Maged1 competitive short peptides and uses thereof

Abstract

The application belongs to the technical field of short peptide medicine, and specifically discloses a Maged1 competitive short peptide and application thereof.The Maged1 competitive short peptide is short peptide MP1 or short peptide MP2, and the amino acid sequence is shown as SEQ ID No.1 or SEQ ID No.2.Experiments prove that the Maged1 competitive short peptide can compete with Maged1 to combine with P2X3 receptors, thereby inhibiting the activation of Maged1 on P2X3 receptors, and has a good clinical application prospect in the treatment of chronic pain.

Description

Technical Field

[0001] This invention belongs to the field of short peptide pharmacology technology, specifically relating to the Maged1 competitive short peptide and its applications. Background Technology

[0002] Chronic pain is defined as persistent or intermittent pain lasting more than three months. It is one of the most common clinical symptoms, often accompanied by psychological distress such as anxiety, depression, insomnia, and functional impairment. Currently, the main clinical treatment for chronic pain is medication. However, most of these drugs act on the central nervous system, frequently causing a range of adverse reactions. For example, experimental and clinical studies have shown that opioids acting through opioid receptors expressed in both the central and peripheral nervous systems can lead to respiratory depression, sedation, dizziness, drowsiness, tolerance, and dependence, among other side effects. In contrast, opioids that target only opioid receptors in the peripheral nervous system produce significant analgesic and anti-inflammatory effects without centrally mediated side effects. Therefore, from a clinical safety perspective, selectively targeting the peripheral nervous system yields a safer therapeutic effect.

[0003] Dorsal root ganglion (DRG) neurons, as primary sensory neurons in the peripheral sensory afferent pathway, possess a typical pseudounipolar structure. The molecular structure within DRG neurons is complex and variable during pain generation. The DRG neuronal cell membrane expresses various pain-related ion channels, such as voltage-gated Nav1.7-1.9, M-type potassium channels, L, N, and T-type calcium channels, and ligand-gated GABA. A Ion channels such as receptors, P2X3 receptors, and TRPV1 channels. Changes in the function, transcription, translation, or modification of these ion channels during pain directly affect the permeability of cell membrane-related ions, thereby regulating the excitability of DRG neuron cell bodies. Studies have shown that the formation of chronic pathological pain depends on the excessive and sustained excitation of DRG neuron cell bodies, and inhibiting neuronal cell body excitability can effectively alleviate peripheral pain. The functional state of ion channels is a crucial factor in the regulation of peripheral pain sensitization (Dawes JM, et al., 2018). Therefore, identifying pain-related factors that regulate the functional state of ion channels within DRG neurons has become an important research direction for elucidating the peripheral mechanisms of pain and for the development of analgesic drugs.

[0004] It has been shown that the modulation of P2X3 receptor affects the transmission of pain signals, P2X3 receptor in DRG is an important regulatory ion channel for peripheral pain, and the activation of P2X3 receptor promotes the transmission of nociceptive signals from the periphery to the spinal cord (Wu YY, et al., 2023). The British "Nature" magazine reported that P2X3 receptor mediates the transmission of neuropathic pain. When stimulated by neuropathic pain, the expression of P2X3 receptor increases, and the P2X3 receptor-mediated ATP-activated gating channel current of sensory neurons is significantly enhanced; the application of P2X3 receptor antisense oligonucleotide and RNA interference technology can down-regulate the P2X3 receptor level of the dorsal root ganglion of the inflammatory pain rat model, and then significantly reduce the nociceptive response of the rat foot caused by P2X3 receptor agonist α, β-meATP and formalin. The inventors' previous work has also shown that melanoma-associated antigen family D1 protein (Maged1) is involved in the regulation of peripheral pain and can act as an endogenous agonist of P2X3, therefore, the development of short peptides that can competitively bind P2X3 receptor with Maged1 is of great significance for analgesia. SUMMARY

[0005] The purpose of the present application is to provide a Maged1 competitive short peptide and its application, which can competitively bind P2X3 receptor with Maged1, thereby inhibiting the activation of Maged1 on P2X3 receptor, and has a broad application prospect in the clinical treatment of chronic pain.

[0006] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0007] In a first aspect, the present application provides a Maged1 competitive short peptide, which is short peptide MP1 or short peptide MP2, wherein the amino acid sequence of short peptide MP1 is shown as SEQ ID No. 1, and the amino acid sequence of short peptide MP2 is shown as SEQ ID No. 2:

[0008] SEQ ID No. 1: Gly-Arg-Tyr-Ala-Asn-Arg-Val-Met-Asp-Val-Ser;

[0009] SEQ ID No. 2: Glu-Val-Asp-Thr-Val-Glu-Met-Pro-Ile-Met.

[0010] In a second aspect, the present application provides the use of the above-mentioned Maged1 competitive short peptide as an active ingredient in the preparation of a drug for treating chronic pain.

[0011] Further, the chronic pain is peripheral chronic pain or spontaneous pain induced by human hMaged1.

[0012] Further, the peripheral chronic pain is chronic inflammatory pain or neuropathic pain.

[0013] In a third aspect, the present application provides a medicine for treating chronic pain, comprising the Maged1 competitive short peptide MP1 or MP2.

[0014] Further, the medicine further comprises a pharmaceutical excipient.

[0015] Further, the medicine is an injection or an oral preparation.

[0016] The present application has the following beneficial effects:

[0017] (1) The Maged1 competitive short peptide has good safety, and its target is P2X3 receptor. The peripheral administration of the Maged1 competitive short peptide achieves the effect of treating chronic pain, and avoids the risk of a series of adverse reactions such as tolerance, dependence, gastrointestinal disorders, respiratory depression and hyperalgesia of existing analgesics, and has a better clinical application prospect.

[0018] (2) The patch clamp experiment proves that the hMaged1 can directly activate the P2X3 receptor and induce inward current; the Maged1 competitive short peptide MP1 or MP2 can inhibit the P2X3 current induced by hMaged1; the chronic inflammatory pain model (CFA model) of mice, the neuropathic pain animal model and the chronic constriction injury (CCI) model of sciatic nerve prove that the short peptide MP1 or MP2 can relieve peripheral chronic pain; in addition, the examples prove that the short peptide MP1 or MP2 can relieve the spontaneous pain induced by hMaged1. The present application provides a theoretical basis for the application of the short peptide MP1 or MP2 to the clinical treatment of chronic pain.

[0019] (3) The synthesis raw materials of the Maged1 competitive short peptide are common amino acids, which are easy to purchase and low in price, and the synthesis cost is low; the synthesis method is convenient and easy to operate, and can be synthesized in large quantities and purified easily. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 Effects of chronic pain on the expression and secretion of Maged1 in dorsal root ganglion (DRG), wherein, Figure 1 A is the result of Western blot of protein disulfide isomerase (PDI) protein in dorsal root ganglion of mice treated with Freund's complete adjuvant (CFA); Figure 1 B is Figure 1 Results of part A (two-sample t-test, P>0.05); Figure 1C represents the change in the RNA transcription level of Maged1 in the dorsal root ganglion after injection of Freund's complete adjuvant (CFA) using real-time quantitative polymerase chain reaction (qPCR) (two-sample t-test, P>0.05, sample size n = 11 per group). Figure 1 D represents the detection of Maged1 secretion in the dorsal root ganglia after injection of Freund's complete adjuvant (CFA) using enzyme-linked immunosorbent assay (ELISA). The results were as follows: Day 3: 0.14468±0.0122 in the control group and 0.29833±0.03671 in the experimental group (n = 6 samples per group); Day 5: 0.15767±0.02138 in the control group and 0.34547±0.0325 in the experimental group (n = 6 samples per group); Day 7: 0.17066±0.02862 in the control group and 0.38375±0.05622 in the experimental group (n = 6 samples per group). A two-sample t-test was performed. P<0.05, P<0.01).

[0021] Figure 2 The effects of Maged1 gene knockout on chronic inflammation and neuropathic pain, among which, Figure 2 A represents the mechanical threshold in the inflammatory CFA model for control WT mice and Maged1 gene knockout mice. P<0.01, P<0.05); Figure 2 B represents the thermal pain threshold in the control WT mice and Maged1 gene knockout mice in the inflammatory CFA model. Figure 2 C represents the thermal pain threshold in the control WT mice and Maged1 gene knockout mice in the CCI model of neuropathic pain. Figure 2 D represents the mechanical threshold in the control WT mice and the Maged1 gene knockout mice in the CCI model of neuropathic pain.

[0022] Figure 3 A typical diagram for electrophysiological recording of hMaged1 and α,β-meATP (P2X3 receptor agonist)-induced P2X3 current ( Figure 3 A) and current statistics ( Figure 3 B).

[0023] Figure 4 This is a schematic diagram of the predicted binding site of Maged1 to the P2X3 receptor using HDOCK 2.4 molecular docking software.

[0024] Figure 5 Typical electrophysiological recordings under different treatment conditions ( Figure 5 A) and current statistics (Figure 5 B).

[0025] Figure 6 Fig. 6 shows the changes of the mechanical pain threshold of mice under different treatment conditions in different pain models, wherein, Figure 6 A shows the changes of the mechanical pain threshold of mice under different treatment conditions in CFA model; Figure 6 B shows the changes of the thermal pain threshold of mice under different treatment conditions in CFA model; Figure 6 C shows the changes of the mechanical pain threshold of mice under different treatment conditions in CCI model; Figure 6 D shows the changes of the thermal pain threshold of mice under different treatment conditions in CCI model.

[0026] Figure 7 Fig. 7 shows the changes of the licking time of mice under different treatment conditions. DETAILED DESCRIPTION

[0027] The present application will be further described below in conjunction with the examples and the accompanying drawings, but the description of the examples does not impose any limitation on the scope of protection of the present application.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application.

[0029] The substances or instruments used in the following examples can be obtained from conventional commercial channels unless otherwise specified.

[0030] Example 1 Maged1 is involved in the regulation of peripheral pain

[0031] To prove that Maged1 is involved in the regulation of peripheral pain, the expression of Maged1 in DRG under pathological state of pain was detected in this example.

[0032] 1. Measurement of the protein expression level of Maged1 in DRG of wild type (WT) mice injected with CFA

[0033] CFA and normal saline were injected into the left and right hind paws of mice, respectively. The L3-L5 DRGs of mice were extracted on the 7th day after injection of CFA, and the results of immunoblotting analysis showed that there was no significant change in the protein level of Maged1 in DRGs treated with CFA (Fig. 1A and Fig. 1B). Figure 1 A and Figure 1 B), and the results of real-time fluorescent quantitative PCR also showed that there was no significant change in the RNA transcription level of Maged1 in DRGs treated with CFA (Fig. 1C). Figure 1 C).

[0034] 2. Secretion changes of Maged1 in the periphery after CFA injection in mice were determined

[0035] The ipsilateral L3-L5 DRGs of control mice injected with saline and experimental mice injected with CFA were extracted on day 3, 5, 7, respectively, and their secretion was determined by ELSA experiment (day 3, 0.14468 ± 0.0122 vs 0.29833 ± 0.03671, n = 6, 6; day 5, 0.15767 ± 0.02138 vs 0.34547 ± 0.0325, n = 6, 6; day 7, 0.17066 ± 0.02862 vs 0.38375 ± 0.05622, n = 6, 6), and the results showed that the secretion of Maged1 protein in the DRGs of the CFA-treated side was significantly increased (P < 0.05, post hoc t-test). Figure 1 D}.

[0036] The above results show that the secretion level of Maged1 in the DRGs is significantly increased under the pathological state of pain.

[0037] Next, the CRISPR / Cas9 technology was used to purchase Maged1 (Maged-KO) knockout mice, and the effect of Maged1 gene knockout on peripheral pain behavior in mice was observed.

[0038] First, the basic response threshold of Maged-KO mice to mechanical and thermal stimulation was detected. The experimental results showed that compared with the control wild type (WT), the basic response threshold of Maged1-KO mice to mechanical or thermal stimulation did not show significant difference (post hoc t-test, P > 0.05). The CFA model of chronic inflammation and the CCI model of chronic compression injury of rat sciatic nerve were established, and the behavior test was performed on day 1, 3, 5, 7, 10, 14 after the model was established, to explore the role of Maged1 in chronic pain.

[0039] The results of the behavior experiment of the CFA model mice showed that the strong mechanical hyperalgesia induced by CFA injection in mice was alleviated after Maged1 gene knockout (Fig. 1A). Figure 2 A), and the thermal hyperalgesia induced by CFA injection was also significantly alleviated in Maged1 knockout mice (Fig. 1B). Figure 2 B). The results of the behavior experiment of the CCI model mice showed that the CCI model induced mechanical and thermal hyperalgesia in mice, and the mechanical and thermal pain thresholds of Maged1 knockout mice were significantly increased compared with WT mice (Fig. 2C and 2D). Figure 2 C and 2D).

[0040] The above results indicate that specifically knocking down Maged1 in mouse DRG neurons and using Maged1 gene knockout mice can significantly alleviate chronic inflammation and neuropathic pain in mice.

[0041] Example 2: Effect of Maged1 on P2X3 receptor

[0042] 1. Cell Culture and Transfection

[0043] HEK293T cells were cultured in DMEM medium containing 10% fetal bovine serum; the P2X3 plasmid was transfected into HEK293T cells using a standard transfection method.

[0044] 2. Patch-clamp electrophysiological recording

[0045] Current clamp recording was performed at room temperature.

[0046] Electrode drawing: Insert a thin-walled borosilicate glass electrode with an outer diameter of 1.50 mm and an inner diameter of 1.14 mm into a horizontal drawing instrument, draw for 3 cycles, and polish with a polishing instrument to make the electrode liquid resistance 2-3 MΩ;

[0047] Recording mode: Whole-cell perforated patch-clamp, using amphotericin B as the perforating agent, recording was performed when the Ra value reached 10⁻¹⁵ MΩ. An Axon patch-clamp recording system was used, in gap-free mode, with a sampling frequency of 5000 Hz.

[0048] Extracellular fluid composition (unit: mM): 160 NaCl, 2.5 KCl, 5 CaCl2, 1 MgCl2, 10 HEPES, 8 Glucose;

[0049] Electrode internal solution composition (unit: mM): 140 KCl, 2 MgCl2, 10 Hepes, 2 Mg-ATP, pH 7.4; osmotic pressure adjusted to 290-300 mOsm.

[0050] 3. Experimental Procedure

[0051] Record the basal currents of HEK293T cells transfected with P2X3 plasmid in an untreated state;

[0052] Recombinant human hMaged1 protein was perfused, and changes in inward current were observed and recorded.

[0053] 4. Results

[0054] like Figure 3 The image shown is a typical diagram of electrophysiological recordings of hMaged1 and α,β-meATP (P2X3 receptor agonist)-induced P2X3 currents. Figure 3A) and current histogram (B) Figure 3 B)

[0055] After perfusion of recombinant human hMagedl protein, the transfected P2X3 plasmid HEK293T cells produced obvious inward current, indicating that human hMagedl can directly activate P2X3 receptor, and Magedl can act as an endogenous agonist of P2X3.

[0056] Example 3 Preparation of Magedl competitive short peptides MP1 and MP2

[0057] First, the HDOCK 2.4 molecular docking software was used to predict the binding site of Magedl and P2X3 receptor, and short peptides were designed based on specific amino acid sites (P2X3 receptor 73th amino acid site and P2X3 receptor 161th amino acid site) Figure 4 ), wherein the short peptide MP1 is designed according to the 73th amino acid site of P2X3 receptor, and the amino acid sequence is shown as SEQ ID No. 1: Gly-Arg-Tyr-Ala-Asn-Arg-Val-Met-Asp-Val-Ser, and the molecular weight is 1267.41; the short peptide MP2 is designed according to the 161th amino acid site of P2X3 receptor, and the amino acid sequence is shown as SEQ ID No. 2: Glu-Val-Asp-Thr-Val-Glu-Met-Pro-Ile-Met, and the molecular weight is 1163.4 g / mol.

[0058] Synthesis of Magedl competitive short peptides MP1 and MP2 includes the following steps:

[0059] (1) The Fmoc solid-phase synthesis method was used to synthesize the target amino acid sequence on the resin, specifically:

[0060] (1-1) The solid-phase carrier wang resin in Fmoc solid-phase synthesis was placed in dichloromethane for swelling for at least 30 minutes;

[0061] (1-2) An appropriate amount of 20% hexahydropyridine N, N-dimethylformamide solution was added to the pretreated wang resin for reaction for 20 min to deprotect the resin amino group; after the reaction was completed, the resin was eluted with N, N-dimethylformamide for 3 times, 5 min each time; and the ninhydrin was used to detect whether the amino group on the resin was completely deprotected;

[0062] (1-3) Under an inert gas atmosphere, a Fmoc solid-phase synthesis condensing agent N, N-diisopropylethylamine / 1-hydroxybenzotriazole / O-benzotriazol-tetramethylurea hexafluorophosphate is added to the resin, and then amino acids are sequentially added from the first amino acid at the C-terminal end of the peptide sequence; all amino acids are sequentially condensed on the peptide resin according to the target peptide sequence (the order of short peptide MP1: Gly-Arg-Tyr-Ala-Asn-Arg-Val-Met-Asp-Val-Ser, the order of short peptide MP2: Glu-Val-Asp-Thr-Val-Glu-Met-Pro-Ile-Met) to obtain a crude peptide resin; wherein the amount of amino acid is 1.5-3 times the amount of substance of the peptide resin, and the amino acid condensation time is 1-1.5 h; the amount of solid-phase synthesis condensing agent used is 3-6 times the amount of resin;

[0063] (2) The target compound is obtained by cleavage reagent cleavage, freeze-drying and preparation column purification, in particular:

[0064] (2-1) The crude peptide resin is treated with a cleavage reagent, which includes trifluoroacetic acid (TFA), triisopropylsilane (TIS) and double distilled water (H2O) in a ratio of 95:2.5:2.5; after the reaction is completed, the mixture is spin-dried; the mixture is extracted with diethyl ether to remove unreacted TFA; the extracted liquid is freeze-dried to obtain a crude peptide;

[0065] (2-2) The crude peptide obtained in step (2-1) is swelled with dichloromethane and compressed with anhydrous methanol for multiple times to further purify the peptide chain;

[0066] (2-3) The treated peptide chain is freeze-dried; reverse phase high performance liquid chromatography (RP-HPLC) is used for preparation column purification, and finally the target compounds Maged1 competitive short peptides MP1 and MP2 are obtained.

[0067] Example 4: Patch clamp electrophysiological experiment verifies that Maged1 competitive short peptides MP1 and MP2 can inhibit Maged1-induced P2X3 current

[0068] Cell culture and transfection, and patch clamp electrophysiological recording are the same as in Example 2.

[0069] MP1 or MP2 short peptides are used in combination with hMaged1 protein, respectively, and the changes in inward current are observed and recorded;

[0070] As a control, the changes of inward current were observed and recorded after perfusion of MP3 or MP4 short peptides in combination with hMagedl protein (MP3 short peptide is a control short peptide designed at the 198th and 208th amino acid sites of P2X3 receptor, with the sequence of Asn-Leu-Thr-Asp-Lys-Asp-Ile-Lys-Lys-Cys-Arg-Phe-His-Pro-Glu-Lys-Ala-Pro-Phe-Cys (SEQ ID No. 3); MP4 short peptide is a control short peptide designed at the 125th amino acid site of P2X3 receptor, with the sequence of Gln-Cys-Gly-Pro-Glu-Arg-Phe-Pro-Gly-Gly (SEQ ID No. 4)).

[0071] As shown in Figure 5 , no changes of inward current were observed after perfusion of MP1 or MP2 short peptides in combination with hMagedl protein; the changes of inward current after perfusion of MP3 and MP4 short peptides in combination with hMagedl protein were similar to those when hMagedl protein was perfused alone.

[0072] The above results show that MP1 and MP2 short peptides have inhibitory effect on the function of P2X3 receptor, while MP3 and MP4 short peptides as control groups do not show significant influence.

[0073] Example 5 Verification experiment of Magedl competitive short peptides MP1 and MP2 for relieving peripheral chronic pain

[0074] 1. Establishing CFA-induced chronic inflammatory pain model

[0075] The mice were subcutaneously injected with Freund's complete adjuvant CFA (25 μL) on the right hind paw.

[0076] 2. Establishing CCI-induced neuropathic pain model

[0077] The mice were anesthetized, placed in a prone position on the operating table, and after shaving and disinfection, the skin and superficial fascia along the surface of the sciatic nerve were cut, the biceps brachii was bluntly separated, the sciatic nerve was exposed and separated, 4 knots were made on the sciatic nerve with a 40-gauge sheep gut, the muscle layer and skin layer were sutured, iodine was evenly applied to the sutured part, penicillin was injected into the left hind leg muscle, and the mice were placed in a cage for sufficient water and food.

[0078] The control group was subjected to sham operation (sutured after operation to expose the sciatic nerve).

[0079] 3. Mechanical pain threshold test method

[0080] The same concentration of short peptides MP1, MP2, MP3, and MP4 were injected into the paw of CFA model mice or CCI model mice, and mice without injection of any liquid were used as the control group (NS group). After injection, the mice were placed on a transparent glass plate and covered with a plastic transparent box, and after the mice were quiet for more than half an hour, the intensity of the thermal pain instrument was adjusted to 15%, and the right paw of the mouse was irradiated with the infrared laser of the thermal pain instrument. The phenomenon of the mouse suddenly lifting or licking its foot was considered a positive reaction, and the latency time of the mouse producing a positive reaction displayed by the thermal pain instrument was recorded (measured in seconds). Each animal was tested 5 times, and the average of the 5 results was taken as the thermal pain threshold (the interval between two tests for each animal was 60 seconds).

[0081] 4. Thermal pain threshold test method

[0082] The same concentration of short peptides MP1, MP2, MP3, and MP4 were injected into the paw of CFA model mice or CCI model mice, and mice without injection of any liquid were used as the control group (NS group). After injection, the mice were placed on a transparent glass plate and covered with a plastic transparent box, and after the mice were quiet for more than half an hour, the intensity of the thermal pain instrument was adjusted to 15%, and the right paw of the mouse was irradiated with the infrared laser of the thermal pain instrument. The phenomenon of the mouse suddenly lifting or licking its foot was considered a positive reaction, and the latency time of the mouse producing a positive reaction displayed by the thermal pain instrument was recorded (measured in seconds). Each animal was tested 5 times, and the average of the 5 results was taken as the thermal pain threshold (the interval between two tests for each animal was 60 seconds).

[0083] 5. Test results

[0084] As shown in Figure 6 A and Figure 6 B, after injection of short peptides MP1 or MP2 into the paw, mechanical and thermal hyperalgesia in the CFA-induced chronic inflammatory pain model were significantly alleviated; as shown in Figure 6 C and Figure 6 D, after injection of short peptides MP1 or MP2 into the paw, mechanical and thermal hyperalgesia in the CCI-induced neuropathic pain model were significantly alleviated.

[0085] Example 6 Verification experiment of Maged1 competitive short peptides MP1 and MP2 alleviating hMaged1-induced spontaneous pain

[0086] 1. Drug injection

[0087] Five solutions were prepared: hMagedl solution (200 μM); hMagedl and MP1 (200 μM) complex solution (5 μL); hMagedl and MP2 (200 μM) complex solution (5 μL); hMagedl and MP3 (200 μM) complex solution (5 μL); hMagedl and MP4 (200 μM) complex solution (5 μL) (MP3 short peptide is a control short peptide designed for P2X3 receptor at 198 and 208 amino acid sites, sequence is Asn-Leu-Thr-Asp-Lys-Asp-Ile-Lys-Lys-Cys-Arg-Phe-His-Pro-Glu-Lys-Ala-Pro-Phe-Cys; MP4 short peptide is a control short peptide designed for P2X3 receptor at 125 amino acid sites, sequence is Gln-Cys-Gly-Pro-Glu-Arg-Phe-Pro-Gly-Gly).

[0088] The above solutions were injected into the right hind paw of mice, respectively, and mice without injection of any solution were used as controls (NS group).

[0089] 2. Behavior test

[0090] The injected mice were placed in an acrylic transparent box to ensure enough space for each mouse to move. A camera was used to take pictures of the mouse's foot area for 40 minutes. Later video analysis recorded the time of the mouse licking its feet as the time of spontaneous pain.

[0091] 3. Results

[0092] As shown in Figure 7 , mice injected with hMagedl (200 μM) alone showed significant spontaneous pain behavior, with frequent licking of the feet; after injection of hMagedl and MP1 or MP2 (200 μM) complex, the licking time of mice was significantly reduced, indicating that MP1 and MP2 can effectively inhibit hMagedl-induced spontaneous pain.

Claims

1. A Maged1 competitive short peptide, characterized in that, The competitive short peptide of Maged1 is either short peptide MP1 or short peptide MP2, wherein the amino acid sequence of short peptide MP1 is shown in SEQ ID No. 1 and the amino acid sequence of short peptide MP2 is shown in SEQ ID No.

2.

2. The use of the Maged1 competitive short peptide of claim 1 as an active ingredient in the preparation of a medicament for treating chronic inflammatory pain, neuropathic pain, and hMaged1-induced spontaneous pain.

3. A medicament for treating chronic inflammatory pain, neuropathic pain, and hMaged1-induced spontaneous pain, characterized in that, It contains the Maged1 competitive short peptide as described in claim 1.

4. The drug according to claim 3, characterized in that, The drug also includes pharmaceutical excipients.

5. The drug according to claim 4, characterized in that, The drug is an injectable or oral preparation.

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