Application of DOT1L as treatment target of opioid drugs for inducing hyperalgesia

Abstract

The invention belongs to the field of biomedicine, and discloses application of DOT1L as a therapeutic target for inducing hyperalgesia by opioids. Experiments discover that the expression of DOT1L in an animal model in which hyperalgesia is induced by opioids is increased, hyperalgesia is relieved after EPZ5676 for inhibiting the expression of DOT1L is used for inhibiting gene expression, and the research results show that DOT1L is a clinically promising drug target capable of relieving hyperalgesia induced by opioids.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to the application of DOT1L as a therapeutic target for opioid-induced hyperalgesia. Background Art

[0002] Opioids are now widely used to treat acute and chronic pain and cancer pain. However, while exerting analgesic effects, opioids also activate the body's pro-nociceptive mechanism, inducing hyperalgesia, namely opioid-induced hyperalgesia (OIH), which is mainly manifested by the body's enhanced responsiveness to noxious stimuli, a lower postoperative pain threshold, an increase in pain scores, and an increase in the demand for analgesics. Remifentanil is an ultra-short-acting μ-opioid receptor agonist with the advantages of rapid onset, short half-life, hydrolysis by nonspecific plasma enzymes, metabolic pathways that are independent of liver and kidney function, and no accumulation effect. It has obvious clinical advantages over other opioids, can significantly shorten anesthesia time, speed up surgical turnover, and is widely used in general anesthesia. However, the incidence of remifentanil-induced postoperative hyperalgesia (RIH) is much higher than that of other opioid analgesics, reaching 85%. Another study found that the incidence of RIH was 32.7% in patients whose surgery time exceeded 2 hours, and the incidence of RIH was as high as 41.8% when the cumulative infusion volume exceeded 30 μg / kg. The main characteristics of RIH are the increase in the degree and range of postoperative incision pain and the increase in the demand for opioid analgesics after remifentanil was infused at a rate of 0.05-0.3 μg / kg / min for 60-90 minutes. RIH not only reduces the analgesic effect of the drug, but also promotes pain perception, produces abnormal pain, and even causes the occurrence of postoperative chronic pain. Patients have an increasing demand for opioid doses, which not only increases hospitalization time, medical expenses, and occupies medical resources, but most importantly, increases the physical and mental trauma of patients, aggravates their pain, and seriously affects their quality of life. At present, the potential mechanism of RIH is still unclear, so there is a lack of effective clinical treatment measures. It is urgent to further clarify the pathogenesis of remifentanil-induced hyperalgesia and find effective treatment strategies. Summary of the invention

[0003] In order to make up for the deficiencies of the prior art, the object of the present invention is to provide an application of preparing a drug for preventing or treating opioid-induced hyperalgesia.

[0004] In order to achieve the above object, the present invention adopts the following technical solution:

[0005] The present invention provides the use of an agent for inhibiting DOT1L expression in the preparation of a pharmaceutical composition for treating remifentanil-induced hyperalgesia.

[0006] The agent that inhibits the expression of DOT1L refers to any substance that can reduce the activity of DOT1L protein, reduce the stability of DOT1L gene or protein, down-regulate the expression of DOT1L protein, reduce the effective action time of DOT1L protein, or inhibit the transcription and translation of DOT1L gene. These substances can be used in the present invention as a substance useful for down-regulating DOT1L, and thus can be used to treat remifentanil hyperalgesia. For example, the inhibitory agent includes a nucleic acid inhibitor and a protein inhibitor. In some embodiments, the agent down-regulates the expression of DOT1L protein, including but not limited to the agent used in the process of inhibiting the expression of DOT1L gene using gene knockout technology, antisense nucleotide technology, and RNAi technology.

[0007] Furthermore, the agent that inhibits the expression of DOT1L includes an agent that inhibits the expression of DOT1L gene mRNA.

[0008] The agents for inhibiting the expression of DOT1L gene mRNA include antisense nucleic acid, dsRNA, ribozyme, and aptamer.

