CN113350363B - N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 - Google Patents
N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 Download PDFInfo
- Publication number
- CN113350363B CN113350363B CN202110731942.7A CN202110731942A CN113350363B CN 113350363 B CN113350363 B CN 113350363B CN 202110731942 A CN202110731942 A CN 202110731942A CN 113350363 B CN113350363 B CN 113350363B
- Authority
- CN
- China
- Prior art keywords
- neuropathic pain
- palmitoyl
- sphingomyelin
- preparation
- preventing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000004296 neuralgia Diseases 0.000 title claims abstract description 26
- 208000021722 neuropathic pain Diseases 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 25
- RWKUXQNLWDTSLO-GWQJGLRPSA-N N-hexadecanoylsphingosine-1-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)[C@H](O)\C=C\CCCCCCCCCCCCC RWKUXQNLWDTSLO-GWQJGLRPSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 208000028389 Nerve injury Diseases 0.000 claims description 4
- 230000008764 nerve damage Effects 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 8
- 150000002632 lipids Chemical class 0.000 abstract description 5
- 229940121367 non-opioid analgesics Drugs 0.000 abstract description 5
- 206010012335 Dependence Diseases 0.000 abstract description 4
- 241000700159 Rattus Species 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 208000000094 Chronic Pain Diseases 0.000 description 9
- 208000002193 Pain Diseases 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 210000005036 nerve Anatomy 0.000 description 6
- 208000000114 Pain Threshold Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 230000037040 pain threshold Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000007913 intrathecal administration Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 210000002683 foot Anatomy 0.000 description 3
- 210000003497 sciatic nerve Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010028331 Muscle rupture Diseases 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000000014 opioid analgesic Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- CCEKAJIANROZEO-UHFFFAOYSA-N sulfluramid Chemical group CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F CCEKAJIANROZEO-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000574 ganglionic effect Effects 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及N‑棕榈酰‑D‑鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用，属于药物制备技术领域。本发明提供了N‑棕榈酰‑D‑鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的新的应用。16:0 SM不同于目前常用的阿片类、非阿片类止痛药以及辅助镇痛药，作为内源性脂质的一种，具有更好的安全性，不易成瘾等显著优势。
Description
技术领域
本发明涉及药物制备技术领域，具体涉及N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。
背景技术
伴随着我国城市化进程的不断加速，人民生活习惯的改变，以及人口老龄化进程的加速，慢性疼痛这一类慢性疾病逐渐受到越来越多人的重视。而我们也同样面临着缺乏有效干预药物的困境。为了有效控制疾病发展，改善患者生活质量的目的，寻找、研发安全、有效的临床干预药物成为目前我国慢性疼痛研究的当务之急。
经历了长时间的探索，人们发现中枢神经系统的损伤是慢性疼痛最可能的原因。“神经性疼痛”目前被学界广泛接受是慢性疼痛的常见来源。神经性疼痛源于神经系统的损伤。而在临床研究中发现，多种不同类型的疾病都可能导致神经性疼痛，例如自身免疫性疾病（如多发性硬化症）、代谢性疾病（如糖尿病神经病变）、感染（如带状疱疹及其后遗症、疱疹后神经痛）、心脑血管疾病（中风）、创伤等。
目前可选择的止痛药品种包括非阿片类止疼药、阿片类止疼药、还有辅助用药三大类。虽然看起来慢性疼痛治疗存在诸多选择，但在实际临床最常用的药物集中在阿片类止疼药和NSAIDs。前者有效但是副作用明显，同时还要承担巨大耐受与依赖的风险；而后者的止疼效果差强人意，同时还有危及生命的副作用。为了满足慢性疼痛治疗越来越大的临床需求，人们亟需开发安全、强效的新型止疼药。根据NIH最新的数据，目前全球范围内以慢性疼痛为适应症的临床试验累计多达2488项（2020年，clinical trial.org）。但遗憾的是2018年美国FDA一共批准59项新药与疗法（这是自1993年以来最多的一年）中没有一项是针对慢性疼痛的。而2005-2009九年间只有极少针对关节炎和纤维肌痛的止痛药品种获得FDA的批准。而这些药物不是对已有药物的改构（普瑞巴林，度洛西汀等），就是已有药物的新剂型（各类缓释阿片类止疼药），目前仍缺乏慢性疼痛治疗的药物。
发明内容
本发明的目的在于提供N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。本发明提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的新的应用。16:0 SM不同于目前常用的阿片类、非阿片类止痛药以及辅助镇痛药，作为内源性脂质的一种，具有更好的安全性，不易成瘾等显著优势。
本发明提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。
本发明还提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗由神经损伤导致的神经性疼痛的药物中的应用。
本发明提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。16:0 SM不同于目前常用的阿片类、非阿片类止痛药以及辅助镇痛药，作为内源性脂质的一种，具有更好的安全性，不易成瘾等显著优势。试验结果表明，PSNL模型16:0 SM鞘内给药对于神经性疼痛具有很好的抑制作用。
附图说明
图1为本发明提供的坐骨神经部分结扎模型；
图2为本发明提供的PNSL模型组与对照组脂质组学数据火山图；
图3为本发明提供的16:0 SM鞘内注射对PSNL模型大鼠机械疼痛阈值具有恢复效果。
具体实施方式
本发明提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。N-棕榈酰-D-鞘磷脂（N-palmitoyl-D-erythro-sphingosylphosphorylcholine，16:0SM (d18:1/16:0)），实施例中简称16:0 SM，CAS：6254-89-3，化学式：C39H79N2O6P，结构式如式I所示：
分子量: 703.03，性状：粉末；具有显著的神经性疼痛抑制作用。16:0 SM不同于目前常用的阿片类、非阿片类止痛药以及辅助镇痛药，作为内源性脂质的一种，具有更好的安全性，不易成瘾等显著优势。16:0 SM不参与目前常见的止痛药的药理通路，是一类全新的药物作用靶点，具有极高的科技与商业价值。本发明对N-棕榈酰-D-鞘磷脂的来源没有特殊限定，采用本领域技术人员熟知的常规N-棕榈酰-D-鞘磷脂市售产品即可，如购自厂商：Avanti Polar Lipids Inc，货号：860584P。
本发明还提供了N-棕榈酰-D-鞘磷脂在制备预防和/或治疗由神经损伤导致的神经性疼痛的药物中的应用。本发明建立PSNL模型，经实施例证明，本申请N-棕榈酰-D-鞘磷脂具有显著的由神经损伤导致的神经性疼痛抑制作用。
下面结合具体实施例对本发明所述的N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用做进一步详细的介绍，本发明的技术方案包括但不限于以下实施例。
实施例1
模型组（坐骨神经部分结扎模型，PSNL模型组），对照组（假手术组）16:0 SM 靶器官附近分布
（1）动物模型构建
模型组造模：采用坐骨神经部分结扎模型（PSNL；详见图1）。具体手术流程：大鼠称重，腹腔注射麻醉10%水合氯醛（3ml/kg），麻醉5~10min后沿着L4-S1脊柱中线做一纵行切口，充分暴露L6横突，L6下关节突关节和S1，暴露L5神经，鉴别L4/L5神经，在L5神经远端用6号线紧扎神经并切断。放回撕起的肌肉，用5号线缝两针把肌肉、皮肤缝上。
对照组造模：大鼠称重，腹腔注射麻醉10%水合氯醛（3ml/kg），麻醉5~10min后沿着L4-S1脊柱中线做一纵行切口，充分暴露L6横突，L6下关节突关节和S1，暴露L5神经。放回撕起的肌肉，用5号线缝两针把肌肉、皮肤缝上。
给与足够的食物与水饲养。14天后处死，采集被根神经节脂质组学分析。
（2）脂质组学分析
A 样本前处理
被根神经节组织称重，置于EP管中，加入10倍生理盐水以及陶瓷珠，置于匀浆机中，10000rpm匀浆3min，制得匀浆液。
100 μl匀浆液+300 μl异丙醇（-20℃ 预冷），涡旋振荡1 min，室温静置10 min后放入冰箱-20℃静置24小时。4℃离心20 min（14000 rpm），取上清用异丙醇:乙腈:水（2:1:1）稀释适当倍数后进样分析。
B HPLC-HRMS分析
采用高效液相色谱-质谱联用方法，以C8填料的反向色谱柱，以乙腈：水（6:4）、异丙醇：乙腈（9:1）作为流动相开展脂质组学分析。
（3）结论
结果发现16:0 SM发生了显著变化。PNSL模型组与对照组脂质组学数据火山图如图2所示，模型组相较对照组16:0 SM降低了近2倍，且这一变化具有显著性（T-检验p值小于0.05）。这预示着16:0 SM是一类特殊的SM分子，在神经性疼痛的过程中发挥着独特的调节作用。
实施例2
PSNL模型16:0 SM鞘内给药对于神经性疼痛的抑制
（1）动物模型构建
模型给药组：如实施例1（1）中所述构建PSNL模型鼠，给与充分饮食培养14天。14天后，向PNSL建模成功的大鼠脊髓中补充16:0 SM（单次给药30μg，1μg/μL），分别在建模前，注射后10min、30min、60min、150min、240min测量大鼠的机械痛阈值。
安慰剂组：如实施例1（1）中所述构建PSNL模型鼠，给与充分饮食培养14天。14天后，向PNSL建模成功的大鼠脊髓中补充生理盐水（单次30μL），分别在建模前，注射后10min、30min、60min、150min、240min测量大鼠的机械痛阈值。
（2）左足机械缩足阈值测定
为了确定大鼠应对机械刺激的缩脚阈值，将大鼠置于具有金属网底的塑料笼中。用一组Von Frey细丝（Semmes-Weinstein Monofilaments）以逐渐增加的压强刺激后脚的足底表面，直到小鼠向上抬脚。每根单丝施用五次。 缩脚阈值被定义为大鼠在五个连续刺激中产生至少三次缩脚反应的阈值。最高截断刺激强度为100N，机械刺激阈值<0.04N，均以0.04N计算。
（3）结论
实验结果表明（图3，16:0 SM鞘内注射对PSNL模型大鼠机械疼痛阈值具有恢复效果，n=3，（Vehicle：安慰剂组；16:0 SM 30μg: 模型给药组）注：MPE最大可能治疗效应），注射16:0 SM的PNSL模型大鼠机械痛阈值自30min后出现明显回复（约为建模前的80%，且两组间p值小于0.05），随后在150min内均有较为显著的效果。这一结果表明，16:0 SM直接参与了神经性疼痛的发生过程，该化合物的异常降低是发生神经性疼痛的原因之一，16:0 SM能够抑制神经性疼痛。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (2)
1.N-棕榈酰-D-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用。
2.N-棕榈酰-D-鞘磷脂在制备预防和/或治疗由神经损伤导致的神经性疼痛的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110731942.7A CN113350363B (zh) | 2021-06-30 | 2021-06-30 | N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110731942.7A CN113350363B (zh) | 2021-06-30 | 2021-06-30 | N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113350363A CN113350363A (zh) | 2021-09-07 |
| CN113350363B true CN113350363B (zh) | 2022-02-22 |
Family
ID=77537306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110731942.7A Active CN113350363B (zh) | 2021-06-30 | 2021-06-30 | N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113350363B (zh) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1481680A1 (en) * | 2003-05-30 | 2004-12-01 | Aventis Pharma Deutschland GmbH | Use of S1P |
| EP2769724A1 (en) * | 2013-02-22 | 2014-08-27 | Université d'Aix-Marseille | Inhibitors of Na(v) 1.9 channel activity and uses thereof for treating pain |
-
2021
- 2021-06-30 CN CN202110731942.7A patent/CN113350363B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113350363A (zh) | 2021-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gianutsos et al. | Effect of apomorphine and nigrostriatal lesions on aggression and striatal dopamine turnover during morphine withdrawal: evidence for dopaminergic supersensitivity in protracted abstinence | |
| Mugabure Bujedo | A clinical approach to neuraxial morphine for the treatment of postoperative pain | |
| US20090048288A1 (en) | Method of treating stress-mediated depression | |
| WO2009021521A2 (en) | Use of gaboxadol for the manufacture of a medicament for treating stress-mediated depression | |
| Gao et al. | Proteomic analysis of differential proteins related to anti-nociceptive effect of electroacupuncture in the hypothalamus following neuropathic pain in rats | |
| Wellman et al. | Basolateral amygdala and the regulation of fear-conditioned changes in sleep: role of corticotropin-releasing factor | |
| Drasner | Local anesthetic systemic toxicity: a historical perspective | |
| Schoenenberger | Characterization, properties and multivariate functions of delta-sleep-inducing peptide (DSIP) | |
| CN113350363B (zh) | N-棕榈酰-d-鞘磷脂在制备预防和/或治疗神经性疼痛的药物中的应用 | |
| CN109350616B (zh) | I-brd9或其衍生物在制备抗癫痫药物中的应用 | |
| EP2762137A1 (en) | Use of myricetin or derivatives thereof as a cathepsin k inhibitor | |
| Wakatsuki et al. | Autonomic nervous system regulation of baseline heart rate in the fetal lamb | |
| Auvil-Novak | The chronobiology, chronopharmacology, and chronotherapeutics of pain | |
| Moghadam et al. | Evaluation of the effect of intranasal lidocaine in the treatment of spasticity in patients with traumatic brain injury | |
| McCranor et al. | Assessment of naloxone as a therapeutic for inhaled carfentanil in the ferret | |
| CN114887063B (zh) | Pacsin1在抑制瑞芬太尼诱发的痛觉过敏中的应用 | |
| CN1054762C (zh) | 一种治疗癫痫病的水丸剂 | |
| Hamiduzzaman et al. | Evaluation of analgesic, antipyretic, hypoglycemic and CNS depressant activity of 2-bromopopylamine hydrobromide, 3-bromopopyl ammonium bromide, ortho-amino aniline and benzimidazole-2-thiol in animal model | |
| Chen et al. | Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys | |
| CN115595315A (zh) | 核糖核酸酶i在抑制疼痛的药物中的新用途 | |
| Lewis | The development of tolerance in rats to some new synthetic analgesics | |
| KR101134146B1 (ko) | 국소 근마비 효과를 갖는 비확산형 보툴리눔 독소와 그의 정제방법 | |
| CN107281183B (zh) | 一种镇痛药物组合物 | |
| CN109021073B (zh) | 秦岭雨蛙镇痛肽ht2的改造体ht12及其应用 | |
| Müller et al. | The effect of pregabalin on the minimum alveolar concentration of sevoflurane: a randomized, placebo-controlled, double-blind clinical trial |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |