Application of dexmedetomidine in preparation of medicine for promoting morphine addiction fading
By using dexmedetomidine to inhibit the activation of the VTA-NAc dopamine system, it solves the problem of limited effectiveness of existing opioid addiction treatment methods, achieves significant addiction elimination effects, and is safe and feasible.
Patent Information
- Application Number
- CN202411177094.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-26
- Publication Date
- 2025-01-21
AI Technical Summary
The existing treatments for opioid addiction are limited in effect, and common drug treatments have side effects and risks of drug dependence, and the long-term efficacy is not ideal and the recurrence rate is high.
Dexmedetomidine is used as a new drug to promote the resolution of morphine addiction by inhibiting morphine-induced activation of the VTA-NAc dopamine system.
Dexmedetomidine can significantly promote the subsidence of morphine addiction in a short period of time without any obvious adverse reactions. It is safe and feasible and improves the compliance and effectiveness of clinical application.
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Figure CN119326756A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of opioid addiction relief, and in particular, to the use of dexmedetomidine in the preparation of a drug for promoting morphine addiction relief. Background Art
[0002] Opioid analgesics mainly include codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl and pethidine (meperidine). Repeated use of opioids will cause the body to tolerate addiction. The symptoms of opioid addiction include craving, anxiety, bad mood, yawning, sweating, goose bumps, tears, runny nose, nausea or vomiting, diarrhea, cramps, muscle pain, fever and insomnia. The use of morphine (such as intravenous use) has many physical consequences, including hepatitis B, hepatitis C, HIV infection, sepsis, endocarditis, pneumonia and lung abscess, thrombophlebitis and rhabdomyolysis, and psychological and social damage is also obvious.
[0003] At present, the main means of treating opioid addiction include drug therapy, psychotherapy and electrical stimulation, but the treatment effects are very limited. Drug therapy is currently the most commonly used treatment method. The drugs used to treat opioid addiction can be divided into three categories: full agonists, partial agonists and antagonists, including methadone, buprenorphine, naloxone, etc. However, the effects of existing drug treatments are very limited. Most drugs not only have large side effects and are prone to drug dependence, but also have unsatisfactory long-term efficacy and extremely high relapse rates.
[0004] Dexmedetomidine (Dex) has the molecular formula C 13 H 16 N2 is an effective α2-adrenoceptor agonist with an affinity for α2-adrenoceptors 8 times higher than that of clonidine. It is clinically suitable for sedation of patients who are intubated and on ventilators during intensive care treatment. Currently, no studies have shown that dexmedetomidine has a therapeutic effect on opioid addiction. Summary of the invention
[0005] The purpose of the present application is to provide the use of dexmedetomidine in the preparation of a drug for promoting the extinction of morphine addiction, which creates a new use of dexmedetomidine.
[0006] In order to solve the above technical problems, the technical solution adopted in this application is:
[0007] The present application discloses for the first time the use of dexmedetomidine in the preparation of a drug for promoting the extinction of morphine addiction.
[0008] Compared with the prior art, the embodiments of the present application have at least the following advantages or beneficial effects:
[0009] 1. Dexmedetomidine is currently commonly used for sedation and analgesia in clinical practice. This application is the first to discover that dexmedetomidine can play a new role in promoting addiction regression, thereby improving the clinical application of dexmedetomidine.
[0010] 2. Dexmedetomidine is widely used in clinical practice. Currently, there is no relevant research showing that long-term use of dexmedetomidine can cause addiction. The present application uses dexmedetomidine to promote the extinction of morphine addiction in mice, which can produce significant effects in a short period of time without obvious adverse reactions, and is safe and feasible.
[0011] 3. Dexmedetomidine is easy and quick to administer, has good compliance, and has strong clinical applicability in promoting the elimination of morphine addiction. BRIEF DESCRIPTION OF THE DRAWINGS
[0012] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.