[0009] "Antisense nucleic acid" refers to a nucleic acid containing a sequence complementary to the mRNA encoding DOT1L. Antisense nucleic acids can be composed of DNA, RNA, or both. Antisense nucleic acids do not need to be 100% complementary to the mRNA of the target gene. Antisense nucleic acids may contain non-complementary bases as long as they can specifically hybridize under stringent conditions. When the antisense nucleic acid is introduced into a cell, it binds to the target polynucleotide and inhibits transcription, RNA processing, translation or stability. In addition to antisense polynucleotides, antisense nucleic acids also include polynucleotide mimics, which contain modified main chains, and 3' and 5' end portions. Such antisense nucleic acids can be appropriately designed based on the DOT1L sequence information and generated using methods known to those skilled in the art.

[0010] "dsRNA" refers to RNA containing a double-stranded RNA structure that inhibits gene expression through RNA interference (RNAi), including siRNA (short interfering RNA) and shRNA (short hairpin RNA). dsRNA does not need to have 100% homology with the target gene sequence, as long as it can inhibit the expression of the target gene. For stabilization or other purposes, a portion of the dsRNA can be replaced with DNA.

[0011] Preferably, siRNA is a double-stranded RNA of 21-23 bases. siRNA can be prepared by methods well known to those skilled in the art, such as by chemical synthesis or as an analog of naturally occurring RNA. shRNA is a short-chain RNA with a hairpin turn structure. shRNA can be prepared by methods well known to those skilled in the art, such as by chemical synthesis or by introducing DNA encoding shRNA into cells and expressing the DNA.

[0012] "Ribozyme" refers to a catalytically active RNA that can cut, paste, insert, and transfer RNA. The structure of ribozymes can include hammerhead, hairpin, etc.

[0013] "Aptamer" refers to a nucleic acid that binds to a substance such as a protein. An aptamer can be RNA or DNA. The form of the nucleic acid can be double-stranded or single-stranded. The length of the aptamer is unlimited as long as it can specifically bind to the target molecule, and can be composed of, for example, 10 to 200 nucleotides, preferably 10 to 100 nucleotides, more preferably 15 to 80 nucleotides, and even more preferably 15 to 50 nucleotides. Aptamers can be selected using methods known to those skilled in the art. For example, SELEX (systematic evolution of ligands by exponential enrichment) can be used.

[0014] Furthermore, agents that inhibit DOT1L expression include agents that inhibit the expression level of DOT1L protein.

[0015] In specific embodiments, the agent that inhibits DOT1L expression is EPZ5676.

[0016] The present invention also provides a pharmaceutical composition for treating remifentanil hyperalgesia, wherein the pharmaceutical composition comprises an effective amount of an agent for inhibiting the expression of DOT1L.

[0017] The agents for inhibiting DOT1L expression were described previously.

[0018] The effective amount of the pharmaceutical composition of the present invention will vary depending on the desired effect. Therefore, the optimal dose to be administered can be easily determined by those skilled in the art, and the optimal dose will vary with the specific drug used, the mode of administration, the strength of the preparation, and the progression of the disease condition. In addition, factors related to the specific subject receiving treatment, including the subject's age, weight, diet, and administration time, will result in the need to adjust the dose to an appropriate treatment level.

[0019] According to specific embodiments, an effective amount or effective dose refers to a therapeutic amount sufficient to achieve one, two, three, four, or more of the following effects: (i) reduce or ameliorate the severity of the disease, disorder, or condition to be treated or symptoms associated therewith; (ii) reduce the duration of the disease, disorder, or condition to be treated or symptoms associated therewith; (iii) prevent the development of the disease, disorder, or condition to be treated or symptoms associated therewith; (iv) cause the regression of the disease, disorder, or condition to be treated or symptoms associated therewith; (v) prevent the development or onset of the disease, disorder, or condition to be treated or symptoms associated therewith (vi) prevent recurrence of the disease, disorder or condition being treated, or symptoms associated therewith; (vii) reduce hospitalization of a subject suffering from the disease, disorder or condition being treated, or symptoms associated therewith; (viii) reduce the length of hospital stay of a subject suffering from the disease, disorder or condition being treated, or symptoms associated therewith; (ix) improve survival of a subject suffering from the disease, disorder or condition being treated, or symptoms associated therewith; (xi) inhibit or reduce symptoms of the disease, disorder or condition being treated, or symptoms associated therewith in a subject; and / or (xii) enhance or improve the prophylactic or therapeutic effect of another therapy.

[0020] The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

[0021] In the present invention, the term "pharmaceutically acceptable carrier" refers to any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid, lipid-containing vesicle, microsphere, liposome encapsulation or other materials known in the art for pharmaceutical preparations. It should be understood that the carrier characteristics will depend on the route of administration for a specific application. As used in the present invention, the term "pharmaceutically acceptable carrier" refers to a non-toxic material that does not interfere with the effect of the pharmaceutical composition according to the present invention or the biological activity of the pharmaceutical composition according to the present invention. It is known in the art to formulate active pharmaceutical ingredients with pharmaceutically acceptable carriers, such as Remington: "The Science and Practice of Pharmacy" (e.g., the 21st edition (2005), and any subsequent editions). Non-limiting examples of pharmaceutically acceptable carriers include: salts (e.g., acid salts / anionic salts, basic salts / cationic salts), excipients, buffers, diluents, solubilizers, tonicity regulators, surfactants, preservatives, isotonic agents, stabilizers and chelating agents. One or more pharmaceutically acceptable carriers can be used to formulate the pharmaceutical composition of the present invention.

[0022] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises an acid salt / anionic salt. Non-limiting examples of acid salts / anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, etopoate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminophenylarsonic acid salt, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiodide.

[0023] In one embodiment of the invention, pharmaceutically acceptable carriers include alkali / cationic salts. Non-limiting examples of alkali / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethamine, or "TRIS"), ammonia, benzathine penicillin, tert-butylamine, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine, N-methyl-D-glucamine, piperidine, potassium, procaine, quinine, sodium, triethanolamine, or zinc.

[0024] In one embodiment of the invention, the pharmaceutically acceptable carrier comprises a buffer. Non-limiting examples of buffers include, but are not limited to, arginine, aspartic acid, bicine, citrate, disodium hydrogen phosphate, fumaric acid, glycine, glycine, histidine, lysine, maleic acid, malic acid, sodium acetate, sodium carbonate, sodium dihydrogen phosphate, sodium phosphate, succinate, tartaric acid, triazine, and tris(hydroxymethyl)aminomethane, and mixtures thereof.

[0025] In one embodiment of the invention, the pharmaceutically acceptable carrier includes a preservative. Non-limiting examples of preservatives include, but are not limited to, benzethonium chloride, benzoic acid, benzyl alcohol, bromonitropropylene glycol, butyl 4-hydroxybenzoate, chlorobutanol, chlorocresol, chlorhexidine, chlorphenesin, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxybenzoate, imidurea, methyl 4-hydroxybenzoate, phenol, 2-phenoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thimerosal, and mixtures thereof.

[0026] In one embodiment of the present invention, pharmaceutically acceptable carriers include isotonic agents. Non-limiting examples of isotonic agents include, but are not limited to, amino acids (such as glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan and threonine), sugar alcohols (such as glycerol, 1,2-propylene glycol, propylene glycol), 1,3-propylene glycol and 1,3-butylene glycol), polyethylene glycol (e.g., PEG400) and mixtures thereof. Another example of isotonic agents includes sugar. Non-limiting examples of sugars can be monosaccharides, disaccharides or polysaccharides, or water-soluble glucans, including, for example, fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, glucan, amylopectin, dextrin, cyclodextrin, α and β-HPCD, soluble starch, hydroxyethyl starch and sodium carboxymethyl cellulose. Another example of isotonic agents is sugar alcohol, wherein the term "sugar alcohol" is defined as a C (4-8) hydrocarbon with at least one -OH group. Non-limiting examples of sugar alcohols include mannitol, sorbitol, inositol, galactitol, hexasol, xylitol, and arabitol.Medicaments comprising each of the isotonic agents listed in this paragraph constitute alternative embodiments of the invention.

[0027] In one embodiment of the present invention, the pharmaceutically acceptable carrier comprises a chelating agent. Non-limiting examples of chelating agents include, but are not limited to, salts of citric acid, aspartic acid, ethylenediaminetetraacetic acid (EDTA), and mixtures thereof.

