Application of deoxycholic acid in treatment of postherpetic neuralgia

Abstract

This invention provides the application of deoxycholic acid in the treatment of postherpetic neuralgia. This invention is the first to discover that deoxycholic acid is effective in treating postherpetic neuralgia, and that inhibiting the nucleus tractus solitarius-paraventricular nucleus circuit of the thalamus is also effective in treating postherpetic neuralgia. A synergistic therapeutic effect was achieved when deoxycholic acid was combined with an inhibitor of the nucleus tractus solitarius-paraventricular nucleus circuit. This invention provides a new strategy for the treatment of postherpetic neuralgia.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to the application of deoxycholic acid in the treatment of postherpetic neuralgia. Background Technology

[0002] Postherpetic neuralgia (PHN) is a relatively common disease, a complication that is easy to diagnose but difficult to treat, occurring after the skin lesions of shingles have healed. Currently, clinically, PHN is diagnosed when pain persists for more than 3 months after the skin lesions have healed. Its main clinical symptoms include abnormal sensations in the skin distribution area, manifesting as knife-like, needle-like, or burning pain. The pain is severe and significantly affects the patient's mood, sleep, and quality of life. Studies have shown that 5%–30% of shingles patients may develop residual neuralgia, and the probability of developing PHN in elderly shingles patients over 60 years of age is as high as 50%–75%.

[0003] Current treatments for PHN mainly include medication, physical therapy, and minimally invasive surgery, but the treatment outcomes are not ideal. Therefore, new treatment strategies need to be developed. Summary of the Invention

[0004] In view of this, in order to overcome the shortcomings of the prior art, the present invention is proposed.

[0005] The first aspect of the present invention provides the use of deoxycholic acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating postherpetic neuralgia.

[0006] A second aspect of the invention provides the use of deoxycholic acid or a pharmaceutically acceptable salt thereof and an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit in the preparation of a medicament for treating postherpetic neuralgia.

[0007] The third aspect of this invention provides the use of an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit in the preparation of a medicament for treating postherpetic neuralgia.

[0008] In this invention, the pharmaceutically acceptable salts of deoxycholic acid include, but are not limited to, any one or more of the following: alkali metal salts, ammonium salts, organic amine salts, basic amino acid salts, and guanidine derivative salts of deoxycholic acid.

[0009] In some implementations, the alkali metal salts of deoxycholic acid include, but are not limited to, sodium deoxycholate and potassium deoxycholate.

[0010] In some embodiments, the organic amine salts of deoxycholic acid include, but are not limited to, salts formed by deoxycholic acid with triethylamine, diethanolamine, meglumine, or choline.

[0011] In some embodiments, the basic amino acid salts of deoxycholic acid include, but are not limited to, salts formed by deoxycholic acid with arginine, lysine, histidine, or ornithine.

[0012] In some embodiments, the guanidinyl derivative salts of deoxycholic acid include, but are not limited to, the salts formed by deoxycholic acid and guanidinylbutylamine.

[0013] In some implementations, the solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor includes an excitatory neuron inhibitor.

[0014] In this invention, the solitary nucleus-paraventricular nucleus neural circuit inhibitor includes any substance that can specifically reduce the activity of neural signal transduction projecting from the solitary nucleus (NTS) to the paraventricular nucleus (PVT) of the thalamus. Examples, but not limited to, small molecule compounds, antibodies, and recombinant adeno-associated viruses.

[0015] In some embodiments, the excitatory neuron inhibitor includes, but is not limited to, a recombinant adeno-associated virus vector comprising a nucleotide sequence encoding hM4D(Gi).

[0016] In some implementations, the excitatory neuron inhibitor further includes an agonist that activates hM4D(Gi).

[0017] In some implementations, the agonist that activates hM4D(Gi) is deschloroclozapine.

[0018] In some implementations, the vector further includes one or more of an excitatory neuron-specific promoter, a transcription termination signal, and a reporter gene.

[0019] In some implementations, the excitatory neuron-specific promoters include, but are not limited to, the CaMKIIα promoter and the hSyn promoter.

[0020] In some implementations, the reporter gene includes, but is not limited to, one or more of mCherry, EGFP, EYFP, or luciferase.

[0021] In some embodiments, the serotypes of the recombinant adeno-associated virus vector include, but are not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10.

