a product for promoting adrenal secretion of corticosteroids; C8) in the development, design or screening of a candidate drug and / or therapeutic method for treating and / or preventing an inflammatory disease due to a pro-inflammatory cytokine or a pro-inflammatory cytokine cascade; C9) in the development, design or screening of a candidate drug and / or therapeutic method for treating and / or preventing an autonomic nervous system disorder disease and a disease due to insufficient catecholamine secretion; C10) in the development, design or screening of a candidate drug and / or therapeutic method for treating and / or preventing an adrenal insufficiency disease. ​ 7. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the TRPV1 ion channel agonist and / or the TRPA1 ion channel agonist as described in claim 4 or 5, and one or more pharmaceutically acceptable carriers.

8. Use according to any one of claims 1 to 6, characterized in that, The pro-inflammatory cytokine is TNFa, IL6, IL1a, IL1ss, IL1f9, IL1rl1, IL1rn, IL2, IL12b, IL13, IL15, IL16, IL20rb, IL27, TNFSF15, TNFSF18, TNFRSF12a, TNFRSF19, CD40, CSF2, CSF3, LIF, TIMP1, TSLP, FAS, OSMR, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL12, CCL17, CCL19, CCL20, CCL22, CCL27, CCR6, CXCL1, CXCL5, CXCL10, CXCL11, CX3CL1, XCL1, IFNa1, IFNa2, IFNa4, IFNa5, IFNa9, IFNab, IFNb1, IFNg, IFIH1, IFIT1, IFIT1bl1, IFIT2, IFIT3, IFIT3b, IFI27l2b, IFI47, IFI204, IFI205, IFI207, IFI211, IRF4 and / or IRF6.

9. Use according to any one of claims 1 to 6, characterized in that, The anti-inflammatory cytokine is IL10.

10. A method of screening for a candidate drug for treating and / or preventing an inflammatory disease caused by a proinflammatory cytokine or a proinflammatory cytokine cascade, characterized by, The method comprises screening drugs to be screened targeting TRPV1 and / or TRPA1 ion channel, and selecting drugs capable of activating TRPV1 and / or TRPA1 ion channel, or up-regulating TRPV1 and / or TRPA1 gene and / or TRPV1 and / or TRPA1 protein level as candidate drugs.

11. Use of a substance stimulating TRPV1+ and / or TRPA1+ sensory nerves in any of the following: E1) preventing, treating or adjuvant treating an inflammatory disease; E2) inhibiting pro-inflammatory cytokine expression or inhibiting pro-inflammatory cytokine cascade; E3) promoting anti-inflammatory cytokine expression or production; E4) preventing, treating or adjuvant treating an autonomic nervous function disorder disease; E5) promoting catecholamine secretion; E6) preventing, treating or adjuvant treating an adrenal insufficiency disease; E7) promoting adrenal secretion of corticosteroids.

12. A method of preventing or treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-10. The method comprises stimulating TRPV1+ and / or TRPA1+ sensory nerves of a subject or patient.

13. The method of claim 12, wherein, The disease comprises an inflammatory disease, an autonomic nervous function disorder disease or an adrenal insufficiency disease.

14. The method according to claim 12 or 13, characterized in that, The method comprises administering to the subject or patient a TRPV1 ion channel agonist and / or a TRPA1 ion channel agonist as described in claim 4 or 5, or a pharmaceutical composition as described in claim 7.

15. The method of claim 14, wherein, The administration includes intramuscular injection, intramuscular injection, subcutaneous injection, intradermal injection, transdermal injection, intravenous injection, arterial injection, intraperitoneal injection, intraperitoneal injection, microneedle injection, mucosal administration, oral administration, oral and nasal cavity spray, aerosol inhalation, skin application, in vivo implantation and in vitro device administration.

16. The method according to claim 14 or 15, characterized in that The administration site includes the abdominal cavity, the whole body skin, the subcutaneous tissue, the muscle, the nape, the waist and the abdomen.

17. The method of claim 12 or 13, wherein, The stimulation includes chemical stimulation, temperature stimulation, mechanical stimulation, electrical stimulation, electrical signal stimulation, ultrasonic stimulation and infrared stimulation.

18. A method of inhibiting the expression of a proinflammatory cytokine, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-17. The method includes stimulating TRPV1+ and / or TRPA1+ sensory nerves of the subject or patient.

19. The method of claim 18, wherein, The pro-inflammatory cytokine is selected from TNFα, IL6, IL1a, IL1β, IL1f9, IL1rl1, IL1rn, IL2, IL12b, IL13, IL15, IL16, IL20rb, IL27, TNFSF15, TNFSF18, TNFRSF12a, TNFRSF19, CD40, CSF2, CSF3, LIF, TIMP1, TSLP, FAS, OSMR, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL12, CCL17, CCL19, CCL20, CCL22, CCL27, CCR6, CXCL1, CXCL5, CXCL10, CXCL11, CX3CL1, XCL1, IFNa1, IFNa2, IFNa4, IFNa5, IFNa9, IFNab, IFNb1, IFNg, IFIH1, IFIT1, IFIT1bl1, IFIT2, IFIT3, IFIT3b, IFI27l2b, IFI47, IFI204, IFI205, IFI207, IFI211, IRF4 and IRF6.

20. A method of promoting expression of an anti-inflammatory cytokine, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19. The method includes stimulating TRPV1+ and / or TRPA1+ sensory nerves of the subject or patient.

21. The method of claim 20, wherein, The anti-inflammatory cytokine is IL10.

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