[0028] In one embodiment of the invention, the pharmaceutically acceptable carrier includes a stabilizer. Non-limiting examples of stabilizers include carboxy- / hydroxycellulose and its derivatives (such as HPC, HPC-SL, HPC-L and HPMC), cyclodextrin, 2-methylthioethanol, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, salts (such as sodium chloride), sulfur-containing substances such as thioglycerol or thioglycolic acid.

[0029] In one embodiment of the invention, the pharmaceutically acceptable carrier comprises one or more surfactants, preferably one surfactant, at least one surfactant or two different surfactants. The term "surfactant" refers to any molecule or ion consisting of a water-soluble portion (hydrophilic) and a fat-soluble portion (lipophilic). For example, the surfactant is selected from: anionic surfactants, cationic surfactants, nonionic surfactants and / or zwitterionic surfactants.

[0030] In one embodiment of the invention, the drug is a liquid formulation. A preferred example of a liquid formulation is an aqueous formulation, i.e. a formulation comprising water. Liquid formulations include, but are not limited to, solutions, suspensions, emulsions, microemulsions or gels. Aqueous formulations typically contain at least 50% w / w of water, or at least 60% w / w, 70% w / w, 75% w / w, 80% w / w, 85% w / w, 90% w / w or at least 95% w / w of water.

[0031] In one embodiment, the drug can be formulated to be injectable, which can be injected, for example, via an injection device (eg, a syringe or an infusion pump). The injection can be delivered, for example, subcutaneously, intramuscularly, intraperitoneally, or intravenously.

[0032] In another embodiment, the drug is a solid preparation, such as a freeze-dried or spray-dried drug, which can be used as is, or a solvent and / or diluent can be added by a physician or patient before use. Solid dosage forms can include tablets, such as compressed and / or coated tablets, and capsules (e.g., hard gelatin capsules or soft gelatin capsules). The pharmaceutical composition can also be in the form of a sachet, dragee, powder, granule, lozenge or powder, for example, for reconstitution.

[0033] The present invention also provides a medicine kit for treating remifentanil hyperalgesia, the medicine kit comprising the above-mentioned pharmaceutical composition, optionally a container and instructions.

[0034] The kit of the present invention comprises separate containers, dividers or compartments for a drug and informational material. For example, the drug may be contained in a bottle, vial or syringe, and the informational material may be contained in conjunction with the container. In some embodiments, the separate elements of the kit are contained in a single, undivided container. For example, the drug is contained in a bottle, vial or syringe (with informational material attached in the form of a label). In some embodiments, the kit comprises a plurality (e.g., a pack) of separate containers, each container comprising an active substance in one or more unit dosage forms (e.g., dosage forms described herein).

[0035] The present invention also provides the use of the DOT1L gene or its encoded protein in screening candidate drugs for treating remifentanil hyperalgesia.

[0036] The present invention also provides a method for screening the use of drugs for preventing or treating opioid-induced hyperalgesia, the method being as follows:

[0037] 1) treating a system expressing or containing the DOT1L gene or its encoded protein with a substance to be screened;

[0038] 2) detecting the expression of the DOT1L gene or its encoded protein in the system;

[0039] When the substance to be screened inhibits the expression level of the DOT1L gene or the protein encoded by it, the substance to be screened is a candidate drug for treating remifentanil hyperalgesia.

[0040] Furthermore, the system is an animal model of remifentanil hyperalgesia. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Figure showing the effect of EPZ5676 on incisional pain sensitivity after remifentanil infusion, where A: paw withdrawal threshold; B: paw withdrawal latency; n = 6; ***P < 0.001, compared with the NS group; $P < 0.05,

[0042] $$$P<0.005, compared with the RI group; two-way ANOVA.

[0043] Figure 2 The graphs show the results of DOT1L expression, where A: immunoblotting graph; B: bar graph. DETAILED DESCRIPTION

[0044] The present invention will be further described in detail below in conjunction with the accompanying drawings and examples. The following examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Simple improvements to the present invention made according to the essence of the present invention all fall within the scope of protection claimed in the present invention.

[0045] Example 1 Study on the correlation between DOT1L expression and remifentanil hyperalgesia

[0046] 1. Experimental materials and experimental procedures (1) Experimental groups:

[0047] Adult male Sprague-Dawley mice, 1 month old, weighing 100-120 g, were purchased from the Experimental Animal Center of the Academy of Military Medical Sciences of the Chinese People's Liberation Army. They were divided into 4 groups (n=6) using a random number table:

[0048] ① Normal saline group (NS group): normal saline with the same volume as remifentanil was continuously infused intraperitoneally for 60 minutes;

[0049] ② Remifentanil + incision pain group (RI group), intraperitoneal infusion of remifentanil 1.2 μg kg -1 ·min -1 A total of 60 min was performed, and the incision pain model was established at the same time;

[0050] ③ Remifentanil + incisional pain + EPZ5676 group (RI + E group): EPZ5676 20 mg / kg (Meilun Biotechnology, Dalian, China) was subcutaneously injected 1 week before remifentanil infusion, and then remifentanil 1.2 μg kg was continuously infused intraperitoneally.-1 ·min -1 A total of 60 min was performed, and the incision pain model was established at the same time;

[0051] ④ Remifentanil + incision pain + saline group (RI + NS group): 1 week before remifentanil infusion, 20 ml / kg of saline was injected subcutaneously, and then remifentanil 1.2 μg kg was continuously infused intraperitoneally. -1 ·min -1 A total of 60 min was performed, and the incision pain model was established at the same time;

[0052] (2) Preparation of incision pain model:

[0053] The mice were anesthetized by inhalation of 2% sevoflurane, and the left hind foot was disinfected. A longitudinal incision of about 1 cm was made from 0.5 cm proximal to the sole to the toe. After the skin was cut, the plantar muscles were lifted with ophthalmic forceps and separated longitudinally to the periosteum, keeping the muscle origin and attachment intact. After pressing to stop bleeding, the skin was sutured with 4-0 silk thread. The incision skin should not overlap, turn inward, or crack. The wound was disinfected with iodine tincture after surgery, and a small amount of erythromycin ointment was applied to prevent infection.

[0054] (3) Behavioral experiments:

[0055] The thermal stimulation paw withdrawal latency (PWL) and mechanical stimulation paw withdrawal threshold (PWT) were measured 24 h before infusion of remifentanil (T0) and 2, 6, 24 and 48 h after infusion was stopped (T1-4). The laboratory temperature was 18-22°C and the environment was quiet. The PWL was measured using a YLS-6B intelligent hot plate instrument (Huaibei Zhenghua Biological Instrument Equipment Co., Ltd.). The time from the right hind foot contacting the hot plate to the occurrence of any reaction such as retraction, tiptoeing, struggling, screaming, or licking the foot was recorded as the PWL. The measurement was repeated three times with an interval of 5 min, and the average value was taken as the PWL (sec). To prevent scalding of the mouse paw, the upper limit of the PWL was set to 20 s. The mice were placed in a 20 cm × 20 cm × 20 cm metal cage. After 30 min, BSEVF3 von Frey fibers (Harvard Apparatus, USA) were used to stimulate the space between the 2nd and 3rd toes of the right hind paw. Vertical pressure was applied and the pressure was recorded when the mice showed a rapid paw withdrawal reaction, licking the right paw, or screaming. The pressure was measured three times with an interval of 5 min and the average value was taken as PWT (g).

[0056] (4) Western Blot:

[0057] After the last behavioral test, the mice were killed, and the L3-6 dorsal root ganglia were taken and the protein expression was determined by Western Blot. The L3-6 dorsal root ganglia tissue was added to the pre-cooled tissue protein lysis buffer and ground into a tissue homogenate. The homogenate was centrifuged at 4°C for 30 minutes, 15000rpm, and the centrifugal radius was 10cm. The supernatant was the total protein of the spinal cord tissue. The membrane protein extraction kit (Thermo, USA) was used to extract membrane proteins according to the instructions. Anti-DOT1L (CST77087S, 1:1000, CST) was used to determine the expression of DOT1L according to the instructions.

[0058] (5) Statistical analysis:

[0059] SPSS18.0 statistical software was used for analysis. Normally distributed quantitative data were expressed as mean ± standard deviation. One-way analysis of variance was used to compare quantitative data of randomized block design, and repeated measurement design analysis of variance was used to compare quantitative data of repeated measurement design. P < 0.05 was considered statistically significant.

[0060] 2. Experimental results

[0061] (1) Remifentanil infusion exacerbates postoperative mechanical and thermal hyperalgesia

[0062] Compared with the normal saline (NS) group, the remifentanil + incisional pain (RI) group received 1.2 μg kg -1 ·min -1 Infusion at a rate of 60 min from 2 h to 48 h resulted in a significant decrease in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) (all P < 0.001, Figure 1 These results show that at 1.2 μg kg -1 ·min -1 Infusion of remifentanil at a rate of 100 μg / cm2 can increase opioid-induced incisional thermal hyperalgesia and mechanical hyperalgesia. The hypersensitivity to incisional thermal and mechanical pain induced by remifentanil infusion and incisional pain model can last from 2 hours to 48 hours.

[0063] (2) Remifentanil infusion and incision increased the expression of DOT1L

[0064] 48 h after the remifentanil and incision pain models, the mice were killed and the dorsal root ganglia were obtained. Western Blot results showed that the expression of DOT1L protein was significantly increased (P<0.001, Figure 2 ). These results indicate that hyperalgesia after remifentanil infusion is associated with increased DOT1L expression.

[0065] (3) Inhibition of DOT1L activity with EPZ5676 can significantly reduce mechanical and thermal hyperalgesia induced by remifentanil incisional pain

[0066] The results are as follows Figure 2 As shown in Figure 2, injection of the DOT1L inhibitor EPZ5676 can reduce the protein expression level of DOT1L (P<0.001, Figure 2 In addition, EPZ5676 could significantly reduce the mechanical hyperalgesia and thermal hyperalgesia induced by remifentanil incisional pain (all P<0.05, Figure 1 ), suggesting the potential analgesic properties of EPZ5676.

[0067] The description of the above embodiments is only used to understand the method and core idea of ​​the present invention. It should be pointed out that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principle of the present invention, and these improvements and modifications will also fall within the scope of protection of the claims of the present invention.

Claims

1. Use of an agent that inhibits DOT1L expression in the preparation of a pharmaceutical composition for treating remifentanil-induced hyperalgesia.

2. The use according to claim 1, characterized in that: The agent for inhibiting DOT1L expression includes substances that reduce the activity of DOT1L protein, reduce the stability of DOT1L gene or protein, downregulate the expression of DOT1L protein, reduce the effective action time of DOT1L protein, or inhibit the transcription and translation of DOT1L gene.

3. The use according to claim 2, characterized in that: The reagents for inhibiting the expression of DOT1L include reagents for inhibiting the expression of DOT1L gene mRNA and reagents for inhibiting the expression level of DOT1L protein.

4. The use according to claim 3, characterized in that: The agent that inhibits the expression level of DOT1L protein is EPZ5676.

5. The use according to claim 1, characterized in that: The hyperalgesia includes thermal hyperalgesia and mechanical hyperalgesia.

6. A pharmaceutical composition for treating remifentanil-induced hyperalgesia, the pharmaceutical composition comprising an effective amount of an agent that inhibits DOT1L expression.

7. The use according to claim 6, characterized in that: The agent that inhibits DOT1L expression is EPZ5676.

8. The use according to claim 6, characterized in that: The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

9. A method for screening a drug for preventing or treating remifentanil-induced hyperalgesia, the method being as follows: 1) treating a system expressing or containing the DOT1L gene or its encoded protein with a substance to be screened; 2) detecting the expression of the DOT1L gene or its encoded protein in the system; When the substance to be screened inhibits the expression level of the DOT1L gene or the protein encoded by it, the substance to be screened is a candidate drug for treating remifentanil hyperalgesia.

10. The use according to claim 9, characterized in that: The system is an animal model of remifentanil-induced hyperalgesia.

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