[0022] In some embodiments, the serotype of the recombinant adeno-associated virus vector is selected from AAV9.

[0023] In some embodiments, the solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor is a combination of rAAV-VGLUT2-CRE-WPRE-hGH pA, rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA and deschloroclozapine, or a combination of AAV9-CaMKIIa-hM4D(Gi)-mCherry and deschloroclozapine.

[0024] The fourth aspect of the present invention provides any of the following products: (1) A pharmaceutical composition comprising deoxycholic acid or a pharmaceutically acceptable salt thereof and / or an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit; (2) A medicine box, the medicine box comprising: Container; deoxycholic acid or its pharmaceutically acceptable salt and / or inhibitors of the nucleus tractus solitarius-paraventricular nucleus neural circuit.

[0025] In this invention, the pharmaceutically acceptable salts of deoxycholic acid include, but are not limited to, any one or more of the following: alkali metal salts, ammonium salts, organic amine salts, basic amino acid salts, and guanidine derivative salts of deoxycholic acid.

[0026] In some implementations, the alkali metal salts of deoxycholic acid include, but are not limited to, sodium deoxycholate and potassium deoxycholate.

[0027] In some embodiments, the organic amine salts of deoxycholic acid include, but are not limited to, salts formed by deoxycholic acid with triethylamine, diethanolamine, meglumine, or choline.

[0028] In some embodiments, the basic amino acid salts of deoxycholic acid include, but are not limited to, salts formed by deoxycholic acid with arginine, lysine, histidine, or ornithine.

[0029] In some embodiments, the guanidinyl derivative salts of deoxycholic acid include, but are not limited to, the salts formed by deoxycholic acid and guanidinylbutylamine.

[0030] In some implementations, the solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor includes an excitatory neuron inhibitor.

[0031] In this invention, the solitary nucleus-paraventricular nucleus neural circuit inhibitor includes any substance that can specifically reduce the neural signal transduction activity projecting from the solitary nucleus (NTS) to the paraventricular nucleus (PVT) of the thalamus.

[0032] In some embodiments, the excitatory neuron inhibitor includes, but is not limited to, a recombinant adeno-associated virus vector comprising a nucleotide sequence encoding hM4D(Gi).

[0033] In some implementations, the excitatory neuron inhibitor further includes an agonist that activates hM4D(Gi).

[0034] In some implementations, the agonist that activates hM4D(Gi) is deschloroclozapine.

[0035] In some implementations, the vector further includes one or more of an excitatory neuron-specific promoter, a transcription termination signal, and a reporter gene.

[0036] In some implementations, the excitatory neuron-specific promoters include, but are not limited to, the CaMKIIα promoter and the hSyn promoter.

[0037] In some implementations, the reporter gene includes, but is not limited to, one or more of mCherry, EGFP, EYFP, or luciferase.

[0038] In some embodiments, the serotypes of the recombinant adeno-associated virus vector include, but are not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10.

[0039] In some embodiments, the serotype of the recombinant adeno-associated virus vector is selected from AAV9.

[0040] In some embodiments, the solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor is a combination of rAAV-VGLUT2-CRE-WPRE-hGH pA, rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA and deschloroclozapine, or a combination of AAV9-CaMKIIa-hM4D(Gi)-mCherry and deschloroclozapine.

[0041] In some embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipient.

[0042] In some implementations, "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation and / or the mammals to be treated therein. Pharmaceutically acceptable carriers and / or excipients may include any solvent suitable for the specific target dosage form.

[0043] In some embodiments, pharmaceutically acceptable carriers and / or excipients for pharmaceutical compositions containing deoxycholic acid include, but are not limited to, diluents, binders, surfactants, humectants, adsorbents, lubricants, and / or disintegrants. The diluents include, but are not limited to, lactose, sodium chloride, glucose, urea, starch, and water; the binders include, but are not limited to, starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginate and alginates, xanthan gum, hydroxypropylcellulose, and hydroxypropyl methylcellulose; the surfactants include, but are not limited to, polyethylene oxide sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, and hexadecyl alcohol; the humectants include, but are not limited to, glycerol and starch; the adsorbents include, but are not limited to, starch, lactose, bentonite, silica gel, kaolin, and soap clay; and the lubricants include, but are not limited to, zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium lauryl sulfate.

[0044] In some embodiments, a suitable carrier for a pharmaceutical composition containing an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit comprises saline, which can be formulated with a variety of buffer solutions (e.g., phosphate-buffered saline). Other exemplary carriers comprise sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, and water. The buffer / carrier should contain components that prevent recombinant AAV (rAAV) from adhering to the infusion tubing without interfering with the in vivo binding activity of rAAV.

[0045] In some embodiments, the pharmaceutical composition comprising an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit may contain a buffered saline solution. The buffered saline solution includes, but is not limited to, one or more of sodium phosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and mixtures thereof in water. The pH of the aqueous solution may be 7.2 or 7.4.

[0046] In some embodiments, the excipients of the pharmaceutical composition comprising an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit include, but are not limited to, diluents, excipients, adjuvants, penetration enhancers, preservatives, and chemical stabilizers.

[0047] In some embodiments, pharmaceutical compositions comprising inhibitors of the nucleus tractus solitarius-paraventricular nucleus neural circuit may contain one or more permeability enhancers. Examples of suitable permeability enhancers may include, for example, mannitol, sodium glycocholate, sodium taurocholate, sodium deoxycholate, sodium salicylate, sodium caprylate, sodium decanoate, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, or EDTA.

[0048] In some embodiments, pharmaceutical compositions containing inhibitors of the nucleus tractus solitarius-paraventricular nucleus neural circuit may also contain other conventional pharmaceutical ingredients, such as preservatives or chemical stabilizers. Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerin, phenol, and p-chlorophenol. Suitable chemical stabilizers include gelatin and albumin.

[0049] In one embodiment, the pharmaceutical composition comprising an inhibitor of the nucleus tractus solitarius-paraventricular nucleus thalamus neural circuit may be, for example, an aqueous liquid suspension buffered to a physiologically compatible pH and salt concentration, and may also be transported as a concentrate diluted for administration to a subject. In other embodiments, the pharmaceutical composition may be lyophilized and reconstituted at the time of administration.

[0050] In some embodiments, the pharmaceutical composition comprising an inhibitor of the nucleus solitarius-thalamic paraventricular nucleus neural circuit is formulated to a physiologically acceptable pH, for example, in the range of pH 6 to 9, or pH 6.5 to 7.5, pH 7.0 to 7.7, or pH 7.2 to 7.8.

[0051] In some embodiments, the pharmaceutical composition is administered in a therapeutically effective amount.

[0052] As used herein, the term “effective dose” is equivalent to “therapeutic effective dose” and means producing the desired therapeutic, ameliorative, inhibitory, or preventative effect in subjects in need.

[0053] As used herein, the term "subject" refers to an animal or any living organism that has sensory and motor abilities and requires oxygen and organic food. Non-limiting examples include rodents (e.g., guinea pigs, hamsters, rats, mice), canines (e.g., dogs), cats (e.g., cats), pigs (e.g., pigs), equines (e.g., horses), non-human primates (e.g., monkeys, apes, baboons, gorillas, chimpanzees, orangutans), or humans. In a preferred embodiment, the subject is selected from humans.

[0054] Administer in a therapeutically effective dose to provide therapeutic benefit without causing excessive side effects or having medically acceptable physiological effects, which can be determined by a technician in the medical field.

[0055] The pharmaceutical compositions described herein can be administered to subjects using any pharmaceutical dosage form known in the art. Non-limiting examples include non-gastrointestinal dosage forms and gastrointestinal dosage forms.

[0056] The non-gastrointestinal dosage forms include at least one of injection dosage forms, respiratory dosage forms, cavity dosage forms, mucosal dosage forms, and skin dosage forms; the gastrointestinal dosage forms include at least one of tablets, granules, capsules, solutions, dry suspensions, powders, sustained-release preparations, effervescent tablets, emulsions, suspensions, syrups, drops, and chewable tablets.

[0057] The injectable dosage forms include, but are not limited to, intravenous injections, intramuscular injections, subcutaneous injections, intradermal injections, and intracavitary injections; the respiratory dosage forms include, but are not limited to, sprays, aerosols, and powder inhalers; the cavity dosage forms include, but are not limited to, suppositories, aerosols, effervescent tablets, drops, and pellets, which can be used for, but are not limited to, rectal, vaginal, urethral, ​​nasal, and ear canal administration; the mucosal dosage forms include, but are not limited to, eye drops, nasal drops, ointments, mouthwashes, sublingual tablets, adhesive tablets, and patches; and the skin dosage forms include, but are not limited to, topical solutions, lotions, liniments, ointments, plasters, pastes, and patches.

[0058] In some embodiments, the pharmaceutical composition containing deoxycholic acid is administered via the gastrointestinal tract.

[0059] In some implementations, a pharmaceutical composition comprising an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit is administered via intracerebral injection.

[0060] The dosage of a pharmaceutical composition will depend primarily on factors such as the condition being treated, the patient's age, weight, and health status, and therefore may vary between patients. For any pharmaceutical composition, the effective dose can initially be estimated in cell culture assays or in relevant animal models (e.g., mice, guinea pigs, chimpanzees, marmosets, or tamarins). Relevant animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine the effective dose and route of administration to humans. Therapeutic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as ED. 50 (Dose effective for 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 In some respects, the effective dose reaches a high therapeutic index. Specifically, the dose includes EDs with little or no toxicity. 50 Within the circulating concentration range. The dosage can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0061] In some embodiments, when the kit comprises deoxycholic acid or a pharmaceutically acceptable salt thereof and an inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit, the container may contain either the deoxycholic acid or a pharmaceutically acceptable salt thereof, or the inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit, in combination or separately. That is, deoxycholic acid or a pharmaceutically acceptable salt thereof, and the inhibitor of the nucleus tractus solitarius-paraventricular nucleus neural circuit can be contained together in the same container or separately in separate containers.

[0062] The fifth aspect of the present invention provides a method for treating postherpetic neuralgia, the method comprising applying any of the products described in the fourth aspect of the present invention.

[0063] The advantages and beneficial effects of this invention are as follows: This invention provides the application of deoxycholic acid in the treatment of postherpetic neuralgia. This invention is the first to discover that deoxycholic acid is effective in treating postherpetic neuralgia, and that inhibiting the nucleus tractus solitarius-paraventricular nucleus circuit of the thalamus is also effective in treating postherpetic neuralgia. A synergistic therapeutic effect was achieved when deoxycholic acid was combined with an inhibitor of the nucleus tractus solitarius-paraventricular nucleus circuit. This invention provides a new strategy for the treatment of postherpetic neuralgia. Attached Figure Description

[0064] Figure 1 The study involved administering different concentrations of deoxycholic acid (DCA) to mice via continuous gavage and observing changes in pain-related behavioral indicators in the model mice. Specifically, AB. After gavage administration of DCA at doses of 10 mg / kg and 20 mg / kg, the sensitivity of the right paw to thermal stimulation in mice decreased; CD. After continuous gavage administration of DCA at doses of 10 mg / kg and 20 mg / kg for 7-14 days, the sensitivity of the right paw to low-intensity stimulation in mice decreased; EF. After continuous gavage administration of DCA at doses of 10 mg / kg and 20 mg / kg for 10-14 days, the sensitivity of the right paw to high-intensity stimulation in mice decreased; GH. After continuous gavage administration of DCA at doses of 10 mg / kg and 20 mg / kg for 10-14 days, the sensitivity of the right hind limb to low-intensity stimulation in mice decreased; IJ. 10 mg / kg After continuous gavage administration of a dose of deoxycholic acid (DCA) for 7-14 days, the sensitivity of the right hind limb of mice to high-intensity stimuli decreased; after continuous gavage administration of a dose of 20 mg / kg deoxycholic acid (DCA) for 3-14 days, the sensitivity of the right hind limb of mice to high-intensity stimuli decreased. Figure 2In mice undergoing subphrenic vagotomy (SDV), the pain-relieving effect of 10 mg / kg deoxycholic acid (DCA) was reversed. Specifically, AB. SDV mice showed no significant reduction in sensitivity to thermal stimulation after gavage administration of DCA; CD. SDV mice showed no significant reduction in sensitivity to low-intensity stimulation after gavage administration of DCA; EF. SDV mice showed no significant reduction in sensitivity to high-intensity stimulation after gavage administration of DCA; GH. SDV mice showed no significant reduction in sensitivity to low-intensity stimulation in the right hind limb after gavage administration of DCA; IJ. Mice that underwent subphrenic vagotomy (SDV) showed no significant reduction in sensitivity to high-intensity stimuli in their right hind limb after gavage administration of deoxycholic acid (DCA). Figure 3 This study investigated changes in the sensitivity of HSV-1 model mice to thermal and mechanical pain in the foot by inhibiting the activity of PVT nuclei neurons to varying degrees. Specifically, AB: mild inhibition of PVT excitatory neuronal activity decreased the sensitivity of the right foot to thermal stimulation; CD: high inhibition of PVT excitatory neuronal activity decreased the sensitivity of the right foot to thermal stimulation; EF: mild inhibition of PVT excitatory neuronal activity showed no significant change in the sensitivity of the foot to low-intensity mechanical stimulation; GH: high inhibition of PVT excitatory neuronal activity decreased the sensitivity of the right foot to low-intensity stimulation; IJ: low inhibition of PVT excitatory neuronal activity decreased the sensitivity of the right foot to high-intensity stimulation; KL: high inhibition of PVT excitatory neuronal activity decreased the sensitivity of the right foot to high-intensity stimulation. Figure 4 This study investigated changes in the sensitivity of HSV-1 model mice to mechanical pain in the lower limbs by inhibiting the activity of PVT nuclei neurons to varying degrees. Specifically, AB. Mild inhibition of the activity of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus resulted in no significant change in the sensitivity to low-intensity mechanical stimulation of the mouse's lower limbs; CD. High inhibition of the activity of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus resulted in decreased sensitivity to low-intensity stimulation in the right lower limb of the mouse; EF. Mild inhibition of the activity of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus resulted in no significant change in the sensitivity to high-intensity mechanical stimulation of the mouse's lower limbs; GH. High inhibition of the activity of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus resulted in decreased sensitivity to high-intensity stimulation in the right foot of the mouse. Figure 5 This study investigated changes in pain-related behaviors in HSV-1 model mice by inhibiting neural transmission of excitatory neurons in the nucleus tractus solitarius (NTS)-paraventricular nucleus thalamus (PVT) neural circuit. Specifically, AB. Inhibition of neural transmission of excitatory neurons in the NTS-PVT circuit resulted in decreased sensitivity to thermal stimulation of the right foot; CD. Inhibition of neural transmission of excitatory neurons in the NTS-PVT circuit resulted in decreased sensitivity to low-intensity stimulation of the right foot; EF. Inhibition of neural transmission of excitatory neurons in the NTS-PVT circuit resulted in decreased sensitivity to high-intensity stimulation of the right foot; GH. Inhibition of neural transmission of excitatory neurons in the NTS-PVT circuit resulted in decreased sensitivity to low-intensity stimulation of the right hind limb; IJ. Inhibition of neurotransmission by excitatory neurons in the nucleus tractus solitarius (NTS)-paraventricular nucleus of thalamus (PVT) neural circuit reduced the sensitivity of mice to high-intensity stimulation in the right hind limb. Figure 6 This study investigated changes in pain-related behaviors in HSV-1 model mice by continuously administering deoxycholic acid (DCA) via gavage in combination with inhibition of neurotransmission in the nucleus tractus solitarius (NTS)-paraventricular nucleus of the thalamus (PVT) neural circuit. Specifically, AB. decreased sensitivity to thermal stimulation in the right paw; CD. decreased sensitivity to low-intensity stimulation in the right paw; EF. decreased sensitivity to high-intensity stimulation in the right paw; GH. decreased sensitivity to low-intensity stimulation in the right hind limb; and IJ. decreased sensitivity to high-intensity stimulation in the right hind limb. Detailed Implementation

[0065] The present invention will be further described below with reference to embodiments. The following description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make equivalent modifications to the disclosed technical content to create equivalent embodiments. Any simple modifications or equivalent changes made to the following embodiments based on the technical essence of the present invention without departing from the scope of the invention are all within the protection scope of the present invention.

[0066] Example 1: Construction of the PHN Model 1. Experimental materials Virus: HSV1 KOS strain Equipment: Von Frey fiber, foot thermal pain meter 2. Experimental Methods After anesthetizing the mice, the hair on the right side of their waist and right limb was removed using a shaver. A needle was gently used to puncture the skin of the right hind limb, and 10 μL of HSV-1 strain suspension (1×10⁻⁶) was injected using a microsyringe. 6 PFU was injected subcutaneously into the tibia region of the right hind limb of mice, while the contralateral limb was not inoculated with the virus. The sham-operated group underwent the same procedure as the infected group, but the virus suspension used was pre-inactivated by heating at 60°C for 1 hour.

[0067] After viral inoculation, mice underwent pain behavior testing at different time points, and samples of the left and right dorsal root ganglia (DRG) and spinal cord tissue were collected. The expression changes of relevant indicators were detected by qPCR.

[0068] 3. Experimental Results After inoculation with HSV-1 virus, mice showed increased pain sensitivity in the right hind limb and right foot 7-14 days after inoculation, while there was no obvious change in pain sensation in the left limb and foot, suggesting the formation of acute pain. As the disease progressed, the acute pain gradually subsided, but a significant pain response reappeared on the right side 35-42 days after inoculation, indicating that the model could further develop into a chronic pain state.

[0069] Example 2: Deoxycholic acid treatment for PHN 1. Experimental materials Drug: Deoxycholic acid (DCA) (MCE Company, Cat: HY-N0593) administered orally at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg. Equipment: Von Frey fiber, foot thermal pain meter 2. Experimental Methods Mice were administered deoxycholic acid (DCA) at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg via continuous gavage. The effect of DCA on improving neuropathic pain phenotypes was evaluated by detecting changes in pain-related behavioral patterns such as mechanodysodynia and thermoodynia.

[0070] 3. Experimental Results After gavage administration of deoxycholic acid (DCA), the analgesic sensitivity of mice was significantly reduced. Significant improvement was observed at both 10 mg / kg and 20 mg / kg doses, with the higher dose group showing a more pronounced analgesic effect, suggesting that the analgesic effect of DCA on pain sensitivity reduction is dose-dependent. Figure 1 ).

[0071] Example 3: Study on the mechanism of action of deoxycholic acid 1. Experimental materials Drug: Deoxycholic acid Equipment: Von Frey fiber, foot thermal pain meter 2. Experimental Methods Mice were administered deoxycholic acid (DCA) via continuous gavage, and vagal nerve conduction was intervened by vagotomy (SDV) to verify whether the effects of DCA are mediated by the vagus nerve. At the same time, changes in pain-related behaviors such as mechanical hyperalgesia and thermal hyperalgesia were detected in mice.

[0072] 3. Experimental Results Deoxycholic acid (DCA) gavage significantly reduced pain sensitivity in mice, indicating a significant ameliorative effect on neuropathic pain behavior. Vagotomy (SDV) significantly attenuated or blocked the analgesic effect of DCA, suggesting that the analgesic effect of DCA on pain sensitivity relief depends at least partially on vagus nerve-mediated signal transduction. Figure 2 ).

[0073] Example 4: Inhibition of the nucleus tractus solitarius (NTS)-paraventricular nucleus of the thalamus (PVT) neural circuit for the treatment of PHN (a) Inhibition of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus for the treatment of PHN 1. Experimental materials Virus: 200 nl of AAV9-CaMKIIa-hM4D(Gi)-mCherry was injected into the paraventricular nucleus of the thalamus via PVT, and the viral titer was 2.00E+12 vg / ml.

[0074] Drug: DREADD agonist DCZ (deschloroclozapine), intraperitoneal injection 0.05 mg / kg or 0.1 mg / kg Equipment: Von Frey fiber, foot thermal pain meter 2. Experimental Methods After anesthetizing mice, a chemogenetic viral vector was injected into the target brain region via stereotactic injection to inhibit PVT (paraventricular nucleus of the thalamus) neurons (intraperitoneal injection of DCZ 0.05 mg / kg or 0.1 mg / kg). Changes in pain-related behaviors in the mice after the intervention were then assessed. This experiment served as a self-control, divided into pre- and post-administration groups. The pre-administration group was the Pre-DCZ group, the DCZ group was the DCZ group, and the group containing only DCZ solvent was the Vehicle group.

[0075] 3. Experimental Results Pain sensitivity in mice is closely related to the activity level of excitatory neurons in the paraventricular nucleus (PVT) of the thalamus. Inhibitory intervention on these neurons decreased the sensitivity of mice to both thermal and mechanical pain stimuli, with the degree of decrease corresponding to the degree of inhibition of neuronal activity, suggesting a correlation between the two. Specifically, the decrease in sensitivity to high-intensity mechanical stimulation of the foot was significant. Figures 3-4 ).

[0076] (II) Inhibition of the nucleus tractus solitarius (NTS)-paraventricular nucleus of the thalamus (PVT) neural circuit for the treatment of PHN 1. Experimental materials Virus: 200 nl rAAV-VGLUT2-CRE-WPRE-hGH pA, type R, was injected into the paraventricular nucleus (PVT) of the thalamus; 100 nl rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA, type 9, was injected into each side of the nucleus tractus solitarius (NTS). The viral titers of both were 2.00E+12 vg / ml.

[0077] Drug: DREADD agonist DCZ, administered via microinjection into the paraventricular nucleus of the thalamus via cannula at a dose of 0.01 μg / μl, 200 nl / animal; Equipment: Von Frey fiber, foot heat pain meter.

[0078] 2. Experimental Methods After anesthetizing mice, a chemogenetic viral vector was injected into the target brain region via stereotactic injection to inhibit the NTS (nucleus tractus solitarius)-PVT (paraventricular nucleus of the thalamus) neural pathway (DREADD agonist DCZ 0.01 μg / μl, 200 nmol / mouse via cannula microinjection into the paraventricular nucleus of the thalamus). Changes in pain-related behaviors in the mice after the intervention were then assessed. This experiment served as a self-control, with participants divided into pre- and post-administration groups. The pre-administration group was the Pre-DCZ group, the administered DCZ group was the DCZ group, and the group containing only DCZ solvent was the Vehicle group.

[0079] 3. Experimental Results Changes in pain sensitivity in mice are closely related to the activity of the neural circuit from the nucleus tractus solitarius (NTS) to the paraventricular nucleus of the thalamus (PVT). Inhibitory intervention of this neural circuit significantly reduced the sensitivity of mice to both thermal and mechanical pain stimuli. Figure 5 ).

[0080] Example 4: Deoxycholic acid combined with inhibition of the nucleus tractus solitarius (NTS)-paraventricular nucleus of the thalamus (PVT) neural circuit for the treatment of PHN 1. Experimental materials Drugs: Deoxycholic acid (DCA) 5 mg / kg continuously by gavage; DREADD agonist (DCZ) 0.01 μg / μl via microinjection into the paraventricular nucleus of the thalamus via cannula, 50 nl / animal; Virus: 200 nl rAAV-VGLUT2-CRE-WPRE-hGH pA, type R, was injected into the paraventricular nucleus (PVT) of the thalamus; 100 nl rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA, type 9, was injected into each side of the nucleus tractus solitarius (NTS). The viral titers of both were 2.00E+12 vg / ml.

[0081] Equipment: Von Frey fiber, foot heat pain meter.

[0082] 2. Experimental Methods Combined drug administration group (DCA+DCZ group): After anesthesia, mice were injected with chemically genetically related viral vectors (200nl rAAV-VGLUT2-CRE-WPRE-hGH pA, R type, into the paraventricular nucleus (PVT) of the thalamus; 100nl rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA, each side of the nucleus tractus solitarius (NTS))) via stereotactic injection into the target brain regions. Mice were also administered deoxycholic acid (DCA) at 5 mg / kg via continuous gavage. In addition, 0.01 μg / μl of the DREADD agonist DCZ was injected into the paraventricular nucleus (PVT) of the thalamus at 50nl / mouse (a reduction in dosage compared to the single drug administration in the previous examples) via microinjection into the cannula to inhibit the NTS (nucleus tractus solitarius)-PVT (paraventricular nucleus) neural circuit. At the same time, changes in pain-related behaviors such as mechanical and thermal hyperalgesia were detected in mice.

[0083] Monotherapy group: Vehicle+Vehicle group: DCA solvent (excluding DCA) + DCZ solvent (excluding DCZ); DCA+Vehicle group: DCA 5mg / kg by gavage + DCZ solvent (without DCZ); Vehicle+DCZ group: DCA solvent (without DCA) + PVT (paraventricular nucleus of the thalamus) injection of 200nl rAAV-VGLUT2-CRE-WPRE-hGH pA, R-type viral vector; Nucleus tractus solitarius (NTS) injection of 100nl rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA) chemical genetically related viral vector + PVT (paraventricular nucleus of the thalamus) DCZ microinjection of 0.01μg / μl, 50nl / animal.

[0084] 3. Experimental Results DCA intervention and NTS-PVT neural circuit inhibition can jointly improve pain sensitivity in model mice, and the two have a certain synergistic effect, suggesting that the pain-relieving effect of DCA partly depends on the central regulatory mechanism mediated by the NTS-PVT neural circuit. Figure 6 ).

[0085] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. The use of deoxycholic acid or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment of postherpetic neuralgia.

2. The use of deoxycholic acid or its pharmaceutically acceptable salts and inhibitors of the nucleus tractus solitarius-paraventricular nucleus neural circuit in the preparation of medicaments for the treatment of postherpetic neuralgia.

3. Application of inhibitors of the solitary tract nucleus-thalamic paraventricular nucleus neural circuit in the preparation of drugs for treating postherpetic neuralgia.

4. Use according to any one of claims 1 to 2, characterized in that, Pharmaceutically acceptable salts of deoxycholic acid include sodium deoxycholate and potassium deoxycholate.

5. Use according to any one of claims 2 to 3, characterized in that, The solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitors include excitatory neuron inhibitors; Preferably, the excitatory neuron inhibitor comprises a recombinant adeno-associated virus vector, the vector comprising a nucleotide sequence encoding hM4D(Gi); Preferably, the excitatory neuron inhibitor further includes an agonist that activates hM4D(Gi); Preferably, the agonist that activates hM4D(Gi) is deschloroclozapine; Preferably, the vector further includes one or more of an excitatory neuron-specific promoter, a transcription termination signal, and a reporter gene; Preferably, the excitatory neuron-specific promoter is selected from the CaMKIIα promoter and the hSyn promoter; Preferably, the reporter gene is selected from one or more of mCherry, EGFP, EYFP, or luciferase; Preferably, the serotype of the recombinant adeno-associated virus vector is selected from AAV9.

6. Use according to claim 5, characterized in that, The solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor is a combination of rAAV-VGLUT2-CRE-WPRE-hGH pA, rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA and deschloroclozapine, or a combination of AAV9-CaMKIIa-hM4D(Gi)-mCherry and deschloroclozapine.

7. Any one of the following products: (1) A pharmaceutical composition, characterized by The pharmaceutical composition comprises deoxycholic acid or a pharmaceutically acceptable salt thereof and / or an inhibitor of the nucleus solitarius-paraventricular nucleus neural circuit; (2) A medicine box, characterized in that the medicine box comprises: Container; deoxycholic acid or its pharmaceutically acceptable salt and / or inhibitors of the nucleus tractus solitarius-paraventricular nucleus neural circuit.

8. The product of claim 7, wherein, Pharmaceutically acceptable salts of deoxycholic acid include sodium deoxycholate and potassium deoxycholate.

9. The product of claim 7, wherein, The solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitors include excitatory neuron inhibitors; Preferably, the excitatory neuron inhibitor comprises a recombinant adeno-associated virus vector, the vector comprising a nucleotide sequence encoding hM4D(Gi); Preferably, the excitatory neuron inhibitor further includes an agonist that activates hM4D(Gi); Preferably, the agonist that activates hM4D(Gi) is deschloroclozapine; Preferably, the vector further includes one or more of an excitatory neuron-specific promoter, a transcription termination signal, and a reporter gene; Preferably, the excitatory neuron-specific promoter is selected from the CaMKIIα promoter and the hSyn promoter; Preferably, the reporter gene is selected from one or more of mCherry, EGFP, EYFP, or luciferase; Preferably, the serotype of the recombinant adeno-associated virus vector is selected from AAV9; Preferably, the solitary nucleus-thalamic paraventricular nucleus neural circuit inhibitor is a combination of rAAV-VGLUT2-CRE-WPRE-hGH pA, rAAV-hSyn-DIO-hM4D(Gi)-EGFP-WPRE-hGH polyA and deschloroclozapine, or a combination of AAV9-CaMKIIa-hM4D(Gi)-mCherry and deschloroclozapine.

10. The product according to any one of claims 7-9, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier and / or excipients.

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