JPWO2014088106A1 - Prevention or treatment of fibromyalgia - Google Patents

Abstract

A substance capable of binding to mSin3B exhibits an analgesic action on an ICS (Intermittent Cold Stress) model mouse, which is an animal experimental model of fibromyalgia, and is useful as a prophylactic or therapeutic agent for fibromyalgia.

Description

  The present invention relates to a prophylactic or therapeutic agent for fibromyalgia, and more particularly to a prophylactic or therapeutic agent for fibromyalgia comprising a compound that binds to mSin3B.

  Fibromyalgia, an example of systemic pain syndrome, is particularly responsive to tender points, and is mainly caused by unexplained generalized pain and mental and neurological symptoms such as insomnia and depression. is there. There are 2% of the national population, and it has been reported that it is overwhelmingly affected among middle-aged and elderly women. Psychological factors due to physical trauma, stress, depression, and anxiety due to surgery and accidents are thought to be greatly involved in the background of the development of fibromyalgia, and as a result, from the lower brainstem nucleus to the dorsal horn of the spinal cord Although the part by attenuation of the descending pain suppression system is said to be large, the initial cause site | part is not specified (refer nonpatent literature 1 and 2).

  For fibromyalgia, most anti-inflammatory analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs), which are applied to general pain treatment, are not very effective. Therefore, in the current treatment, mainly antidepressants, pharmacotherapy that orally administers anticonvulsants, Chinese herbal medicines, and psychotherapy such as psychotherapy, relaxation, and exercise therapy are performed. As the antidepressant administered orally, amitriptyline, amoxapine, fluvoxamine, milnacipran and the like are used. However, although the conventional treatment methods can improve fibromyalgia symptoms to some extent, there are problems that the treatment effects are not sufficient or cannot be completely cured.

  Recently, it has been disclosed that an extract of inflamed tissue inoculated with vaccinia virus (for example, neurotropin) is effective for fibromyalgia (see Patent Document 1). According to the invention described in Patent Document 1, there is a need for a therapeutic agent for fibromyalgia that can effectively treat fibromyalgia but has a better therapeutic effect and fewer side effects. ing.

  On the other hand, chronic pain (neuropathic pain) due to nerve damage is a complex pain with a mixture of positive symptoms (pain hypersensitivity and allodynia (strong pain induced by tactile stimulation)) and negative symptoms (hyperperception). Symptoms are present. Moreover, since this abnormal pain shows resistance to an anti-inflammatory drug and morphine, it is regarded as intractable pain.

Recently, in the primary sensory nerve after neuropathy, the expression of the neuroselective transcriptional repressor NRSF / REST has increased, and pain-related genes (Na _v 1.8) via epigenetics modification (decrease histone acetylation) , MOP, TRPM8, _TRPAl, and silencing the expression of the K v 4.3), and C fibrotic desensitizing is characteristic of neuropathic pain, it has been reported to induce morphine resistance (non-patent Literature 3-6).

  On the other hand, the present inventors have identified a compound that binds to the PAH domain of mSin3B that specifically binds to NRSF, and this compound restores modulation such as disappearance of morphine analgesia and dull perception observed in neuropathic pain. It was made clear (Patent Document 2). In addition, as described in the above-mentioned Patent Document 1, the effect of the mSin3B binding compound is not pain suppression, but is a therapeutic effect for negative symptoms related to pain such as paradoxical pain bluntness, and for positive symptoms such as pain hypersensitivity and allodynia. Did not show any efficacy at all (unpublished).

By the way, the known neuropathic pain is not systemic pain but specific to the impaired side. That is, neuropathic pain can identify a site of injury (injury) on the pain transmission pathway. On the other hand, in fibromyalgia, the disease responsible site is not specified. Moreover, systemic administration of morphine is neuropathic pain and has an analgesic effect 10 times weaker than that of normal mice, but is not effective at all in fibromyalgia (100 times or more).
When morphine was administered into the ventricle, the neuropathic pain model was the same as that in normal mice, but was completely ineffective in the fibromyalgia model (see Non-Patent Documents 7 and 8).
In addition, gabapentin showed a significant pain hypersensitivity suppressing effect for 3 days or more in a fibromyalgia model in a single intraventricular administration, but it is completely ineffective in a neuropathic pain model (see Non-Patent Document 9).
Therefore, fibromyalgia and neuropathic pain are diseases with the same pain, but are considered to be completely different diseases because differences in onset mechanism and drug effects are observed.

The present inventors have clarified that the repeated stress-related chronic pain model is a good model of systemic pain syndrome such as fibromyalgia (see Patent Document 3), and further using this model in clinical practice. By examining the therapeutic agents used (anti-depressants), we found that systemic pain and psychological factors are closely related pharmacologically, and certain antidepressants are in the spinal subarachnoid space It is clarified that it can be used as a therapeutic agent for fibromyalgia by internal administration (see Patent Document 4). In the literature, such therapeutic agents include milnacipran, paroxetine, amitriptyline and mianserin.
However, intrathecal administration of these antidepressants with a spinal cord is highly invasive, continuous administration to patients is heavy, and the degree of satisfaction with the therapeutic effect for fibromyalgia is not yet sufficient, and fibromyalgia There was a need for new drugs.

WO2004 / 039383 WO2011 / 099502 JP 2009-195200 A JP 2009-007278 A

Mayo Clin Proc. , 2011; 86 (9): 907-911. Acta Reumator Port. 2010; 35 (1): 10-15. Neuroscience, 166, 1-4, 2010. J. et al. Neurosci. , 30, 4806-4814, 2010. Mol. Pain, 4:11, 2008. Pharmacol. Ther. 109: 57-77, 2006. Neurosci. Lett. 2010, 26; 472 (3): 184-187. J. et al. Pharmacol. Exp. Ther. , 2004; 309 (1): 380-387. Mol. Pain. 4: 52,2008

  An object of the present invention is to provide a prophylactic / therapeutic agent for fibromyalgia having an excellent prophylactic / therapeutic effect.

  In the process of searching for a therapeutic agent for fibromyalgia, the present inventors created an ICS (Intermittent Cold Stress) model mouse as an animal experiment model of fibromyalgia. The inventors of the present invention, when a compound that specifically binds to mSin3B, which is a corepressor that specifically binds to the neuroselective transcription repressor NRSF, gave a thermal stimulus in the ICS model mouse, The disappearance of analgesia was found to be observed. The present invention has been completed based on these findings.

That is, the gist of the present invention is as follows.
[1] A prophylactic or therapeutic agent for fibromyalgia comprising a substance capable of binding to mSin3B.
[2] The prophylactic or therapeutic agent according to [1] above, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.
[3] The prophylactic or therapeutic agent according to the above [1], wherein the substance capable of binding to mSin3B has a human medulloblastoma cell line growth inhibitory activity.
[4] A substance capable of binding to mSin3B, which is used for prevention or treatment of fibromyalgia.
[5] The substance according to [4] above, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.
[6] The substance described in [4] above, wherein the substance capable of binding to mSin3B has a growth inhibitory activity on a human medulloblastoma cell line.
[7] A method for preventing or treating fibromyalgia, comprising administering an effective amount of a substance capable of binding to mSin3B to a mammal.
[8] The method according to [7] above, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.
[9] The method according to [7] above, wherein the substance capable of binding to mSin3B has a growth inhibitory activity on a human medulloblastoma cell line.
[10] Use of a substance capable of binding to mSin3B for the manufacture of a prophylactic or therapeutic agent for fibromyalgia.
[11] The use according to [10] above, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.
[12] The use according to [10] above, wherein the substance capable of binding to mSin3B has a growth inhibitory activity of a human medulloblastoma cell line.

  According to the present invention, a prophylactic / therapeutic agent for fibromyalgia having an excellent prophylactic / therapeutic effect can be provided.

FIG. 1 shows STD (saturation transfer difference) (compound / mSin3B: 400 μM / 10 μM) of 3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (Example 1). FIG. 2 shows STD (saturation transfer difference) of 1- [4- (difluoromethoxy) phenyl] -2- (3,5-dimethylpiperidyl) ethane-1-one (compound / mSin3B: 400 μM / 10 μM) ( Example 1). FIG. 3 shows the test schedule (upper part) and results (lower part) of the pain-related behavior evaluation test of the ICS model mouse (Example 3). "-○ -Control-Veh" is a control group (non-stressed mouse) vehicle administration group, "-□ -ICS-155" is an ICS model mouse compound 155 administration group, "-■ -ICS-A28" is , ICS model mouse compound A28 administration group, “-● -ICS-Veh” represents a vehicle administration group of ICS model mice, and all show an average value of n = 3.

  The present invention provides a prophylactic or therapeutic agent for fibromyalgia comprising a substance capable of binding to mSin3B. Details will be described below.

(Fibromyalgia)
Fibromyalgia is a disease that causes severe pain throughout the body, and the classification standard proposed by the American College of Rheumatology in 1990 is currently used worldwide as a diagnostic method. According to this standard, pain is observed in any of the five parts of the upper body and lower body, the right and left bodies, and the spine and sternum from the umbilicus, and they persist for at least 3 months, or When a gentle load of 4 kg is applied to the prescribed 18 points of tender points throughout the body and pain is felt at 11 or more points, it is referred to as fibromyalgia.
“Treatment of fibromyalgia” means to completely cure the pathophysiology of fibromyalgia, to suppress the progression and worsening of symptoms without complete cure, or to stop the progression of the pathology, or It means improving part or all of the pathological condition and leading to the direction of healing.
“Prevention of fibromyalgia” means preventing, suppressing or delaying the onset of fibromyalgia pathology.
An “effective amount for treating fibromyalgia” is sufficient to effect such treatment for fibromyalgia when administered to an animal to treat fibromyalgia. Means quantity.
An “effective amount for preventing fibromyalgia” is sufficient to achieve such prophylaxis for fibromyalgia when administered to an animal to prevent fibromyalgia. Means quantity.

(Substance that can bind to mSin3B)
“MSin3B” is a corepressor that specifically binds to the neuroselective transcription repressor NRSF / REST, and the N-terminal transcription repression domain of NRSF / REST is histone deacetylase (HDAC) via the corepressor mSin3B. In the C-terminal domain, HDAC is recruited via CoREST, and the chromatin structure is inactivated via histone deacetylation, thereby suppressing transcription (Proc. Natl Acad. Sci. USA, 96, 13691-13696 (1999)). mSin3B has four PAH domains (PAH1 to 4) with different binding partners and an HDAC synthesis action domain (HID). Among these, PAH1 forms a complex with the N-terminal transcription repression domain of NRSF / REST (J. Mol. Biol., 314, 903-915 (2005)). The molecular biological relationship between mSin3B (particularly the combined action of mSin3B and NRSF / REST) and fibromyalgia is not known at the time of filing of the present application.

The substance that can bind to mSin3B in the present invention (hereinafter, the substance may be referred to as “mSin3B binding compound”) may be any substance as long as it can specifically bind to mSin3B. The binding site (domain) is not particularly limited, but a substance that can bind to the PAH1 domain of mSin3B is preferable.
The binding between mSin3B binding compound and mSin3B is known per se binding assay (radio binding assay etc.), NMR method (chemical shift mapping method, NMR titration method, STD (Saturation transfer difference) -NMR (saturation transfer difference NMR) method) Although it can measure by such as, preferably, it can be confirmed by the STD-NMR method described later.

The mSin3B binding compound of the present invention is not limited as long as it binds to mSin3B, but preferably inhibits mSin3B.
“Inhibition of mSin3B” is not particularly limited as long as it can suppress the function of mSin3B and change the expression of a gene involved in mSin3B. For example, the interaction between mSin3B and NRSF / REST Inhibiting the transcriptional repressive action by inhibiting, inhibiting the transcriptional repressive action by inhibiting the interaction between mSin3B and HDAC, inhibiting the interaction between mSin3B and MeCP2 (methylated DNA is And binding to the transcriptional repressing factor MeCP2 and further binding to mSin3 leads to HDAC function activation). Among these, an embodiment in which the mSin3B binding compound binds to the PAH1 domain and inhibits the formation of a complex of mSin3B and NRSF / REST, thereby inhibiting the transcriptional repressing action.
NRSF (neuron-restrictive sirencer factor) suppresses the expression of nerve-specific genes, which are said to be about 1000 types. Therefore, when NRSF is present even in a small amount of cells, the expression of various neural genes is suppressed and normal nerves are suppressed. As a result of impaired function, it is thought to be the root cause of neurological diseases such as fibromyalgia. Even if NRSF is present in nerve cells, if the binding to mSin3B is inhibited, the mSin3B / HDAC complex cannot be recruited. As a result, the expression of the nerve gene is not suppressed, and the abnormality of the nerve function does not occur. Expected to have therapeutic effects on neurological diseases such as fibromyalgia.

Further, the mSin3B binding compound of the present invention preferably has a human medulloblastoma cell line growth inhibitory activity.
Medulloblastoma is the most malignant childhood brain tumor, and the expression level of NRSF / REST is very high in medulloblastoma cells. Recombinant protein REST-VP16, which antagonizes NRSF / REST and activates the target gene of NRSF / REST, induces apoptosis by promoting the expression of neural genes and further activating the caspase cascade. NRSF / REST has the potential to be a target molecule for therapeutic drugs for medulloblastoma (Nature Med., 7, 826-831 (2000)).
The growth inhibitory activity against the human medulloblastoma cell line of the mSin3B binding compound of the present invention can be measured, for example, by the method described in WO2011 / 099502. Further, it is disclosed in the same literature that an mSin3B binding compound exhibits a growth inhibitory action against a human medulloblastoma cell line.

  The mSin3B binding compound of the present invention is not particularly limited as long as it is defined above. For example, an antibody having an affinity for mSin3B (polyclonal antibody, monoclonal antibody), a compound described in WO2011 / 099502 Pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, and the like (hereinafter, the compound may be referred to as “mSin3B-binding compound of the present invention”).

(Model mouse for fibromyalgia)
In order to prove that the mSin3B binding compound of the present invention is useful for prevention or treatment of fibromyalgia, an ICS (Intermittent Cold Stress) model mouse was used as an animal experimental model of fibromyalgia. This model mouse has been shown to develop systemic hyperalgesia in the long term (several weeks) after stress. Thermal pain hypersensitivity, mechanical allodynia, and pain against chemicals found in the Writing acetate test It exhibits generalized abnormal pain against various stimuli such as hypersensitivity and hypersensitivity caused by electrical stimulation. In addition, female dominance and morphine analgesia are not observed, but antiepileptic drugs such as gabapen and antidepressants have significant pain-inhibiting effects, such as human fibromyalgia in pain pathology and pharmacological sensitivity. Very similar to the patient's clinical symptoms. Details of a specific procedure for preparing an ICS model mouse will be described in the examples described later.

The present inventors have already published a constant cold stress (CCS) model as a control model (which is always left at 4 degrees without repeated temperature changes), and in this model, abnormal pain only lasts for several days. (Mol Pain. 2008 Nov 6; 4:52). In addition, unlike the ICS model mouse used in the present invention, which will be described later, the SART model mouse as an autonomic nerve modulation model subjected to low-temperature stress at 1 hour intervals may only maintain abnormal pain within one week. I know (unpublished). On the other hand, in the ICS model mouse used in the present invention, symptoms similar to fibromyalgia such as long-term generalized hypersensitivity for several weeks and allodynia are observed. Furthermore, the present inventors have also found that female-dominated chronic pain can be obtained by gonadectomy in ICS model mice (Mol Pain. 2008 Nov 6; 4:52).
From these, it can be seen that the ICS model mouse used in the present invention is very useful as an animal experimental model of fibromyalgia.

The preventive or therapeutic effect on fibromyalgia of an mSin3B binding compound using an ICS model mouse can be evaluated based on a known pain-related behavior evaluation method.
The pain-related behavior evaluation methods include Hargreaves test (Thermal Paw Withdrawal test: thermal stimulation pain test method), Paw Pressure test, electrical stimulation-induced pain withdrawal (EPW) test, chemical stimulation test Law.

  The Hargreaves test evaluates a pain threshold for heat stimulation, and can be performed according to a known method (for example, Inoue et al., Nature Medicine, 10: 712-718, 2004) or the like. Specifically, it can be carried out by the method described in Examples below.

(Pharmaceutical preparation comprising mSin3B binding compound)
The mSin3B-binding compound of the present invention can be used as a pharmaceutical preparation (eg, injection, capsule, tablet, powder, granule, etc.) formulated by a conventional method as a human or animal (eg, mouse, rat, hamster, rabbit, cat). , Mammals such as dogs, cows, sheep, monkeys). For example, in terms of the amount of the active ingredient, the dose is about 0.1 to 1000 mg / kg (body weight) per day, preferably about 1 to 500 mg / kg (body weight) per day, once or several times However, the dosage, administration method, and frequency of administration can be appropriately changed depending on symptoms, age, and the like. For example, when formulated into injections, carriers such as distilled water and physiological saline may be used. When formulated into capsules, tablets, powders, granules, starch, lactose, sucrose, calcium carbonate Excipients such as starch paste, gum arabic, gelatin, sodium alginate, carboxymethylcellulose, hydroxypropylcellulose and other binders, magnesium stearate, talc and other lubricants, starch, agar, crystalline cellulose, calcium carbonate Disintegrants such as sodium bicarbonate and sodium alginate may be used. The content of the active ingredient in the preparation can be varied between 1 and 99% by weight. For example, when taking the form of tablets, capsules, granules, powders, etc., it is preferable to contain 5 to 80% by weight of the active ingredient, and in the case of injection, it contains 1 to 10% by weight of the active ingredient. It is preferable to do so.
Although it does not specifically limit as an administration method, Oral administration, intraperitoneal administration, etc. are mentioned.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

[Example 1] Measurement of binding ability to mSin3B by STD-NMR The experiment was conducted under the following STD-NMR measurement conditions.
1. Samples (1) ^Protein: 15 by the method described in Example 1 of N-mSin3B (WO2006 / ^030722, prepared ¹⁵ N-mSin3B (15 N-labeled body PAH1 domain mSin3B (a.a.28-107)) Was used.
(2) Ligand: 3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (purchased from SPECS), 1- [4- (difluoromethoxy) phenyl] -2- (3,5- Dimethylpiperidyl) ethane-1-one (purchased from Enamine) was used.

2. Sample preparation (1) The sample volume required for measurement was 500 μL.
(2) The protein concentration was 10 μM and the ligand concentration was 400 μM.
(3) The solvent was 100 mM phosphate buffer-pH 7.2 (5% d-DMSO), and the protein and the ligand were mixed.

3. NMR measurement conditions 1H-STD, integration 4, measurement time 2 minutes NMR apparatus Bruker AVANCE 600 MHz (cryo-probe), Bruker AVANCE 700 MHz (cryo-probe)
The results are shown in FIGS. The ligand used for the measurement was observed to have an STD spectrum and was determined to be able to bind to the PAH1 domain of mSin3B.

[Example 2] Preparation of fibromyalgia model mouse An ICS model mouse was prepared by repeating the room temperature at room temperature (24 ° C) and low temperature (4 ° C) every 30 minutes during the day and at low temperature at night. did. Specific breeding conditions and environmental temperature are as follows.
(1) On day 0, the mouse to be used was moved to a refrigerator under low temperature conditions at 16:30, and was reared until 10:00 on the next day.
(2) It moved to room temperature at 10:00 of the following day (the 1st day), and was reared alternately by low temperature condition and room temperature condition every 30 minutes until 16:30 thereafter. After 16:30, the animals were raised under low temperature conditions until 10:00 the next morning.
(3) On the second day, the animals were reared in the same manner as on the first day, and transferred to room temperature at 10:00 on the third day.
(4) The control group (non-stressed mice) was kept at room temperature for 3 days.

In this mouse, symptoms similar to fibromyalgia were observed, such as long-term generalized hypersensitivity that lasted for several weeks and also induced allodynia. As described above, this symptom is completely different from neuropathic pain produced by partial nerve ligation or the like.
As a breeding environment for mice, crushed solid feed for general experiments (MF, Oriental, Tokyo), free sterilized purified water solidified with agar (Asahi Co., Ltd.) as water, The mice were bred under constant humidity (55 ± 5%) under light / dark 12 hours (light hours 8-20 hours).

[Example 3] Therapeutic effect of mSin3B binding compound A compound that binds to mSin3B was administered to the ICS model mouse obtained in Example 2 to determine whether the mSin3B binding compound has a therapeutic effect on fibromyalgia. It investigated by conducting the behavioral analysis test about pain.

(1) Preparation of mSin3B binding compound Each mSin3B binding compound is dissolved in DMSO, and a DMSO solution of the mSin3B binding compound is diluted with physiological saline immediately before administration (final concentration of DMSO: 10%), 5 mg / kg. Was administered intraperitoneally (ip). At this time, DMSO (10%) diluted with physiological saline was administered as a vehicle to the control group.
The mSin3B binding compounds used in this example are as follows:
3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (compound 155) (purchased from SPECS) and 1- [4- (difluoromethoxy) phenyl] -2- (3,5-dimethylpiperidyl) ethane- 1-one (compound A28) (purchased from Enamine).

(2) Behavioral analysis related to pain For behavioral analysis related to pain, “Harmreaves test (thermal paw test: thermal stimulation pain test method)” (Inoue et al., Nature Medicine) for evaluating a pain threshold for thermal stimulation. 10: 712-718, 2004). The experimental technique of the Hargreaves test is as follows.
(Hargreaves test method)
ICS model mice were placed in plastic cages placed on glass plates and allowed to adapt in the same environment for over 30 minutes. Thermal stimulation was projected from the bottom of the glass plate to the center of the hind limb footpad, and the latency until the mouse showed a hind limb escape response (Paw Withdrawal Latency: PWL) was measured and evaluated. In the experiment, a normal animal was stimulated to a latency of 10-12 seconds, and the cut off time was set to 20 seconds to prevent tissue damage.
The day when ICS stress starts to be applied is day 0, and the day when ICS stress is applied is post stress day 1 (P1). From P5 to P11 once a day in the morning, 3,5-dimethylpiperidyl 3 as an mSin3B binding compound -Methyl-4-nitrophenyl ketone and 1- [4- (difluoromethoxy) phenyl] -2- (3,5-dimethylpiperidyl) ethane-1-one were physiologically adjusted so that the final concentration of DMSO was 10%. A drug solution dissolved in saline was intraperitoneally administered at 5 mg / kg. However, the pain threshold measurement of P5, P6, P8 and P10 was performed before drug administration.
Pain thresholds were measured at P5, P6, P8, P10, P12, P14 and P16. The latency and strength were measured three times or more and the average value was adopted. Further, an interval of 10 minutes was left before measuring the next threshold value. The experimental group was an ICS stress load group, a non-stress group, a drug administration group, and a non-drug administration group (10% DMSO) (n = 3). The test schedule and results are shown in FIG.

The upper part of FIG. 3 shows the test schedule, and the lower part shows the results of the Hargreaves test. In the lower graph of FIG. 3, PWL (Paw Withdrawal Latency) on the vertical axis indicates the latency (sec) until the mouse exhibits a hindlimb escape response, and the horizontal axis indicates the day when the ICS stress is applied. The number of days elapsed as the day (P1) is shown. “-○ -Control-Veh” is a vehicle administration group of a control group (non-stressed mouse), “-□ -ICS-155” is an ICS model mouse compound 155 administration group, “-■ -ICS-A28”. "Denotes a group administered with Compound A28 of an ICS model mouse, and"-● -ICS-Veh "denotes a vehicle administration group of an ICS model mouse, and each shows an average value of n = 3.
As shown in the lower graph of FIG. 3, when Compound A28 and 115 were administered to ICS model mice, recovery of the pain threshold was observed. Therefore, it was revealed that the mSin3B binding compound shows a therapeutic effect in the ICS model mouse which is a fibromyalgia model.

A substance capable of binding to mSin3B is useful as a prophylactic and / or therapeutic agent for fibromyalgia.
This application is based on Japanese Patent Application No. 2012-267599 for which it applied in Japan, The content is altogether included in this specification.
While the invention has been presented or described with reference to preferred embodiments thereof, various changes in form and detail have been made herein without departing from the scope of the invention as encompassed by the appended claims. It will be appreciated by those skilled in the art. All patents, patent publications and other publications shown or referenced herein are incorporated by reference in their entirety.

Claims (12)

  A prophylactic or therapeutic agent for fibromyalgia comprising a substance capable of binding to mSin3B.   The prophylactic or therapeutic agent according to claim 1, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.   The prophylactic or therapeutic agent according to claim 1, wherein the substance capable of binding to mSin3B has an activity of inhibiting the growth of a human medulloblastoma cell line.   A substance capable of binding to mSin3B, which is used for prevention or treatment of fibromyalgia.   The substance according to claim 4, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.   The substance according to claim 4, wherein the substance capable of binding to mSin3B has a growth inhibitory activity of a human medulloblastoma cell line.   A method for preventing or treating fibromyalgia, comprising administering an effective amount of a substance capable of binding to mSin3B to a mammal.   The method according to claim 7, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.   The method according to claim 7, wherein the substance capable of binding to mSin3B has a growth inhibitory activity of a human medulloblastoma cell line.   Use of a substance capable of binding to mSin3B for the manufacture of a prophylactic or therapeutic agent for fibromyalgia.   The use according to claim 10, wherein the substance capable of binding to mSin3B is a substance that inhibits mSin3B.   The use according to claim 10, wherein the substance capable of binding to mSin3B has a growth inhibitory activity of a human medulloblastoma cell line.