Application of FABP7 inhibitor in preparation of medicine for treating inflammatory pain

Abstract

The invention discloses application of an FABP7 inhibitor in preparation of a medicine for treating inflammatory pain, and belongs to the technical field of medicines. A complete Freund's adjuvant induced inflammatory pain model is constructed based on KM mice, an FABP7 inhibitor MF6 is given to the inflammatory pain model three days later, and the analgesic effect of the FABP7 inhibitor on the inflammatory pain mice is evaluated through behavioral experiments. Results show that the FABP7 inhibitor can significantly reduce the pain sensitivity of mice with inflammatory pain, which indicates that the FABP7 inhibitor has potential application value in treatment of inflammatory pain and is expected to be developed into a potential therapeutic drug for inflammatory pain.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to the application of FABP7 inhibitors in the preparation of drugs for treating inflammatory pain. Background Art

[0002] Inflammatory pain is a persistent pain caused by tissue damage or chronic inflammation, and is clinically manifested as pain hypersensitivity and spontaneous pain, which seriously affects the quality of life of patients. At present, non-steroidal anti-inflammatory drugs (NSAIDs) and opioid drugs are the main treatment means, but the above treatment methods have side effects such as gastrointestinal damage and addiction, and there is an urgent need to develop new therapeutic drugs.

[0003] Recent studies have shown that astrocytes play a key role in the inflammatory response and pain signal transmission in the central nervous system. In the inflammatory pain model, astrocytes exacerbate neuroinflammation and pain hypersensitivity by releasing pro-inflammatory factors (such as IL-1β, TNF-α) and reactive oxygen species (ROS). Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide the application of FABP7 inhibitors in the preparation of drugs for treating inflammatory pain.

[0005] The purpose of the present invention is achieved by the following technical solutions:

[0006] A drug for treating inflammatory pain, comprising an FABP7 inhibitor.

[0007] Further, the FABP7 inhibitor is MF6, and the structural formula is:

[0008]

[0009] The application of FABP7 inhibitors in the preparation of drugs for treating inflammatory pain.

[0010] Further, the treatment of inflammatory pain includes increasing the pain threshold of inflammatory pain.

[0011] Further, the drug further comprises a pharmaceutically acceptable lipid nanoparticle carrier.

[0012] Further, the dosage form of the drug is tablets, granules, capsules or injections. Further, the FABP7 inhibitor is MF6, and the structural formula is:

[0013]

[0014] A method for constructing a mouse model, comprising the following steps:

[0015] Step 1: Select experimental animal mice and conduct experimental grouping. The experimental grouping is as follows:

[0016] Saline group: 40 μl of saline was injected into the plantar surface, and 0.1 ml of saline was used for gavage for three consecutive days.

[0017] Inflammatory pain group: 40 μl of CFA was injected into the plantar surface, and 0.1 ml of saline was used for gavage for three consecutive days.

[0018] Inflammatory pain treatment group: 40 μl of CFA was injected into the plantar surface, and 0.1 ml of MF6 was used for gavage for three consecutive days.

[0019] Step 2: Prepare for pain threshold detection of experimental animals. Behavioral tests were conducted before pain threshold detection. The behavioral tests were carried out in a double-blind manner. Before the behavioral tests, all mice were allowed to acclimatize to the test environment for 1 hour.

[0020] Step 3: Conduct pain threshold detection, which includes mechanical pain test and thermal pain test, and finally obtain experimental data.

[0021] Furthermore, the mechanical pain test includes using two calibrated von Frey filaments. The 0.07 g Von Frey filament representing low-intensity stimulus-evoked pain and the 0.4 g Von Frey filament representing high-intensity stimulus-induced hyperalgesia were respectively selected to apply stimuli to the central skin of the plantar surface of the left hind limb of the mouse. After the filament vertically penetrated the grid holes, the filament was evenly forced to bend into a "C" shape, and the stimulation application time lasted about 1.5 seconds. It was repeated 10 times, with an interval of more than 5 minutes between each stimulation. The paw withdrawal response of the mouse was observed and recorded, and the paw withdrawal frequency of the mouse under different stimulation intensities was calculated.

[0022] Furthermore, for the thermal pain test, the central skin of the posterior plantar surface of the mouse was irradiated with a heat radiation instrument, and the irradiation duration from the start to when the mouse lifted its foot or licked the plantar surface was recorded. It was repeated 5 times, with an interval of more than 10 minutes between each irradiation. The average value of the 5 irradiation times was taken as the thermal paw withdrawal latency.

[0023] Advantages of the present invention:

[0024] Through the application of the FABP7 inhibitor MF6 in the inflammatory pain model, experiments show that it can significantly reduce pain-like behaviors in diseased mice and inhibit the upregulation of the FABP7 molecule, providing a new strategy for the treatment of inflammatory pain. Description of the Drawings

[0025] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0026] Figure 1 : Effect of MF6 on the pain threshold of inflammatory pain mice;

[0027] Figure 2 : The molecular formula of MF6. Specific implementation manner

[0028] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0029] Example 1

[0030] Evaluate the effect of the FABP7 inhibitor MF6 on the pain threshold of inflammatory pain.

[0031] Experimental animals: KM male mice aged 8 - 10 weeks, with a body weight of 25 - 30 g. All mice lived in a breeding cage with free access to food and water, and the light was controlled for a 12 - hour day and night cycle.

[0032] Experimental grouping: normal saline group (control group, n = 8), CFA + solvent control (inflammatory pain group, n = 8), CFA + MF6 (inflammatory pain treatment group, n = 8). The above are all CFA model mice.

[0033] Normal saline group: Inject 40 μl of normal saline into the plantar surface, and intragastrically administer 0.1 ml of normal saline for three consecutive days;

[0034] Inflammatory pain group: Inject 40 μl of CFA into the plantar surface, and intragastrically administer 0.1 ml of normal saline for three consecutive days;

[0035] Inflammatory pain treatment group: Inject 40 μl of CFA into the plantar surface, and intragastrically administer 0.1 ml of MF6 for three consecutive days.

[0036] The experimental model is: an inflammatory pain model induced by complete Freund's adjuvant.

[0037] The CFA model is a pain model that uses complete Freund's adjuvant to form local inflammation in tissues to induce inflammatory pain. The model construction method is as follows: expose the left hind limb of the mouse, and the model group is subcutaneously injected with complete Freund's adjuvant, while the control group is injected with normal saline.

[0038] Animal treatment: The saline group (control group, n = 8), CFA + vehicle control (inflammatory pain group, n = 8), and CFA + MF6 (inflammatory pain treatment group, n = 8) were completed. Among them, 40 μL of CFA was injected into the left plantar surface of the mice to obtain mice with an inflammatory pain model induced by complete Freund's adjuvant. The control group of mice was injected with an equal volume of normal saline into the plantar surface. After the injection, the needle was stopped for a moment and the mice were put back into the original cage for breeding. From the day after surgery, the inflammatory pain model mice were treated with MF6 by gavage for three consecutive days. Pain threshold detection was performed four days later.

[0039] Behavioral tests: Behavioral tests were conducted in a double-blind manner. Before the basic behavioral tests, all mice were acclimated to the test environment for 1 hour.

[0040] Mechanical pain test: Two calibrated von Frey filaments (0.07 g and 0.4 g) were used. The 0.07 g and 0.4 g von Frey filaments were applied to the plantar surface of the two hind paws 10 times respectively. A quick paw withdrawal was considered a positive response. The number of positive responses in the 10 applications was recorded as PWF [(number of paw withdrawals / 10 trials) × 100 = % response frequency].

[0041] Thermal pain test: The paw withdrawal latency (PWL) to noxious heat stimulation was tested using an analgesia meter model 336 (IITC336 analgesia meter). The mice were placed in a plexiglass chamber on a glass plate, and a beam of noxious light (heat) was applied to the middle plantar surface of each hind paw. When the paw was quickly lifted, the light beam was automatically turned off. The time from the start to the stop represented the paw withdrawal latency (PWL). Five trials were performed at 5-minute intervals. A cutoff time of 20 seconds was used to avoid tissue damage to the paw.

[0042] The results are as Figure 1 shown. Administration of MF6 can increase the pain threshold of mice with inflammatory pain, indicating that the FABP7 inhibitor can relieve pain-like behaviors in mice with inflammatory pain.

[0043] Figure 1 In Sal+veh: saline group, CFA+veh: inflammatory pain group, CFA+MF6: inflammatory pain treatment group; PWF: (number of foot withdrawals / 10 trials) X100 = % response frequency; PWL: time from the start of irradiating the middle of the mouse's plantar surface with noxious light to paw withdrawal; Figure 1 In A: irradiating the mouse's plantar surface with noxious light, time from the start of irradiation to the mouse's paw withdrawal; Figure 1 In B: frequency of paw withdrawal in mice after stimulating the middle of the mouse's plantar surface with a 0.07 g Von Frey filament; Figure 1 In C: frequency of paw withdrawal in mice after stimulating the middle of the mouse's plantar surface with a 0.4 g Von Frey filament.

[0044] Unless otherwise specified, the reagents or instruments used in the present invention are commercially available.

[0045] In the description of this specification, the descriptions referring to the terms "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0046] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and the descriptions in the specification only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed.

Claims

1. A drug for treating inflammatory pain, characterized in that, Comprising an FABP7 inhibitor.

2. The drug for treating inflammatory pain according to claim 1, wherein The FABP7 inhibitor is MF6, and its structural formula is:

3. Use of an FABP7 inhibitor in the preparation of a drug for treating inflammatory pain.

4. Use of the FABP7 inhibitor according to claim 3 in the preparation of a medicament for treating inflammatory pain, characterized in that, The treatment of inflammatory pain includes increasing the pain threshold of inflammatory pain.

5. Use of the FABP7 inhibitor according to claim 3 in the preparation of a medicament for treating inflammatory pain, characterized in that, The drug further comprises a pharmaceutically acceptable lipid nanoparticle carrier.

6. Use of the FABP7 inhibitor according to claim 3 in the preparation of a medicament for treating inflammatory pain, characterized in that, The dosage form of the drug is tablets, granules, capsules or injections.

7. Use of the FABP7 inhibitor according to claim 3 in the preparation of a medicament for treating inflammatory pain, characterized in that, The FABP7 inhibitor is MF6, and its structural formula is:

8. A method for constructing a mouse model, characterized in that, Comprising the following steps: Step 1: Select experimental animal mice and conduct experimental grouping. The experimental grouping is as follows: Saline group: Inject 40 μl of saline into the plantar surface, and gavage with 0.1 ml of saline for three consecutive days. Inflammatory pain group: Inject 40 μl of CFA into the plantar surface, and gavage with 0.1 ml of saline for three consecutive days. Inflammatory pain treatment group: Inject 40 μl of CFA into the plantar surface, and gavage with 0.1 ml of MF6 for three consecutive days. Step 2: Prepare for pain threshold detection of the experimental animals. Conduct a behavioral test before the pain threshold detection. The behavioral test is carried out in a double-blind trial manner. Before the behavioral test, allow all mice to adapt to the test environment for 1 hour. Step 3: Conduct pain threshold detection. The pain threshold detection includes mechanical pain test and thermal pain test, and finally obtain experimental data.

9. The method for constructing a mouse model according to claim 8, wherein The mechanical pain test includes using two calibrated von Frey filaments. Select the 0.07 g Von Frey filament representing low-intensity stimulus-induced pain and the 0.4 g Von Frey filament representing high-intensity stimulus hyperalgesia to apply stimuli to the central skin of the plantar surface of the left hind limb of the mouse. After the filament vertically penetrates the grid holes, apply force evenly to bend the filament into a "C" shape. The stimulation application time lasts for about 1.5 seconds, repeat 10 times, with an interval of more than 5 minutes between each stimulation. Observe the paw withdrawal response of the mouse and record it, and calculate the paw withdrawal frequency of the mouse under different stimulation intensities.

10. The method for constructing a mouse model according to claim 8, wherein The thermal pain test irradiates the central skin of the posterior plantar surface of the mouse with a thermal radiation instrument, record the irradiation duration from the start to when the mouse lifts its paw or licks the plantar surface, repeat 5 times, with an interval of more than 10 minutes between each irradiation, and take the average value of the 5 irradiation times as the thermal paw withdrawal latency.

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