[0013] Figure 1 The effect of dexmedetomidine on morphine addiction in Example 1 of the present application;
[0014] Figure 2 The dopamine content in the NAc brain region in Example 2 of the present application;
[0015] Figure 3 Schematic diagram of virus injection and optical fiber embedding in Example 2 of the present application;
[0016] Figure 4 The fluorescence intensity and AUC of the calcium signal in Example 2 of the present application;
[0017] Figure 5 This is a schematic diagram of mouse hybridization in Example 2 of the present application;
[0018] Figure 6 This is a schematic diagram of action potential in Example 2 of the present application;
[0019] Figure 7 The c-Fos fluorescence expression and statistical graph in the MS brain region in Experimental Example 3 of this application;
[0020] Figure 8 This is a schematic diagram of drug injection in the MS brain region in Experimental Example 3 of this application;
[0021] Fig. 9 The animal movement trajectory diagram and CPP statistical diagram in Experimental Example 3 of this application;
[0022] Fig.10 The fluorescence intensity and AUC of NAc dopamine in Experimental Example 3 of this application;
[0023] Fig.11 It is the fluorescence intensity and AUC of VTA calcium signal in Experimental Example 3 of this application. DETAILED DESCRIPTION
[0024] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.
[0025] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present application will be described in detail below with reference to specific embodiments.
[0026] Application of dexmedetomidine in the preparation of drugs for promoting the extinction of morphine addiction.
[0027] In some embodiments of the present application, the amount of dexmedetomidine added to the above-mentioned drug is 50-100 μg / kg.
[0028] In some embodiments of the present application, the dexmedetomidine mentioned above promotes the extinction of morphine addiction by inhibiting the activation of the VTA-NAc dopamine system induced by morphine.
[0029] In some embodiments of the present application, the above-mentioned dexmedetomidine promotes the extinction of morphine addiction by inhibiting the activation of VTA dopaminergic neurons induced by morphine and the release of dopamine in the NAc brain region.
[0030] The features and performance of the present application are further described in detail below in conjunction with the embodiments.
[0031] Example 1
[0032] 1. Construction of a mouse morphine addiction model
[0033] The conditioned place preference experiment (CPP) was divided into three stages. The first stage was pre-adaptation. Normal male C57BL / 6J mice of the same age were placed in the CPP test box and moved freely for 900s for a total of 2 days. The CPP test box consisted of two chambers, one side had black and white striped walls and a grid-like floor, and the other side had black and white checkered walls and a frosted floor. On the second day of adaptation, the time the mice spent in each compartment (baseline level) was recorded, and the chamber where the mice spent less time would be selected as the morphine-paired chamber. The second stage was drug administration training, in which morphine was paired with the corresponding compartment and saline was paired with the other compartment. It lasted for a total of 6 days. The morphine dose was increased from 10 mg / kg to 50 mg / kg every day at 15:00 p.m., and the same amount of saline was injected at 9:00 a.m. Immediately after the injection, the mice were confined to the appropriate chamber and the partition was closed for 45 minutes. CPP measurement was performed in the third stage, and the CPP score was calculated as the time in the morphine-paired chamber after administration minus the time in the chamber before administration.
[0034] The criterion for successful modeling is that the mice stay on the non-preferred side for a longer time. On the seventh day, the mice were placed in a two-chamber experimental box where they could move freely for 15 minutes, and then the CPP score was calculated. CPP score (seconds) = non-preferred side stay time after modeling (seconds) - non-preferred side stay time before modeling (seconds). Mice with CPP greater than 90 seconds were selected for the next round of experiments.
[0035] 2. Dexmedetomidine promotes addiction recovery
[0036] After 24 hours of the CPP test, dexmedetomidine was injected intraperitoneally at 15:00 every day. Two doses of 50 μg / kg and 100 μg / kg were injected intraperitoneally. CPP test was performed 36 hours later. Dosing and CPP test were repeated for a total of 14 days. The mice were observed to see whether the time they stayed on the non-preferred side was shorter than before. The results were as follows: Figure 1 shown. Figure 1 Morphine represents the normal saline group, Dex50 represents the dexmedetomidine 50 μg / kg group; Dex100 represents the dexmedetomidine 100 μg / kg group; the results showed that both 50 μg / kg and 100 μg / kg dexmedetomidine could quickly reduce morphine-induced CPP, indicating that dexmedetomidine can promote the extinction of morphine addiction.
[0037] Example 2
[0038] The increase in dopamine concentration in the NAC brain region is an important cause of morphine addiction, so this example explores the effect of morphine on NAC dopamine.
[0039] Adult C57BL / 6 mice were randomly divided into control group, model group, and Dex group. Three weeks before modeling, all mice were injected with rAAV-hSyn-DA3h150nl in the NAc brain region (AP: 1.2mm, ML: -1mm, DV: -4.5mm) using a microsyringe, and then the optical fiber was buried. After the morphine addiction model was established in the model group and Dex group mice, the model group was intraperitoneally injected with 50mg / kg of morphine, and then the fluorescence intensity was recorded. The Dex group was intraperitoneally injected with 50μg / kg of Dex 30 minutes before the intraperitoneal injection of morphine (according to the first part of the experiment, we found that 50μg / kg of Dex can quickly promote the recovery of CPP in addicted mice to normal, so we chose this dose experiment in subsequent experiments), and then the fluorescence intensity was recorded. The control group mice were intraperitoneally injected with normal saline, and then the fluorescence intensity was recorded. The relative fluorescence intensities of the three groups of mice were analyzed to evaluate the effects of Dex on dopamine release in NAc, such as Figure 2-6 shown.
[0040] The results showed that the electrochemical method improved by the applicant's team found that the dopamine concentration in the NAc brain region of morphine-addicted mice was increased, while the administration of Dex could reduce the dopamine concentration (see Figure 2 ). Further fiber optic recording methods revealed that intraperitoneal injection of morphine significantly increased the calcium signal of dopaminergic neurons in the VTA brain region, while simultaneous injection of Dex inhibited the increase in calcium signal induced by morphine (see Figure 3 , 4 Then, DAT-cre and Ai 14 double-transfected mice were used to label dopaminergic neurons (see Figure 5 ), further whole-brain patch clamp detection revealed that the frequency of action potential firing of dopaminergic neurons in the VTA of morphine-addicted mice increased, while Dex was able to inhibit its firing frequency and amplitude (see Figure 6 ). The above preliminary experiments showed that Dex could inhibit the activation of VTA-NAc dopamine system induced by morphine.
[0041] Example 3
[0042] This example explores the effect of dexmedetomidine on VTA dopaminergic neurons; the applicant team constructed a morphine addiction mouse model, treated it with Dex for 3 days, and then performed whole-brain c-Fos detection, and found that c-Fos expression in multiple brain regions such as MS increased, indicating that neurons in this brain region were activated ( Figure 7 ). Microtubules were embedded in the MS brain region, and it was found that local application of Dex (20 ng / kg, for 3 consecutive days) in MS could reverse morphine-induced CPP and inhibit morphine-induced activation of VTA dopaminergic neurons and release of dopamine in the NAc brain region ( Figure 8-11 ).
[0043] In summary, the use of dexmedetomidine in the embodiments of the present application in the preparation of a drug for promoting the extinction of morphine addiction has the following advantages:
[0044] 1. Dexmedetomidine is currently commonly used for sedation and analgesia in clinical practice. This application is the first to discover that dexmedetomidine can play a new role in promoting addiction regression, thereby improving the clinical application of dexmedetomidine.
[0045] 2. Dexmedetomidine is widely used in clinical practice. Currently, there is no relevant research showing that long-term use of dexmedetomidine can cause addiction. The present application uses dexmedetomidine to promote the extinction of morphine addiction in mice, which can produce significant effects in a short period of time without obvious adverse reactions, and is safe and feasible.
[0046] 3. Dexmedetomidine is easy and quick to administer, has good compliance, and has strong clinical applicability in promoting the elimination of morphine addiction.
[0047] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the scope of protection of the present application.
Claims
1. The application of dexmedetomidine in the preparation of drugs for promoting the extinction of morphine addiction.
2. The use of dexmedetomidine according to claim 1 in the preparation of a drug for promoting the elimination of morphine addiction, characterized in that: The added amount of dexmedetomidine in the medicine is 50-100 μg / kg.
3. The use of dexmedetomidine according to claim 1 in the preparation of a drug for promoting the elimination of morphine addiction, characterized in that: Dexmedetomidine promotes the extinction of morphine addiction by inhibiting the activation of the VTA-NAc dopamine system induced by morphine.
4. The use of dexmedetomidine according to claim 3 in the preparation of a drug for promoting the elimination of morphine addiction, characterized in that: The dexmedetomidine promotes the extinction of morphine addiction by inhibiting the activation of VTA dopaminergic neurons and the release of dopamine in the NAc brain region induced by morphine.