CN103845730A - Application of anti-ST2/IL-1R4 antibody in preparation of pain relieving medicament - Google Patents
Application of anti-ST2/IL-1R4 antibody in preparation of pain relieving medicament Download PDFInfo
- Publication number
- CN103845730A CN103845730A CN201210517242.9A CN201210517242A CN103845730A CN 103845730 A CN103845730 A CN 103845730A CN 201210517242 A CN201210517242 A CN 201210517242A CN 103845730 A CN103845730 A CN 103845730A
- Authority
- CN
- China
- Prior art keywords
- pain
- antibody
- mouse
- cancer
- medicament
- 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.)
- Granted
Links
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to the field of a pain relieving medicament, and particularly relates to an application of an anti-ST2/IL-1R4 antibody in preparation of the pain relieving medicament. As proved by experiments, the anti-ST2/IL-1R4 antibody has a remarkable inhibition effect on cryalgesia acroesthesia of a mouse model suffering from neuropathic pain and hyperpathia acroesthesia of a mouse suffering from cancer pain and can be used for further preparing the pain relieving medicament as an effective component of the medicament, for clinically treating chronic pain and particularly for treating neuropathic pain or cancer pain.
Description
Technical field
The present invention relates to analgesic field, and in particular to application of the anti-ST2/IL-1 R4 antibody in analgesic is prepared, and especially anti-ST2/IL-1 R4 antibody is in the purposes in treatment neurogenic pain, Cancer pain medicament is prepared.
Background technology
It is not only a kind of symptom that research, which discloses chronic ache, but a kind of disease.Clinical common trigeminal neuralgia, sciatica, pain in waist and lower extremities, osteoarthrosis pain, pain caused by cancer etc. belong to the category of chronic ache.Described pain is that a kind of cure-pain is stimulated, and causes psychology and spirit change, causes depression and anxiety, influences patients ' life quality, cause heavy social economical burden.According to the relevent statistics, about 30% adult suffers from chronic ache, and the expense that the whole world is used for chronic pain treatment every year reaches hundreds billion of dollars.
" eliminating the fundamental right that pain is patient ".In reality patient this in fundamental right do not realized very well.The analgesic and treatment means of prior art are extremely limited to the analgesic effect of chronic ache, and due to its higher adverse reaction rate, limit its further using clinically.Even if at present to the highly effective Endorphins medicine such as morphine of acute pain, patient uses for a long time can also produce drug resistance.Therefore the mechanism that further investigation chronic pain occurs, developed, finds new AD-targeted drugs, more effective treatment method is explored, as medical domain a main points and difficult point urgently to be resolved hurrily.
ST2 is one of Toll-like/IL-1 acceptors (IL-1R) superfamily member, encodes a kind of soluble ST2 (soluable ST2, sST2) and a kind of cross-film form ST2 parts（ST2 Ligand,ST2L）.Both are produced by premessenger RNA alternative splicing, and with common extracellular domain, but sST2 lacks cross-film and intracellular Toll/IL-1 receptor domains.Research shows, transmembrane ST2L and auxilin (AcP) collectively constitute the film surface receptor of IL-33 (newfound a kind of inflammatory cytokine in 2005).Research shows that IL-33/ST2 signal pathways participate in the cell-mediated immune responses of Th2, adjusts development and the function of mast cell, is played a role in the lysises such as inflammatory, LADA, angiocarpy, tumour.
Research relevant reports of the ST2 in pain only has one.2008, the research such as Verri WA was found, murine antigen is subcutaneously or after ankle-joint intracavitary administration, inflammation part ST2 expression increases；SST2 can suppress mechanical hyperalgesia caused by antigen injection, and this effect is realized by TNF-α-IL-1 β-IFN γ-ET-1-PGE2 paths.The above results prompting periphery ST2 participates in arthritis bitterly.So far, there is not yet ST2 and neurogenic pain and the report of pain caused by cancer, the also direct analgesic report of nonreactive ST2 antibody, and have no that anti-ST2 antibody carries out the report of Clinical Pain treatment by Analgesic Mechanism.
The content of the invention
It is an object of the invention to provide the new application of anti-ST2/IL-1 R4 antibody, and in particular to anti-ST2/IL-1 R4 antibody is preparing the application in treating chronic neuralgia, the medicine of pain caused by cancer.
The purpose of the present invention is achieved through the following technical solutions：
1st, anti-ST2 antibody is purchased from R＆D companies（Mouse ST2/IL-1 R4 Antibody, AF1004）.
2nd, anti-ST2 antibody is used to treat neuralgia experiment：
From male BALB/c mouse, mouse sciatic nerve branch ligation cut-out Neuropathic pain model is set up according to a conventional method（SNI models）, occur significantly and stable neuralgia within the 7th day after modeling, anti-ST2 antibody, influence of the observation medicine to pain behavior, including super quick and Mechanical hyperalgesia the influence of cryalgesia are given in intrathecal injection,
As a result confirm：Anti- ST2 antibody has notable analgesic activity to Neuropathic pain model mouse.
3rd, anti-ST2 antibody is used to treat pain caused by cancer experiment：
From female BAl BIc/c mouse, mouse femur pain caused by cancer model is set up according to a conventional method, is occurred significantly and stable pain caused by cancer within the 11st day after modeling, and anti-ST2 antibody is given in intrathecal injection, and observation medicine is to pain behavior（Cryalgesia is super quick and Mechanical hyperalgesia）Influence,
As a result confirm：Anti- ST2 antibody has notable analgesic activity to pain caused by cancer model mice, intrathecal to give anti-ST2 antibody and significantly alleviate the pain behavior of neuralgia and pain caused by cancer mouse.The anti-ST2/IL-1 R4 antibody of the present invention can further be prepared as effective ingredientAnalgesic, for clinical treatmentChronic pain, especially treats neurogenic pain or pain caused by cancer.
Brief description of the drawings：
Fig. 1 neuralgia Establishment of mouse model, * * P<0.01, compared with Normal groups.
Effect of the anti-ST2 antibody of Fig. 2 various doses to neuralgia mouse cryalgesia allergy and mechanical hyperalgesia, * * P<0.01, compared with model+IgG groups.
Fig. 3 pain caused by cancer Establishment of mouse model, * * P<0.01, compared with Normal groups.
Effect of the anti-ST2 antibody of Fig. 4 various doses to pain caused by cancer mouse cryalgesia allergy and mechanical hyperalgesia, * * P<0.01, compared with model+IgG groups.
Embodiment：
1st, experimental animal：
The SPF level BALB/C mices that this experiment is used（Male, which is used for Neuropathic pain model making, female, is used for pain caused by cancer modelling）, 8 week old, body weight 16-20g（Chinese Academy of Sciences's Experimental Animal Center）.Rearing conditions are cleaning grade, 5-6/cage, any to supply water.Experimental animal is grouped with complete randomized.
2nd, model is made
1. Neuropathic pain model is cut off in mouse sciatic nerve branch ligation（SNI models）：After the anesthesia of mouse peritoneal injection yellow Jackets, skin is cut in mouse hind leg upper limb, longitudinal dissociation muscle, exposure sciatic nerve trunk and its under branch --- nervus tibialis, nervus peroneus communis and nervus suralis, ligature and cut nervus tibialis and nervus peroneus communis, retain tiny nervus suralis, while avoiding any damage.By muscle, skin layer-by-layer suture, then abdominal cavity injection of antibiotics makees antibacterial prevention.Sham-operation group animal is in addition to ligaturing and cutting off without nerve, and remaining operation is identical with operation group.
2. mouse femur pain caused by cancer model：By the method for the reports such as Schwei, mouse femur pain caused by cancer model is set up.After Animal Anesthesia, the skin incision of a long 0.5-1.0 cm is cut at knee joint along rectus femoris tendon direction, careful exposure kneecap, first punctured and punched along femur long axis direction in kneecap with disposable sterilized 1 mL syringe needles, then 10 uL microsyringes are changed and enter marrow cavity of femur, 4 uL are slowly injected into containing 1 × 104The cell suspending liquid of individual 4T1 mouse mastopathy cells（2.5×106Individual/ml）（Shanghai Inst. of Life Science, CAS cell resource center）To femur.Injection seals pin hole with gelfoam after finishing, aseptic cotton carrier dips in physiological saline cleaning wound, applies a small amount of penicillin powder, skin closure.Control group injects equivalent PBS or waits calorimetric to inactivate dead cell, and remaining operation is identical with operation group.
3rd, pain behavior evaluation
1. Mechanical hyperalgesia（mechanical allodynia）：The up-and-down methods introduced according to Dixon, using von Frey filaments（Stoelting, Wood Dale, Illinois, USA）The reaction of contracting pin is used as Mechanical hyperalgesia index caused by stimulating.
2. cryalgesia is super quick（cold allodynia）：Using the acetone of the syringe per injection 50ul equipped with passivity syringe needle（Analyze pure, Chemical Reagent Co., Ltd., Sinopharm Group）At the skin that nervus suralis is dominated on the outside of to mouse sole, lift is sufficient after observed and recorded injection acetone/the sufficient time is licked as the super quick index of cryalgesia.
3. thermal hyperalgesia（thermal hyperalgesia）：In quiet environment, 1 DEG C of 22 scholar of room temperature, mouse is placed in the cylindrical space that bottom is Metal constant temperature flat board, Metal constant temperature plate maintains temperature in 0.5 DEG C of 50 scholar by electronic feedback system, records it since foot is put into device to occurring licking rear solid end or jumping out Metal constant temperature plate timing terminating to lick the pawl response latency as thermal hyperalgesia incubation period index in this period of time.
4th, medication
1. intrathecal drug delivery:After mouse isoflurane anesthesia, micro-sampling pin is inserted perpendicularly into along L5, L6 spinous process middle, has into cavum subarachnoidale and clearly breaks through sense, and visible tail whipping.
2. pharmaceutical intervention：The intrathecal change given anti-ST2 antibody, observe 0.5,1.5,3,5,7,9,12 h mouse pain behaviors after administration in the 7th day after neuralgia mouse modeling.The intrathecal change given anti-ST2 antibody, observe 1,2,3,4,6,8,24 h mouse pain behaviors after administration in the 11st day after pain caused by cancer mouse modeling.
Experimental data is with mean ± standard error（mean ± SE）Represent, counted using SPSS16.0 softwares, using one-way analysis of variance（one way ANOVA）.With P<0.05 thinks that difference has conspicuousness.
As a result show：
1）Neuralgia Establishment of mouse model：Occur within 1st day that significant cryalgesia is super quick and Mechanical hyperalgesia after the ligation cut-out of mouse sciatic nerve branch, pain status started stabilization in the 7th day, it is possible to continue to that observation in the 14th day terminates, and sham-operation group pain behavior does not have significant changes（As shown in Figure 1）；
2）Analgesic activity of the anti-ST2 antibody to neuralgia mouse：The anti-ng of ST2 antibody 30,100 ng, 300ng are given in intrathecal injection in the 7th day after modeling, as a result show, 0.5 hour after 300ng administrations, the crymodynia threshold of mouse is notable rises, this, which is acted on 5 hours, reaches peak, still there is analgesic effect, the 12nd hour event resolves at 9 hours；And certain analgesic activity is also presented within 3-7 hours after the anti-ST2 antibody administrations of 10ng；Dose dependent analgesic activity is presented after anti-ST2 antibody administrations（As shown in Figure 2）；
3）Pain caused by cancer Establishment of mouse model：Occur within 2nd day that significant thermalgesia is super quick and Mechanical hyperalgesia after mouse femur injection 4T1 breast cancer cells, pain status started stabilization in the 10th day, continueed to that observation in the 14th day terminates, and PBS and dead cell（Heat killed group）Control group pain behavior does not have significant changes（As shown in Figure 3）,
4）Analgesic activity of the anti-ST2 antibody to pain caused by cancer mouse：The anti-ng of ST2 antibody 100 is given in intrathecal injection in the 11st day after modeling, 200 ng, 400ng, as a result show, 2 hours after the anti-ST2 antibody administrations of 400ng, the hot threshold of pain of mouse significantly rises, this, which is acted on 3 hours, reaches peak, still there are analgesic effect, the 12nd hour event resolves at 9 hours, and certain analgesic activity is also presented within 3-7 hours after the anti-ST2 antibody administrations of 10ng；Dose dependent analgesic activity is presented after anti-ST2 antibody administrations（As shown in Figure 4）.
Test result indicate that, it is intrathecal to give anti-ST2 antibody and significantly alleviate the pain behavior of neuralgia and pain caused by cancer mouse.The anti-ST2/IL-1 R4 antibody of the present invention can further prepare analgesic as effective ingredient, for clinical treatment chronic pain, especially treat neurogenic pain or pain caused by cancer.
Claims (4)
1. purposes of the anti-ST2/IL-1 R4 antibody in analgesic is prepared.
2. anti-ST2/IL-1 R4 antibody is preparing the purposes in preventing and treating chronic pain medicine.
3. described purposes according to claim 2, wherein described chronic pain is neurogenic pain or pain caused by cancer.
4. the purposes according to claim 1 or 2, wherein described anti-ST2 antibody is Mouse ST2/IL-1 R4 Antibody, AF1004.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210517242.9A CN103845730B (en) | 2012-12-05 | 2012-12-05 | Anti-ST2/IL-1 R4 antibody is preparing the purposes in analgesic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210517242.9A CN103845730B (en) | 2012-12-05 | 2012-12-05 | Anti-ST2/IL-1 R4 antibody is preparing the purposes in analgesic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103845730A true CN103845730A (en) | 2014-06-11 |
| CN103845730B CN103845730B (en) | 2015-12-09 |
Family
ID=50854133
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210517242.9A Active CN103845730B (en) | 2012-12-05 | 2012-12-05 | Anti-ST2/IL-1 R4 antibody is preparing the purposes in analgesic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103845730B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113796349A (en) * | 2021-08-06 | 2021-12-17 | 南通大学 | Animal model for attacking nerves and inducing pain of breast cancer and preparation method thereof |
| CN117487905A (en) * | 2023-12-29 | 2024-02-02 | 中日友好医院(中日友好临床医学研究所) | Use of IL-33 in the preparation of therapeutic/detection SANFH products |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101821412A (en) * | 2007-08-15 | 2010-09-01 | 艾德拉药物股份有限公司 | TOLL sample receptor modulators |
-
2012
- 2012-12-05 CN CN201210517242.9A patent/CN103845730B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101821412A (en) * | 2007-08-15 | 2010-09-01 | 艾德拉药物股份有限公司 | TOLL sample receptor modulators |
Non-Patent Citations (4)
| Title |
|---|
| HAN P ET AL.: "Research progress on interleukin-33 and its roles in the central nervous system", 《NEUROSCIENCE BULLETIN》 * |
| LIU T ET AL.: "Emerging role of Toll-like receptors in the control of pain and itch", 《NEUROSCI BULL》 * |
| VERRI WA JR ET AL.: "IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice", 《PRO NATL ACAD SCI USA》 * |
| 贾泽军等: "Toll样受体4：神经病理性疼痛潜在的治疗靶标", 《中国医学科学院学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113796349A (en) * | 2021-08-06 | 2021-12-17 | 南通大学 | Animal model for attacking nerves and inducing pain of breast cancer and preparation method thereof |
| CN117487905A (en) * | 2023-12-29 | 2024-02-02 | 中日友好医院(中日友好临床医学研究所) | Use of IL-33 in the preparation of therapeutic/detection SANFH products |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103845730B (en) | 2015-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Li et al. | Antistress effect of TRPV1 channel on synaptic plasticity and spatial memory | |
| Goodchild et al. | Intrathecal midazolam in the rat: evidence for spinally-mediated analgesia | |
| Smith et al. | The TRPv1 receptor is a mediator of the exercise pressor reflex in rats | |
| Braga et al. | Involvement of l‐glutamate and ATP in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the commissural nucleus tractus solitarii of awake rats and in the working heart–brainstem preparation | |
| Yang et al. | Inhibition of connexin 43 and phosphorylated NR2B in spinal astrocytes attenuates bone cancer pain in mice | |
| Takakusaki et al. | Medullary reticulospinal tract mediating a generalized motor inhibition in cats: III. Functional organization of spinal interneurons in the lower lumbar segments | |
| Gianino et al. | Intrathecal drug therapy for spasticity and pain: Practical patient management | |
| CN111358797A (en) | Intravenous infusion compound anesthetic for dogs | |
| Bell et al. | In vivo investigation of communication between the distal intertarsal and tarsometatarsal joints in horses and ponies | |
| CN103845730A (en) | Application of anti-ST2/IL-1R4 antibody in preparation of pain relieving medicament | |
| Krivoy et al. | Actions of morphine on the segmental reflex of the decerebrate-spinal cat | |
| CN103830170B (en) | Ivermectin is at body gel injection and preparation method thereof | |
| Wu et al. | Differential effects of m1 and m2 receptor antagonists in perirhinal cortex on visual recognition memory in monkeys | |
| CN105311622B (en) | A kind of combination medicine that treating pain and its preparation, preparation method | |
| CN108066337B (en) | Application of the KB-R7943 or Bepridil in the drug of preparation treatment glioma | |
| Gao et al. | Inhibition of metabotropic glutamate receptor subtype 1 alters the excitability of the commissural pyramidal neuron in the rat anterior cingulate cortex after chronic constriction injury to the sciatic nerve | |
| CN112569237B (en) | Application of combination or compound of imatinib and derivatives thereof and nicotine or analogues thereof in preventing and treating nicotine addiction and relapse | |
| CN107375311A (en) | Liquiritin treats the pharmaceutical applications of neurogenic pain | |
| Leino et al. | Fadolmidine–Favourable adverse effects profile for spinal analgesia suggested by in vitro and in vivo models | |
| Rockhold et al. | Acute tachycardia and pressor effects following injections of kainic acid into the antero-dorsal medial hypothalamus | |
| Solt et al. | An altered state of consciousness illuminated | |
| Shimizu et al. | Electroencephalographic studies of haloperidol | |
| Cao et al. | Elimination of serotonergic neurons by stereotaxic injection of 5, 7-Dihydroxytryptamine in the dorsal raphe nuclei of mice | |
| Eliasson et al. | Interaction effects of chlorpromazine and reticular stimulation on visual attention behavior in rats | |
| CN115770239B (en) | Application of furochrome and pharmaceutically acceptable salt in preparation of medicines for treating peripheral neuropathy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |