消痰通络凝胶对骨癌痛大鼠骨代谢及辣椒素受体1表达的影响
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摘要
目的:观察消痰通络凝胶对骨癌痛大鼠机械痛阈值、体重、血清骨代谢标志物及辣椒素受体1表达的影响,探讨其治疗骨癌痛的作用和可能机制。方法:建立骨癌痛大鼠模型,分别以空白凝胶和消痰通络凝胶干预,观察大鼠行为变化,运用免疫组化、ELISA、实时荧光定量PCR及Western blot等分子生物学方法,检测血清Ⅰ型胶原吡啶交联终肽(ICTP)和骨特异碱性磷酸酶(BAP)及组织辣椒素受体1的表达(TRPV1)。结果:消痰通络凝胶干预后大鼠的机械痛觉阈值较模型组明显升高(p<0.05),消痰通络凝胶干预后大鼠血清ICTP水平较模型组明显降低(p<0.05),大鼠骨及下丘脑TRPV1蛋白及mRNA表达较模型组不同程度下调(p<0.05)。结论:消痰通络凝胶可有效抑制骨癌痛,其治疗骨癌痛的机理可能与减少骨吸收、下调骨及下丘脑TRPV1的表达有关。
Objective: To observe the analgesic effects and mechanisms of Xiaotan Tongluo Gel (XTTL Gel消痰通络凝胶)on cancer pain by evaluating the mechanical allodynia threhold , body weight, markers of bone metabolism in serum and TRPV1 expression in a rat model of bone cancer pain (BCP). Methods: A rat model of BCP was established, the rats were applied with placebo gel and XTTL gel, observing the behavior of the rats, detecting ICTP , BAP and TRPV1 expression of the rats by methods of molecular biology as immunohistochemistry, ELISA, real-time PCR and Western blot. Results: The mechanical allodynia threshold of rats applied with XTTL Gel was significantly higher than that of model group(p<0.05),the ICTP in serum of rats with XTTL Gel was much lower than that of model group(p<0.05),and TRPV1 mRNA and protein expression in the bone and hypothalamus of the rats given XTTL Gel were lower than that of model group(p<0.05). Conclusion: XTTL Gel may alleviate bone cancer pain by inhibition of bone resorption and down regulation TRPV1 expression in the bone and hypothalamus .
Objective: To observe the analgesic effects and mechanisms of Xiaotan Tongluo Gel (XTTL Gel消痰通络凝胶)on cancer pain by evaluating the mechanical allodynia threhold , body weight, markers of bone metabolism in serum and TRPV1 expression in a rat model of bone cancer pain (BCP). Methods: A rat model of BCP was established, the rats were applied with placebo gel and XTTL gel, observing the behavior of the rats, detecting ICTP , BAP and TRPV1 expression of the rats by methods of molecular biology as immunohistochemistry, ELISA, real-time PCR and Western blot. Results: The mechanical allodynia threshold of rats applied with XTTL Gel was significantly higher than that of model group(p<0.05),the ICTP in serum of rats with XTTL Gel was much lower than that of model group(p<0.05),and TRPV1 mRNA and protein expression in the bone and hypothalamus of the rats given XTTL Gel were lower than that of model group(p<0.05). Conclusion: XTTL Gel may alleviate bone cancer pain by inhibition of bone resorption and down regulation TRPV1 expression in the bone and hypothalamus .
引文
[1]于世英.恶性肿瘤骨转移的诊断与治疗[M].北京:中国协和医科大学出版社,2006年10月1版:1-14,17-18,33-35,38-67.
[2]于世英.癌症疼痛治疗进展[ J ].医学临床研究, 2003, 20 ( 10) :745.
[3]冯艺.慢性癌性疼痛评估与治疗策略[ J ].中国医刊,2005,40(4):11-14.
[4]项红兵,招伟贤,董航,等.癌性骨痛的病理机制与药物治疗进展[J].Review and CME lecture,2006,13(4): 350-352.
[5] Luger NM, Honore P,Sabino MAC,et a1.Osteoprotegerin diminishes advanced bone cancer pain[J].Cancer Res,2001,61:4047-4038.
[6] Ghilardi JR, Rohrich H, Lindsay TH, et al. Mantyh PW Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain[J]. Neurosci,2005,25:3126–3131.
[7]Medhurst SJ,Walker K,Bowes M,et al.A rat model of bone cancer pain[J]. Pain, 2002, 96: 129-140.
[8] Dixon WJ. Efficient analysis of experimental observations[J]. Annu Rev Pharmacol Toxicol, 1980, 20: 441–62.
[9] Katharine Walkera, Stephen J. Medhurstb, Bruce L. Kiddc.Disease modifying and anti -nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain [J].Pain,2002,100:219–229.
[10]Vetter CS,Groh V,thor Straten P,et a1.Expression of stress-nduced MHC class I related chain molecules on human melanoma[J]. Invest Dermato1,2002,l18(4):600-605.
[11]Lei PEI,Chuan-You LIN,Jia-Pei DAI,et al.Facial pain induces the alteration oftransient receptor potential vanilloid receptor 1 expression in rat trigeminal ganglion[J].Neuroscie- nce Bulletin March, 30,2007,23(2):92-100.
[12]刘朝霞,李秀荣.焦中华治疗肺癌骨转移的经验[J].辽宁中医药杂志,2003,30(11): 872.
[13]罗海英,徐凯,陈达灿.朱良春教授治疗骨转移癌痛32例分析[J].中医药刊,2004,22 (6):975-989.
[14]曹建雄,周勇.壮骨止痛散治疗骨转移癌痛疗效观察[J].中国中医急症,2005,14(5): 425-426.
[15]黄立中,蒋益兰,曾松林,等.阳和汤加味治疗骨转移癌疼痛63例[J].胡南中医学院学报,1997,11(10):20-21.
[16]孙建芝.痰浊证微观辨证指标的实验研究[J].河南中医,1996, 16(2): 21-22.
[17]范美华,周志源.半夏的研究进展[J].西北药学杂志,2004,19(2):90-92.
[18]周效思.威灵仙镇痛抗炎药效研究[J].中华临床药学,2003,4(5):12-13.
[19] Colvin L, Fallon M.Challenges in cancer pain management–bone pain[J].Europan Journal of cancer,2008,44:1083-1090.
[20]Peters CM,Ghilardi JR,Keyser CP,et al.Tumor-induced injury of primary afferent sens- ory nerve fibers in bone cancer pain[J].Experimental Neurology,2005,193:85-100.
[21]Martin CD,Jimenez-Andrade JM,Ghilardi JR,et al.Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum:implications for the genera- tion and maintenance of bone fracture pain[J].Neurosci Lett, 2007,427: 148–152.
[22]DeLeo JA,Colburn RW,Rickman AJ.Cytokine and growth factor immunohistochemic- al spinal profiles in two animal models of mononeuropathy[J].Brain Research,1997,759:50–57.
[23]Wagner R,Myers RR.Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves[J]. Neuroscience,1996,73: 625–629.
[24]Woolf CJ,Ma Q-P,Allchorne A,et al.Peripheral cell types contributing to the hyperalg- esic action of nerve growth factor in inflammationhehe.The Journal of Neuroscience,1996, 16(9):2716–2723.
[25]Sabino MC,Ghilardi JR, Feia KJ, et al. The involvement of prostaglandins intumorige- nesis, tumor-induced osteolysis and bone cancer pain[J]. Journal of Musculoskeletal Neuronal Interactions, 2002,2: 561–562.
[26]Cain DM, Wacnik PW,Turner M,et al. Functional interactions between tumor and peripheral nerve: Changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain[J]. J Neuroscience,2001,21: 9367–9376.
[27]Buijs JT, Henriquez NV, van Overveld PG, et al.TGF-beta and BMP7 interactions in tumour progression and bone metastasis[J].Clinical & Experimental Metastasis,2007,24:609–617.
[28]Sato S, Futakuchi M, Ogawa K, et al.Transforming growth factor beta derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activationassoci- ated osteolysis in the bone microenvironment[J].Cancer Science, 2008, 99: 316-323.
[29]Kingsley LA, Fournier PG, Chirgwin JM, et al. Molecular biology of bone metastasis. Molecular Cancer Therapeutics[J]. 2007, 6: 2609–2617.
[30]Boyle WJ,Simonet WS,Lacey DL.Osteoclast differentiation and activation[J]. Nature, 2008,423:337–342.
[31]Yamamoto J, Kawamata T, Niiyama Y, et al. Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain[J].Neuroscience,2008,151:843–853.
[32]Luger NM, Sabino MA, Schwei MJ, et al. Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain[J]. Pain, 2002,99:397–406.
[33]King T,Vardanyan A, Majuta L, et al. Morphine treatment accelerates sarcoma- induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer[J].Pain,2007,132:154–68.
[34]Honore P, Schwei J, Rogers SD, et al.Cellular and neurochemical remodeling of the spinal cord in bone cancer pain[J]. Prog Brain Res, 2000,129: 389–397.
[35]Vanderah TW, Ossipov MH, Lai J, et al. Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin[J]. Pain,2001, 92:5–9.
[36]Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation[J]. Trends in Neurosciences, 2002,25:319–325.
[37]Nauta, H. J. W. et al. Punctate midline myelotomy for the relief of visceral cancer pain[J]. Neurosurg,2000,92:125–130.
[38]Willis, WD, Al-Chaer, ED, Quast, MJ, et al.A visceral pain pathway in the dorsal column of the spinal cord[J].Proc. Natl Acad. Sci. USA,1999,96:7675–7679.
[39]Kinder M, Chislock E, Bussard KM, et al.Metastatic breast cancer induces an osteobl-ast inflammatory response[J].Experimental Cell Research,2008,314:173–183.
[40]Reale C, Turkiewicz AM, Reale CA. Antalgic treatment of pain associated with bone metastases[J].Critical Reviews in Oncology Hematology, 2001,37(1):1-11.
[41]Kjonniksen I,Winderen M,Bruland O, et al.Validity and usefulness of human tumor models established by intratibial cell inoculation in nude rats[J].Cancer Res,1994,54: 17152-17191.
[42]Schwei MJ,Honore P,Rogers SD, et a1.Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain[J]. Neurosci.1999, 24(19): 10886- 10897.
[43]Wacnik PW.Eikmeier LJ.Ruggles TR, et a1.Functional interactions between tumor and peripheral nerve:morphology,algogen identification,and behavioral characteriza-tion of a new murine model of cancer pain[J]. Neurosci,2001, 21:9355-9366.
[44]Sarlak A,Gundes H,Ozkurkcugil C,et a1.Solitary calcaneal metastasis in superficial bladder carcinoma[J].Int. J .Clin Pract, 2000, 54: 681-682.
[45]项红兵,杨辉,安珂,等.骨癌痛模型和相关疼痛病理机制研究进展[J].临床麻醉学杂志,2005,21(5):520-522.
[46]Mao-Ying QL, Zhao J, Dong ZQ, et al. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells[J]. Biochem and Biophy Res Commu,2006,345(4): 1292–1298.
[47]Pitcher GM, Ritchie J, Henry JL. Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands[J]. Neurosci Methods, 1999;87(2):185- 193.
[48]Sevcik MA, Luger NM, Mach DB, et al. Bone cancer pain: the effects of the bisphosp- honate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis[J]. Pain, 2004;111(1-2):169-180.
[49] M.J. Favus (Ed.). Primer on the Metabolic Bone Diseases an Disorders of Mineral Metabolism [J].Endocrinologist. 1994;4(2):148-149.
[50]Coleman RE.The role of bone markers inmetastatic bone disease[J]. Cancer Treat Rev, 2006,32, Suppl:1-2.
[51]Quinn DL, Ostrow LB, Poerter DK, et al. Staging of non-small cell bronchogenic carcinoma: relationship of the clinical evaluation to organ scans[J]. Chest,1986, 89: 270– 275.
[52]Honore P, Luger N, Sabino M, et al.Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord[J]. Nat Med,2000,6(5):521-528.
[53]Kanakis I, Nikolaou M, Pectasides D,et al.Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer[J].Journal of Pharmaceutical & Biomedical Analysis,2004,34(4): 827-832.
[54]Vinholes J,Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis imaging and assessment of response to cancer treatment[J]. Cancer Treat Rev,1996,22:289–331.
[55]Evans AJ,Robertson JF.Magnetic resonance imaging versus radionuclide scintigraph- yfor screening in bone metastases[J].Clin Radiol, 2000,55:653.
[56]Godersky JC, Smoker WR, Knutzon R.Use of magnetic resonance imaging in the evaluation of metastatic spinal disease[J]. Neurosurgery,1987,21:676–680.
[57]Hamaoka T,Madewell JE, Podoloff DA,et al.Bone imaging in metastatic breast cancer [J]. J Clin Oncol, 2004,22:2942–2953.
[58].Gayed I, Vu T, Johnson M, et al. Comparison of bone and 2-deoxy-2-[18F]Fluoro-d- glucose positron emission tomography in the evaluation of bony metastases in lung cancer [J].Mol Imag Biol,2003,5:26–31.
[59]Van Tinteren H,Hekstra OS,Smit EF,et al.Effectiveness of PET in the preoperative assessment of patients with suspected NSCLC: the PLUS multicenter randomised trial [J]. Lancet, 2002,359:1388–1393.
[60]Watts NB.Clinical utility of biochemical markers of bone remodeling[J].Clin Chem, 1999,45:1359–1368.
[61]Ivaska KK, Kakonen S-M, Gerdhem P, et al. Urinary osteocalcin as a marker of bonemetabolism[J].Clin Chem, 2005,51:618–628.
[62]Sassi ML, Eriksen H, Risteli L, et al.Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K[J].Bone, 2000,26:367–373.
[63]Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover[J].Endocr Rev,1996,17:333–368.
[64]Cole RE,Major P,Lipton A, et al.Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate:zoledr-onic acid[J]. J Clin Oncol, 2005,23:4925-4935.
[65]Berruti A, Dogtiotti L,Gor-zegno G, et al.Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases [J]. Clin Chem,1999,45:1240-1247.
[66]Scher HI, Kelly WK, Zhang ZF, et at.Post-therapy serum prostate specific antigen Level and survival in patients with androgenindependent prostate cancer[J]. J Natl Cancer Inst,1999,91:244-251.
[67]Koga H,Naito S,Koto S,et at.Use of bone turnover marker, pyridinotine cross-Linked carboxyterminat teLopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancel[J].Prostate,1999,39:1-7.
[68]Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma[J]. Haematologica,2004,89 :567–577.
[69] Abildgaard N, Brixen K, Kristensen JE,et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pretreatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy[J]. Br J Haematol, 2003,120:235–242.
[70]Fonseca R,Trendle MC, Leong T,et al.Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients[J].Br J Hoematol, 2000,109:23-29.
[71]Terpos E, Politou M,Szyclo R,et al.Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma[J].Leukemia,2004,18;1420-1426.
[72] Leeming DJ, Koizumi M, Byrjalsen I,et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients[J]. Cancer Epidemiol Biomarkers Prev 2006,15(1):32-38.
[73]Kataoka A, Yuasa T, Kageyama S,et al.Diagnosis of Bone Metastasis in Men with Prostate Cancer by Measurement of Serum ICTP in Combination with Alkali Phosphatase and Prostate-specific AntigenClinical[J]. Oncology, 2006,18:480-484.
[74]Tamada I, Sone I, Tomomitsu T, et at. Biochemical markers for the detection of bone metastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy[J]. J Bone Miner Netob,2001,19:45-51.
[75]Koizumi M, Takahashi S, Ogata E. Comparison of serum bone resorption markers in the diagnosis of skeletal metastasis. Anticancer Res 2003,23(5b):4095-4099.
[76]Sabino MA,Mantyh PW. Pathophysiology of bone cancer pain[J].J SupportOncol, 2005;3(1):15–24.
[77]Sevcik MA,Luger NM,Mach DB,et al.Bone cancer pain: the effects of the bisphospho- nate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis[J].Pain, 2004, 111(1–2) :169–180.
[78]Body JJ.Clinical research update:zoledronate[J].Cancer,1997,80(8 Supp1): 1699-1701.
[79]Skerjance A,Berenson J,Hsu C,et a1.The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function[J].J Clin Pharmacol,2003,43(2):154-162.
[80]Moran, MM, Xu H, Clapham DE. TRP ion channels in the nervous system. Curr Opin Neurobiol 2004,14(3):362–369.
[81]Van Der Stelt M, Di Marzo V, Endovanilloids.Putative endogenous ligands of transient receptor potential vanilloid 1 channels[J].Eur J Biochem, 2004, 271: 1827–1834.
[82]Caterina MJ, Leffler A, Malmberg AB, et al.Impaired nociception and pain sensation in mice lacking the capsaicin receptor[J].Science, 2000,288:306–313.
[83]Davis JB,Gray J,Gunthorpe MJ,et al.Vanilloid receptor-1 is essential forinflammatory thermal hyperalgesia[J].Nature, 2000,405:183–187.
[84]Honore P, Wismer CT, Mikusa J, et al.A-425619 [1-isoquinolin-5-yl-3-(4-trifluorome-thyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats[J].J Pharmacol Exp Ther, 2005,314:410–421.
[85]Gomtsyan A, Bayburt EK, Schmidt RG, et al. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure–activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties[J].J Med Chem, 2005,48:744–752.
[86]Culshaw AJ, Bevan S, Christiansen M, et al. Identification and biological characteriza- tion of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain[J].J Med Chem, 2006,26:471–474.
[87]Ognyanov VI, Balan C, Bannon AW, et al. Design of potent, orally available antagoni- sts of the transient receptor potential vanilloid 1,structure–activity relationships of 2-piper- azin-1-yl -1Hbenzimidazoles[J].J Med Chem 2006,49: 3719–3742.
[88]Chuang HH, Prescott ED, Kong H, et al.Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition[J].Nature, 2001,411:957- 962.
[89]Ji RR, Samad TA, Jin SX, et al.p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia[J]. Neuron, 2002, 36: 57-68.
[90]Lee SY, et al. Sensitization of vanilloid receptor involves an increase in the phosphor- rylated form of the channel[J].Arch Pharm Res, 2005,28:405–412.
[91]Numazaki M, et al. Direct phosphorylation of capsaicin receptor VR1 by protein Kinase C epsilon and identification of two target serine residues[J].J Biol Chem, 2002,277 :13375–13378.
[92]Prescott ED, Julius D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity[J]. Science, 2003,300:1284–1288.
[93]Premkumar LS, Ahern GP.Induction of vanilloid receptor channel activity by protein kinase C[J]. Nature, 2000,408:985–990.
[94]Arpad Szallasi, Francisco Cruz and Pierangelo Geppetti. TRPV1: a therapeutic target for novel analgesic drugs[J]? Trends in Molecular Medicine,12(11):545-554.
[95]Caterina, M.J,et al.The capsaicin receptor: a heat-activated ion channel in the pain pathway[J].Nature,1997,389:816–824.
[96]Mezey E,et al.Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1 -like immunoreactivity, in the central nervous system of the rat and human[J]. Proc.Natl. Acad. Sci,2000,97: 3655–3660.
[97]Toth A, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res,2005,135:162–168.
[98]Krause J.E,Chenard B.L.,Cortright D.N. Transient receptor potentialion channels as targets for the discovery of pain therapeutics[J].Curr. Opin. Investig. Drugs. 2005,6:48– 57.
[99]Tominaga M,Caterina M.J.,Malmberg A.B,et al.The cloned capsaicin receptor integra- tes multiple pain-producing stimuli[J].Neuron,1998,21:531-543.
[100] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C[J].Nature, 2000,408:985–990.
[101]Vellani V, Mapplebeck S, Moriondo A,et al.Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide[J] Physiol, 2001,534:813–825.
[102]Crandall M, Kwash J, Yu W, et al. Activation of protein kinase C sensitizes human VR1 to capsaicin and to moderate decreases in pH at physiological temperatures in Xenopus oocytes[J].Pain, 2002, 98:109–117.
[103]Alessandri-Haber N,et al. A transient receptor potential vanilloid 4-dependent mecha- nism of hyperalgesia is engaged by concerted action of inflammatory mediators [J].J. Neurosci,2006, 26:3864–3874.
[104]Gavva NR, Tamir R, Qu Y,et al.AMG 9810 [(E)-3-(4-t-butylphenyl) -N-(2,3- dihydrobenzo [b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic[J].Pharmacol Exp Ther 2005,313(1):474-484.
[105]Honore P, Wismer CT, Mikusa J, et al. A-425619 [1-isoquinolin-5-yl-3 -(4-trifluoro-methyl- benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats[J]. J Pharmacol Exp Ther, 2005, 314:410-421.
[106]Pomonis JD, Harrison JE, Mark L,et al. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyr- idin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties, II: In vivo characterization in rat models of inflammatory and neuropathic pain[J].J Pharmacol ExpTher, 2003, 306:387- 393.
[107]Walker KM, Urban L, Medhurst SJ,et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain[J]. J Pharmacol Exp Ther, 2003,304:56-62.
[108]Ghilardi JR, Rohrich H, Lindsay TH, et al. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain[J]. J Neurosci, 2005,25: 3126-3131.
[1] Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97: 59–69.
[2] Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80:1588–94.
[3] Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999;45:1359–68.
[4] Krane SM. Identifying genes that regulate bone remodeling as potential therapeutic targets. J Exp Med 2005;201:841–3.
[5]de Baat P, Heijboer MP, de Baat C. Development, physiology, and cell activity of bone. Ned Tijdschr Tandheelkd 2005;112: 258–63.
[6] Seeman E, Delmas PD. Bone quality– the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250–61.
[7] Fohr B, Dunstan CR, Seibel MJ. Clinical review 165: markers of bone remodeling in metastatic bone disease. J Clin Endocrinol Metab 2003;88:5059–75.
[8] Tanaka S, Miyazaki T, Fukuda A, et al. Molecular mechanism of the life and death of the osteoclast. Ann N Y Acad Sci 2006;1068:180–6.
[9] Take I, Takahash N, Kurihara S. Molecules which are involved in osteoclastic bone resorption: from the aspect of targets of treatment for osteoporosis. Clin Calcium 2005;15:741–6.
[10] Katagiri T, Fukuda T. Molecular mechanisms of bone formation and bone-forming factors. Clin Calcium 2005;15:17–22.
[11] Thomsen JS, Ebbesen EN, Mosekilde L. Predicting human vertebral bone strength by vertebral static histomorphometry. Bone 2002;30:502–8.
[12] Tothill P, Hannan WJ. Precision and accuracy of measuring changes in bone mineral density by dual-energy X-ray absorptiometry. Osteoporos Int 2007;18:1515–23.
[13] Balcerzak M, Hamade E, Zhang L, et al. The roles of annexins and alkaline phosphatase in mineralization process. Acta Biochim Pol 2003;50:1019–38.
[14] Cole RE,Major P,Lipton A, etal.Predictive value of bone resorption and formationmarkers in cancer patients with bone metastases receiving the bisphosphonate: zoledronic acid. J Clin Oncol 2005;23:4925-35.
[15] Berruti A, Dogtiotti L, Gor-zegno G, et al. Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 1999;45:1240-7.
[16] Scher HI, Kelly WK, Zhang ZF, et at. Post-therapy serum prostate specific antigen Level and survival in patients with androgenindependent prostate cancer. J Natl Cancer Inst 1999;91:244-51.
[17] Ivaska KK, Kakonen SM, Gerdhem P, et al. Urinary osteocalcin as a marker of bone metabolism. Clin Chem 2005;51:618–28.
[18] Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev 1996;17:333–68.
[19] Terpos E, Politou M, Rahemtulla A. The role of markers of bone remodeling in multiple myeloma. Blood Rev 2005;19:125–42.
[20] Thurairaja R, Iles RK, Jefferson K, et al. Serum amino-terminal propeptide of type 1 procollagen (P1NP) in prostate cancer: a potential predictor of bone metastases and prognosticator for disease progression and survival. Urol Int 2006;76:67–71.
[21] Brasso K, Christensen IJ, Johansen JS, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate 2006;66:503–13.
[22] Ju H-S, Leung S, Brown B, et al. Comparison of analytical performance and biologic- al variability of three bone resorption assays. Clin Chem 1997;43:1570–6.
[23] Demers LM, Costa L, Chinchilli VM, et al. Biochemical markers of bone turnover in patients with metastatic bone disease. Clin Chem 1995;41:1489–94.
[24] Leeming DJ, Koizumi M, Byrjalsen I, et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomarkers Prev 2006;15: 32–8.
[25] Terpos E, Szydlo R, Apperley JF, et al. Soluble receptor activator of nuclear factorkappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064–9.
[26] Sassi ML, Eriksen H, Risteli L, et al. Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 2000;26:367–73.
[27] Jakob C, Zavrski I, Heider U, et al. Serum levels of carboxyterminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifesta- tions in magnetic resonance imaging but lacking lytic bone lesions in conventionalradiogr- aphy. Clin Cancer Res 2003;9:3047–51.
[28] Koga H, Naito S, Koto S, et at. Use of bone turnover marker, pyridinotine cross- Linked carboxyterminat telopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancel: Prostate 1999;39:1-7.1-7.
[29] Abildgaard N,Brixen K,Eriksen EF,et al.Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma. Haematologica 2004;89: 567–77.
[30] Abildgaard N, Brixen K, Kristensen JE, et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pretreatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy. Br J Haematol 2003;120:235–42.
[31]. Fonseca R,Trendle MC, Leong T,et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients.Br J Hoematol 2000;109:23-9.
[32] Terpos E, Politou M, Szyclo R, et al. Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. Leukemia 2004;18;1420-6.
[33] Kataoka A., Yuasa T., Kageyama S, et al. Diagnosis of Bone Metastasis in Men with Prostate Cancer by Measurement of Serum ICTP in Combination with Alkali Phosphatase and Prostate-specific Antigen Clinical Oncology (2006) 18: 480-484
[34] Tamada I, Sone I, Tomomitsu T, et at. Biochemical markers for the detection of bonemetastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy. J Bone Miner Netob 2001 ;19:45-51
[35] Alatalo SL, Ivaska KK, Waguespack SG, et al. Osteoclast-derived serum tartrate- resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 2004;50:883–90..
[36] Raynal C, Delmas PD, Chenu C. Bone sialoprotein stimulates in vitro bone resorption. Endocrinology 1996;137:2347–54.
[37] Valverde P, Tu Q, Chen J. BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res 2005;20:1669–79.
[38] Nagata T, Bellows CG, Kasugai S, et al. Biosynthesis of bone proteins [SPP-1 (secreted phosphoprotein-1, osteopontin), BSP (bone sialoprotein) and SPARC (osteonec- tin)] in association with mineralized-tissue formation by fetal-rat calvarial cells in culture. Biochem J 1991;274: 513–20.
[39]Fedarko NS, Jain A, Karadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7: 4060–6.
[40] Jung K, Lein M, Stephan C, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer 2004;111:783–91.
[41] Woitge HW, Pecherstorfer M, Horn E, et al. Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma. Br J Cancer 2001;84:344–51.
[42] Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142: 5050–5.
[43] Dovio A, Data V, Angeli A. Circulating osteoprotegerin and soluble RANKL: do they have a future in clinical practice? J Endocrinol Invest 2005;28(Suppl.):14–22.
[44] Rogers A, Eastell R. Review: circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 2005;90:6323–31.
[45] Mountzios G, Dimopoulos MA, Bamias A, et al. Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. Acta Oncol 2007;46:221–9.
[46] Aoshima H, Kushida K, Takahashi M, et al. Circadian variation of urinary type I collagen crosslinked C-telopeptide and free and peptide-bound forms of pyridinium crosslinks. Bone 1998;22:73–8.
[47] Pedersen BJ, Schlemmer A, Rosenquist C, et al. Circadian rhythm in type I collagen formation in postmenopausal women with and without osteopenia. Osteoporos Int 1995;5:472–7.
[1] Cortright DN, Krause JE, Broom DC.TRP channels and pain[J]. Biochimica et Biophysica Acta 2007,1772: 978–988.
[2] Oh U, Hwang SW, Kim D. Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons[J]. Neurosci 1996,16:1659–1667.
[3] Wood JN, Winter J, James IF, et al.Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture[J]. Neurosci 1988,8:3208–3220.
[4]Reichling DB,Levine JD.Heat transduction in rat sensory neurons by calcium-dependent activation of a cation channel[J]. Proc Natl Acad Sci 1997,94: 7006–7011.
[5] Cesare P, McNaughton P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin[J]. Proc Natl Acad Sci 1996,93:15435–15439.
[6] Niemeyer BA, Suzuki E, Scott K, et al. The Drosophila light-activated conductance is composed of the two channels TRP and TRPL[J]. Cell 1996,85:651–659.
[7] Scott K, Sun Y, Beckingham K, et al. Calmodulin regulation of Drosophila light-activated channels and receptor function mediates termination of the light response in vivo[J]. Cell 1999,91:375–383.
[8] Vriens J,Owsianik G,Voets T,et al. Invertebrate TRP proteins as functional modelsfor mammalian channels[J]. Pflugers Arch 2004,449(3): 213-226.
[9] Xu H,Blair NT,Clapham DE.Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism [J]. Neurosci. 2005,25:8924–8937.
[10] Macpherson LJ, Geierstanger BH, Viswanath V, et al.The pungency of garlic:activate- ion of TRPA1 and TRPV1 in response to allicin[J]. Curr Biol 2005,15 :929–934.
[11] Macpherson LJ, Hwang SW, Miyamoto T, et al.More than cool: promiscuous relation- ships of menthol and other sensory compounds[J]. Mol Cell Neurosci 2006, 32 : 335–343.
[12] Yoshida T, Inoue R, Morii T, et al. Nitric oxide activates TRP channels by cysteine S- nitrosylation[J]. Nat Chem Biol 2006, 2: 596 - 607.
[13] Trevisani M, Smart D, Gunthorpe MJ, et al. Ethanol elicits and potentiates nociceptorresponses via the vanilloid receptor-1. Nat Neurosci 2002,5:546–551.
[14] Ahern GP, Brooks IM, Miyares RL, et al. Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling[J]. Neurosci 2005,25:5109–5116.
[15] Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat- activated ion channel in the pain pathway[J]. Nature 1997,389: 816–824.
[16] Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. [J] Neuron 1998,21 :531–543.
[17] Behrendt HJ, Germann T, Gillen C, et al.Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay[J]. Br J Pharmacol 2004, 141: 737–745.
[18] Roberts JC, Davis JB, Benham CD. [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution [J] . Brain Res 2004,995:176–183.
[19] Doly S, Fischer J, Salio C, et al. The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes[J]. Neurosci Lett 2004,357:123–126.
[20] Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells[J]. Proc Natl Acad Sci 2001,98:13396–13401.
[21] Inoue K, Koizumi S, Fuziwara S, et al. Functional vanilloid receptors in cultured normal human epidermal keratinocytes[J]. Biochem Biophys Res Commun 2002, 291: 124–129.
[22] Mezey E, Toth ZE, Cortright DN, et al., Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human[J]. Proc Natl Acad Sci 2000, 97: 3655–3660.
[23] Toth A, Boczan J, Kedei N, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res 2005,135:162–168.
[24] Sanchez JF, Krause JE, Cortright DN. The distribution and regulation of vanilloid receptor VR1 and VR1 5' splice variant RNA expression in rat[J]. Neuroscience 2001,107:373–381.
[25] Tóth A, Boczán J, Kedei N, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res 2005,135: 162-168.
[26] Caterina MJ. Transient Receptor Potential Ion Channels as Participants in Thermo- sensation and Thermoregulation[J]. Am J Physiol Regul Integr Comp Physiol 2007,292 (1):64-72.
[27] Caterina M, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor[J]. Science 2000,288:306-313.
[28] Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflamm- atory thermal hyperalgesia[J]. Nature 2000,405:183–187.
[29] T Moriyama, T Iida, K Kobayashi, et al.Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity[J]. Neurosci 2003,23:6058–6062.
[30] Calixto JB, Kassuya CA, Andre E, et al. Contribution of natural products to the disco- very of the transient receptor potential (TRP) channels family and their functions [J]. Pharmacol Ther 2005,106:179–208.
[31] Tominaga M, Caterina MJ. Thermosensation and pain[J]. Neurobiol 2004,61: 3–12.
[32] Tominaga M, Tominaga T. Structure and function of TRPV1[J]. Pflugers Arch 2005 ,451:143–150.
[33] Ji RR, Samad TA, Jin SX, et al. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia[J]. Neuron 2002,36:57–68.
[34] Zhang X, Huang J, McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels[J]. EMBO 2005,24:4211–4223.
[35] Mohapatra DP, Nau C. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway[J]. Biol Chem 2003,278:50080–50090.
[36] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by proteinkinase C[J]. Nature 2000,408: 985–990.
[37] Bhave G, .t. Gereau RW. Posttranslational mechanisms of peripheralsensitization [J]. Neurobiol 2004,61:88–106.
[38] Shin J, Cho H, Hwang SW, et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia[J]. Proc Natl Acad Sci 2002,99:10150–10155.
[39] Amadesi S, Cottrell GS, Divino L, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice[J]. Physiol 2006,575:555–571.
[40] Bolcskei K, Helyes Z, Szabo A, et al. Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using genedeficient mice[J]. Pain 2005,117:368–376.
[41] Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/ capsaicin sensitization model[J]. NeuroReport 1999,10:1511–1516.
[42] Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway[J]. Annu Rev Neurosci 2001,24:487–517.
[43] Szabo A, Helyes Z, Sandor K, et al. Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice[J]. Pharmacol Exp Ther 2005,314:111–119.
[44] Christoph T, Grunweller A, Mika J, et al. Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo[J]. Biochem Biophys Res Commun 2006,350:238–243.
[45] Fukuoka T, Tokunaga A, Tachibana T, et al. VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation[J]. Pain 2002,99: 111–120.
[46] Wu G, Ringkamp M, Hartke TV,et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers[J]. Neurosci 2001,21: 140.
[47] Ghilardi JR, Rohrich H, Lindsay TH, et al.Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 2005, 25:3126–3131.
[48] Sevcik MA, Luger NM, Mach DB, et al.Bone cancer pain: the effects of the bisphosp-honate alendronate on pain, skeletal remodeling, tumor growth and tumornecrosis.Pain 2004,111:169–180.
[49] Boyle WJ, Simonet WS, Lacey DL.Osteoclast differentiation and activation. Nature 2003,423:337–342.
[50] Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998,21:531–543.
[51] Numazaki M, Tominaga T, Toyooka H, et al. Direct phosphorylation of capsaicin receptor VR1 by protein kinase C; epsilon and identification of two target serine residues. J Biol Chem2002,277:13375–13378.
[52] Moriyama T,Higashi T, Togashi K,et al.Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 2005,1:3.
[53] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature 2000, 408:985–990.
[54] Yamamoto H, Kawamata T, Ninomiya T, et al. Endothelin-1 enhances capsaicin -evoked intracellular Ca2+ response via activation of endothelin a receptor in a protein kinase C epsilon-dependent manner in dorsal root ganglion neurons. Neuroscience 2006, 137:949–960.
[55] Van Buren JJ, Bhat S, Rotello R, et al. Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain 2005,1:17.
[56] Zhang X, Huang J, McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO 2005,24:4211–4223.
[57] Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch 2005,451 :143–150
[58] Sabino MA, Ghilardi JR, Jongen JL, et al. Simultaneous reduction in cancer pain,bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res 2002,62:7343–7349.
[59] Peters CM, Lindsay TH, Pomonis JD,et al. Endothelin and the tumorigenic component of bone cancer pain. Neuroscience 2004,126:1043–1052.
[2]于世英.癌症疼痛治疗进展[ J ].医学临床研究, 2003, 20 ( 10) :745.
[3]冯艺.慢性癌性疼痛评估与治疗策略[ J ].中国医刊,2005,40(4):11-14.
[4]项红兵,招伟贤,董航,等.癌性骨痛的病理机制与药物治疗进展[J].Review and CME lecture,2006,13(4): 350-352.
[5] Luger NM, Honore P,Sabino MAC,et a1.Osteoprotegerin diminishes advanced bone cancer pain[J].Cancer Res,2001,61:4047-4038.
[6] Ghilardi JR, Rohrich H, Lindsay TH, et al. Mantyh PW Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain[J]. Neurosci,2005,25:3126–3131.
[7]Medhurst SJ,Walker K,Bowes M,et al.A rat model of bone cancer pain[J]. Pain, 2002, 96: 129-140.
[8] Dixon WJ. Efficient analysis of experimental observations[J]. Annu Rev Pharmacol Toxicol, 1980, 20: 441–62.
[9] Katharine Walkera, Stephen J. Medhurstb, Bruce L. Kiddc.Disease modifying and anti -nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain [J].Pain,2002,100:219–229.
[10]Vetter CS,Groh V,thor Straten P,et a1.Expression of stress-nduced MHC class I related chain molecules on human melanoma[J]. Invest Dermato1,2002,l18(4):600-605.
[11]Lei PEI,Chuan-You LIN,Jia-Pei DAI,et al.Facial pain induces the alteration oftransient receptor potential vanilloid receptor 1 expression in rat trigeminal ganglion[J].Neuroscie- nce Bulletin March, 30,2007,23(2):92-100.
[12]刘朝霞,李秀荣.焦中华治疗肺癌骨转移的经验[J].辽宁中医药杂志,2003,30(11): 872.
[13]罗海英,徐凯,陈达灿.朱良春教授治疗骨转移癌痛32例分析[J].中医药刊,2004,22 (6):975-989.
[14]曹建雄,周勇.壮骨止痛散治疗骨转移癌痛疗效观察[J].中国中医急症,2005,14(5): 425-426.
[15]黄立中,蒋益兰,曾松林,等.阳和汤加味治疗骨转移癌疼痛63例[J].胡南中医学院学报,1997,11(10):20-21.
[16]孙建芝.痰浊证微观辨证指标的实验研究[J].河南中医,1996, 16(2): 21-22.
[17]范美华,周志源.半夏的研究进展[J].西北药学杂志,2004,19(2):90-92.
[18]周效思.威灵仙镇痛抗炎药效研究[J].中华临床药学,2003,4(5):12-13.
[19] Colvin L, Fallon M.Challenges in cancer pain management–bone pain[J].Europan Journal of cancer,2008,44:1083-1090.
[20]Peters CM,Ghilardi JR,Keyser CP,et al.Tumor-induced injury of primary afferent sens- ory nerve fibers in bone cancer pain[J].Experimental Neurology,2005,193:85-100.
[21]Martin CD,Jimenez-Andrade JM,Ghilardi JR,et al.Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum:implications for the genera- tion and maintenance of bone fracture pain[J].Neurosci Lett, 2007,427: 148–152.
[22]DeLeo JA,Colburn RW,Rickman AJ.Cytokine and growth factor immunohistochemic- al spinal profiles in two animal models of mononeuropathy[J].Brain Research,1997,759:50–57.
[23]Wagner R,Myers RR.Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves[J]. Neuroscience,1996,73: 625–629.
[24]Woolf CJ,Ma Q-P,Allchorne A,et al.Peripheral cell types contributing to the hyperalg- esic action of nerve growth factor in inflammationhehe.The Journal of Neuroscience,1996, 16(9):2716–2723.
[25]Sabino MC,Ghilardi JR, Feia KJ, et al. The involvement of prostaglandins intumorige- nesis, tumor-induced osteolysis and bone cancer pain[J]. Journal of Musculoskeletal Neuronal Interactions, 2002,2: 561–562.
[26]Cain DM, Wacnik PW,Turner M,et al. Functional interactions between tumor and peripheral nerve: Changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain[J]. J Neuroscience,2001,21: 9367–9376.
[27]Buijs JT, Henriquez NV, van Overveld PG, et al.TGF-beta and BMP7 interactions in tumour progression and bone metastasis[J].Clinical & Experimental Metastasis,2007,24:609–617.
[28]Sato S, Futakuchi M, Ogawa K, et al.Transforming growth factor beta derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activationassoci- ated osteolysis in the bone microenvironment[J].Cancer Science, 2008, 99: 316-323.
[29]Kingsley LA, Fournier PG, Chirgwin JM, et al. Molecular biology of bone metastasis. Molecular Cancer Therapeutics[J]. 2007, 6: 2609–2617.
[30]Boyle WJ,Simonet WS,Lacey DL.Osteoclast differentiation and activation[J]. Nature, 2008,423:337–342.
[31]Yamamoto J, Kawamata T, Niiyama Y, et al. Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain[J].Neuroscience,2008,151:843–853.
[32]Luger NM, Sabino MA, Schwei MJ, et al. Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain[J]. Pain, 2002,99:397–406.
[33]King T,Vardanyan A, Majuta L, et al. Morphine treatment accelerates sarcoma- induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer[J].Pain,2007,132:154–68.
[34]Honore P, Schwei J, Rogers SD, et al.Cellular and neurochemical remodeling of the spinal cord in bone cancer pain[J]. Prog Brain Res, 2000,129: 389–397.
[35]Vanderah TW, Ossipov MH, Lai J, et al. Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin[J]. Pain,2001, 92:5–9.
[36]Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation[J]. Trends in Neurosciences, 2002,25:319–325.
[37]Nauta, H. J. W. et al. Punctate midline myelotomy for the relief of visceral cancer pain[J]. Neurosurg,2000,92:125–130.
[38]Willis, WD, Al-Chaer, ED, Quast, MJ, et al.A visceral pain pathway in the dorsal column of the spinal cord[J].Proc. Natl Acad. Sci. USA,1999,96:7675–7679.
[39]Kinder M, Chislock E, Bussard KM, et al.Metastatic breast cancer induces an osteobl-ast inflammatory response[J].Experimental Cell Research,2008,314:173–183.
[40]Reale C, Turkiewicz AM, Reale CA. Antalgic treatment of pain associated with bone metastases[J].Critical Reviews in Oncology Hematology, 2001,37(1):1-11.
[41]Kjonniksen I,Winderen M,Bruland O, et al.Validity and usefulness of human tumor models established by intratibial cell inoculation in nude rats[J].Cancer Res,1994,54: 17152-17191.
[42]Schwei MJ,Honore P,Rogers SD, et a1.Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain[J]. Neurosci.1999, 24(19): 10886- 10897.
[43]Wacnik PW.Eikmeier LJ.Ruggles TR, et a1.Functional interactions between tumor and peripheral nerve:morphology,algogen identification,and behavioral characteriza-tion of a new murine model of cancer pain[J]. Neurosci,2001, 21:9355-9366.
[44]Sarlak A,Gundes H,Ozkurkcugil C,et a1.Solitary calcaneal metastasis in superficial bladder carcinoma[J].Int. J .Clin Pract, 2000, 54: 681-682.
[45]项红兵,杨辉,安珂,等.骨癌痛模型和相关疼痛病理机制研究进展[J].临床麻醉学杂志,2005,21(5):520-522.
[46]Mao-Ying QL, Zhao J, Dong ZQ, et al. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells[J]. Biochem and Biophy Res Commu,2006,345(4): 1292–1298.
[47]Pitcher GM, Ritchie J, Henry JL. Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands[J]. Neurosci Methods, 1999;87(2):185- 193.
[48]Sevcik MA, Luger NM, Mach DB, et al. Bone cancer pain: the effects of the bisphosp- honate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis[J]. Pain, 2004;111(1-2):169-180.
[49] M.J. Favus (Ed.). Primer on the Metabolic Bone Diseases an Disorders of Mineral Metabolism [J].Endocrinologist. 1994;4(2):148-149.
[50]Coleman RE.The role of bone markers inmetastatic bone disease[J]. Cancer Treat Rev, 2006,32, Suppl:1-2.
[51]Quinn DL, Ostrow LB, Poerter DK, et al. Staging of non-small cell bronchogenic carcinoma: relationship of the clinical evaluation to organ scans[J]. Chest,1986, 89: 270– 275.
[52]Honore P, Luger N, Sabino M, et al.Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord[J]. Nat Med,2000,6(5):521-528.
[53]Kanakis I, Nikolaou M, Pectasides D,et al.Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer[J].Journal of Pharmaceutical & Biomedical Analysis,2004,34(4): 827-832.
[54]Vinholes J,Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis imaging and assessment of response to cancer treatment[J]. Cancer Treat Rev,1996,22:289–331.
[55]Evans AJ,Robertson JF.Magnetic resonance imaging versus radionuclide scintigraph- yfor screening in bone metastases[J].Clin Radiol, 2000,55:653.
[56]Godersky JC, Smoker WR, Knutzon R.Use of magnetic resonance imaging in the evaluation of metastatic spinal disease[J]. Neurosurgery,1987,21:676–680.
[57]Hamaoka T,Madewell JE, Podoloff DA,et al.Bone imaging in metastatic breast cancer [J]. J Clin Oncol, 2004,22:2942–2953.
[58].Gayed I, Vu T, Johnson M, et al. Comparison of bone and 2-deoxy-2-[18F]Fluoro-d- glucose positron emission tomography in the evaluation of bony metastases in lung cancer [J].Mol Imag Biol,2003,5:26–31.
[59]Van Tinteren H,Hekstra OS,Smit EF,et al.Effectiveness of PET in the preoperative assessment of patients with suspected NSCLC: the PLUS multicenter randomised trial [J]. Lancet, 2002,359:1388–1393.
[60]Watts NB.Clinical utility of biochemical markers of bone remodeling[J].Clin Chem, 1999,45:1359–1368.
[61]Ivaska KK, Kakonen S-M, Gerdhem P, et al. Urinary osteocalcin as a marker of bonemetabolism[J].Clin Chem, 2005,51:618–628.
[62]Sassi ML, Eriksen H, Risteli L, et al.Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K[J].Bone, 2000,26:367–373.
[63]Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover[J].Endocr Rev,1996,17:333–368.
[64]Cole RE,Major P,Lipton A, et al.Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate:zoledr-onic acid[J]. J Clin Oncol, 2005,23:4925-4935.
[65]Berruti A, Dogtiotti L,Gor-zegno G, et al.Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases [J]. Clin Chem,1999,45:1240-1247.
[66]Scher HI, Kelly WK, Zhang ZF, et at.Post-therapy serum prostate specific antigen Level and survival in patients with androgenindependent prostate cancer[J]. J Natl Cancer Inst,1999,91:244-251.
[67]Koga H,Naito S,Koto S,et at.Use of bone turnover marker, pyridinotine cross-Linked carboxyterminat teLopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancel[J].Prostate,1999,39:1-7.
[68]Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma[J]. Haematologica,2004,89 :567–577.
[69] Abildgaard N, Brixen K, Kristensen JE,et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pretreatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy[J]. Br J Haematol, 2003,120:235–242.
[70]Fonseca R,Trendle MC, Leong T,et al.Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients[J].Br J Hoematol, 2000,109:23-29.
[71]Terpos E, Politou M,Szyclo R,et al.Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma[J].Leukemia,2004,18;1420-1426.
[72] Leeming DJ, Koizumi M, Byrjalsen I,et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients[J]. Cancer Epidemiol Biomarkers Prev 2006,15(1):32-38.
[73]Kataoka A, Yuasa T, Kageyama S,et al.Diagnosis of Bone Metastasis in Men with Prostate Cancer by Measurement of Serum ICTP in Combination with Alkali Phosphatase and Prostate-specific AntigenClinical[J]. Oncology, 2006,18:480-484.
[74]Tamada I, Sone I, Tomomitsu T, et at. Biochemical markers for the detection of bone metastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy[J]. J Bone Miner Netob,2001,19:45-51.
[75]Koizumi M, Takahashi S, Ogata E. Comparison of serum bone resorption markers in the diagnosis of skeletal metastasis. Anticancer Res 2003,23(5b):4095-4099.
[76]Sabino MA,Mantyh PW. Pathophysiology of bone cancer pain[J].J SupportOncol, 2005;3(1):15–24.
[77]Sevcik MA,Luger NM,Mach DB,et al.Bone cancer pain: the effects of the bisphospho- nate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis[J].Pain, 2004, 111(1–2) :169–180.
[78]Body JJ.Clinical research update:zoledronate[J].Cancer,1997,80(8 Supp1): 1699-1701.
[79]Skerjance A,Berenson J,Hsu C,et a1.The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function[J].J Clin Pharmacol,2003,43(2):154-162.
[80]Moran, MM, Xu H, Clapham DE. TRP ion channels in the nervous system. Curr Opin Neurobiol 2004,14(3):362–369.
[81]Van Der Stelt M, Di Marzo V, Endovanilloids.Putative endogenous ligands of transient receptor potential vanilloid 1 channels[J].Eur J Biochem, 2004, 271: 1827–1834.
[82]Caterina MJ, Leffler A, Malmberg AB, et al.Impaired nociception and pain sensation in mice lacking the capsaicin receptor[J].Science, 2000,288:306–313.
[83]Davis JB,Gray J,Gunthorpe MJ,et al.Vanilloid receptor-1 is essential forinflammatory thermal hyperalgesia[J].Nature, 2000,405:183–187.
[84]Honore P, Wismer CT, Mikusa J, et al.A-425619 [1-isoquinolin-5-yl-3-(4-trifluorome-thyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats[J].J Pharmacol Exp Ther, 2005,314:410–421.
[85]Gomtsyan A, Bayburt EK, Schmidt RG, et al. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure–activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties[J].J Med Chem, 2005,48:744–752.
[86]Culshaw AJ, Bevan S, Christiansen M, et al. Identification and biological characteriza- tion of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain[J].J Med Chem, 2006,26:471–474.
[87]Ognyanov VI, Balan C, Bannon AW, et al. Design of potent, orally available antagoni- sts of the transient receptor potential vanilloid 1,structure–activity relationships of 2-piper- azin-1-yl -1Hbenzimidazoles[J].J Med Chem 2006,49: 3719–3742.
[88]Chuang HH, Prescott ED, Kong H, et al.Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition[J].Nature, 2001,411:957- 962.
[89]Ji RR, Samad TA, Jin SX, et al.p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia[J]. Neuron, 2002, 36: 57-68.
[90]Lee SY, et al. Sensitization of vanilloid receptor involves an increase in the phosphor- rylated form of the channel[J].Arch Pharm Res, 2005,28:405–412.
[91]Numazaki M, et al. Direct phosphorylation of capsaicin receptor VR1 by protein Kinase C epsilon and identification of two target serine residues[J].J Biol Chem, 2002,277 :13375–13378.
[92]Prescott ED, Julius D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity[J]. Science, 2003,300:1284–1288.
[93]Premkumar LS, Ahern GP.Induction of vanilloid receptor channel activity by protein kinase C[J]. Nature, 2000,408:985–990.
[94]Arpad Szallasi, Francisco Cruz and Pierangelo Geppetti. TRPV1: a therapeutic target for novel analgesic drugs[J]? Trends in Molecular Medicine,12(11):545-554.
[95]Caterina, M.J,et al.The capsaicin receptor: a heat-activated ion channel in the pain pathway[J].Nature,1997,389:816–824.
[96]Mezey E,et al.Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1 -like immunoreactivity, in the central nervous system of the rat and human[J]. Proc.Natl. Acad. Sci,2000,97: 3655–3660.
[97]Toth A, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res,2005,135:162–168.
[98]Krause J.E,Chenard B.L.,Cortright D.N. Transient receptor potentialion channels as targets for the discovery of pain therapeutics[J].Curr. Opin. Investig. Drugs. 2005,6:48– 57.
[99]Tominaga M,Caterina M.J.,Malmberg A.B,et al.The cloned capsaicin receptor integra- tes multiple pain-producing stimuli[J].Neuron,1998,21:531-543.
[100] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C[J].Nature, 2000,408:985–990.
[101]Vellani V, Mapplebeck S, Moriondo A,et al.Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide[J] Physiol, 2001,534:813–825.
[102]Crandall M, Kwash J, Yu W, et al. Activation of protein kinase C sensitizes human VR1 to capsaicin and to moderate decreases in pH at physiological temperatures in Xenopus oocytes[J].Pain, 2002, 98:109–117.
[103]Alessandri-Haber N,et al. A transient receptor potential vanilloid 4-dependent mecha- nism of hyperalgesia is engaged by concerted action of inflammatory mediators [J].J. Neurosci,2006, 26:3864–3874.
[104]Gavva NR, Tamir R, Qu Y,et al.AMG 9810 [(E)-3-(4-t-butylphenyl) -N-(2,3- dihydrobenzo [b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic[J].Pharmacol Exp Ther 2005,313(1):474-484.
[105]Honore P, Wismer CT, Mikusa J, et al. A-425619 [1-isoquinolin-5-yl-3 -(4-trifluoro-methyl- benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats[J]. J Pharmacol Exp Ther, 2005, 314:410-421.
[106]Pomonis JD, Harrison JE, Mark L,et al. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyr- idin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties, II: In vivo characterization in rat models of inflammatory and neuropathic pain[J].J Pharmacol ExpTher, 2003, 306:387- 393.
[107]Walker KM, Urban L, Medhurst SJ,et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain[J]. J Pharmacol Exp Ther, 2003,304:56-62.
[108]Ghilardi JR, Rohrich H, Lindsay TH, et al. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain[J]. J Neurosci, 2005,25: 3126-3131.
[1] Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97: 59–69.
[2] Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80:1588–94.
[3] Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999;45:1359–68.
[4] Krane SM. Identifying genes that regulate bone remodeling as potential therapeutic targets. J Exp Med 2005;201:841–3.
[5]de Baat P, Heijboer MP, de Baat C. Development, physiology, and cell activity of bone. Ned Tijdschr Tandheelkd 2005;112: 258–63.
[6] Seeman E, Delmas PD. Bone quality– the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250–61.
[7] Fohr B, Dunstan CR, Seibel MJ. Clinical review 165: markers of bone remodeling in metastatic bone disease. J Clin Endocrinol Metab 2003;88:5059–75.
[8] Tanaka S, Miyazaki T, Fukuda A, et al. Molecular mechanism of the life and death of the osteoclast. Ann N Y Acad Sci 2006;1068:180–6.
[9] Take I, Takahash N, Kurihara S. Molecules which are involved in osteoclastic bone resorption: from the aspect of targets of treatment for osteoporosis. Clin Calcium 2005;15:741–6.
[10] Katagiri T, Fukuda T. Molecular mechanisms of bone formation and bone-forming factors. Clin Calcium 2005;15:17–22.
[11] Thomsen JS, Ebbesen EN, Mosekilde L. Predicting human vertebral bone strength by vertebral static histomorphometry. Bone 2002;30:502–8.
[12] Tothill P, Hannan WJ. Precision and accuracy of measuring changes in bone mineral density by dual-energy X-ray absorptiometry. Osteoporos Int 2007;18:1515–23.
[13] Balcerzak M, Hamade E, Zhang L, et al. The roles of annexins and alkaline phosphatase in mineralization process. Acta Biochim Pol 2003;50:1019–38.
[14] Cole RE,Major P,Lipton A, etal.Predictive value of bone resorption and formationmarkers in cancer patients with bone metastases receiving the bisphosphonate: zoledronic acid. J Clin Oncol 2005;23:4925-35.
[15] Berruti A, Dogtiotti L, Gor-zegno G, et al. Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 1999;45:1240-7.
[16] Scher HI, Kelly WK, Zhang ZF, et at. Post-therapy serum prostate specific antigen Level and survival in patients with androgenindependent prostate cancer. J Natl Cancer Inst 1999;91:244-51.
[17] Ivaska KK, Kakonen SM, Gerdhem P, et al. Urinary osteocalcin as a marker of bone metabolism. Clin Chem 2005;51:618–28.
[18] Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev 1996;17:333–68.
[19] Terpos E, Politou M, Rahemtulla A. The role of markers of bone remodeling in multiple myeloma. Blood Rev 2005;19:125–42.
[20] Thurairaja R, Iles RK, Jefferson K, et al. Serum amino-terminal propeptide of type 1 procollagen (P1NP) in prostate cancer: a potential predictor of bone metastases and prognosticator for disease progression and survival. Urol Int 2006;76:67–71.
[21] Brasso K, Christensen IJ, Johansen JS, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate 2006;66:503–13.
[22] Ju H-S, Leung S, Brown B, et al. Comparison of analytical performance and biologic- al variability of three bone resorption assays. Clin Chem 1997;43:1570–6.
[23] Demers LM, Costa L, Chinchilli VM, et al. Biochemical markers of bone turnover in patients with metastatic bone disease. Clin Chem 1995;41:1489–94.
[24] Leeming DJ, Koizumi M, Byrjalsen I, et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomarkers Prev 2006;15: 32–8.
[25] Terpos E, Szydlo R, Apperley JF, et al. Soluble receptor activator of nuclear factorkappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064–9.
[26] Sassi ML, Eriksen H, Risteli L, et al. Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 2000;26:367–73.
[27] Jakob C, Zavrski I, Heider U, et al. Serum levels of carboxyterminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifesta- tions in magnetic resonance imaging but lacking lytic bone lesions in conventionalradiogr- aphy. Clin Cancer Res 2003;9:3047–51.
[28] Koga H, Naito S, Koto S, et at. Use of bone turnover marker, pyridinotine cross- Linked carboxyterminat telopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancel: Prostate 1999;39:1-7.1-7.
[29] Abildgaard N,Brixen K,Eriksen EF,et al.Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma. Haematologica 2004;89: 567–77.
[30] Abildgaard N, Brixen K, Kristensen JE, et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pretreatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy. Br J Haematol 2003;120:235–42.
[31]. Fonseca R,Trendle MC, Leong T,et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients.Br J Hoematol 2000;109:23-9.
[32] Terpos E, Politou M, Szyclo R, et al. Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. Leukemia 2004;18;1420-6.
[33] Kataoka A., Yuasa T., Kageyama S, et al. Diagnosis of Bone Metastasis in Men with Prostate Cancer by Measurement of Serum ICTP in Combination with Alkali Phosphatase and Prostate-specific Antigen Clinical Oncology (2006) 18: 480-484
[34] Tamada I, Sone I, Tomomitsu T, et at. Biochemical markers for the detection of bonemetastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy. J Bone Miner Netob 2001 ;19:45-51
[35] Alatalo SL, Ivaska KK, Waguespack SG, et al. Osteoclast-derived serum tartrate- resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 2004;50:883–90..
[36] Raynal C, Delmas PD, Chenu C. Bone sialoprotein stimulates in vitro bone resorption. Endocrinology 1996;137:2347–54.
[37] Valverde P, Tu Q, Chen J. BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res 2005;20:1669–79.
[38] Nagata T, Bellows CG, Kasugai S, et al. Biosynthesis of bone proteins [SPP-1 (secreted phosphoprotein-1, osteopontin), BSP (bone sialoprotein) and SPARC (osteonec- tin)] in association with mineralized-tissue formation by fetal-rat calvarial cells in culture. Biochem J 1991;274: 513–20.
[39]Fedarko NS, Jain A, Karadag A, et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7: 4060–6.
[40] Jung K, Lein M, Stephan C, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer 2004;111:783–91.
[41] Woitge HW, Pecherstorfer M, Horn E, et al. Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma. Br J Cancer 2001;84:344–51.
[42] Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142: 5050–5.
[43] Dovio A, Data V, Angeli A. Circulating osteoprotegerin and soluble RANKL: do they have a future in clinical practice? J Endocrinol Invest 2005;28(Suppl.):14–22.
[44] Rogers A, Eastell R. Review: circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 2005;90:6323–31.
[45] Mountzios G, Dimopoulos MA, Bamias A, et al. Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. Acta Oncol 2007;46:221–9.
[46] Aoshima H, Kushida K, Takahashi M, et al. Circadian variation of urinary type I collagen crosslinked C-telopeptide and free and peptide-bound forms of pyridinium crosslinks. Bone 1998;22:73–8.
[47] Pedersen BJ, Schlemmer A, Rosenquist C, et al. Circadian rhythm in type I collagen formation in postmenopausal women with and without osteopenia. Osteoporos Int 1995;5:472–7.
[1] Cortright DN, Krause JE, Broom DC.TRP channels and pain[J]. Biochimica et Biophysica Acta 2007,1772: 978–988.
[2] Oh U, Hwang SW, Kim D. Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons[J]. Neurosci 1996,16:1659–1667.
[3] Wood JN, Winter J, James IF, et al.Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture[J]. Neurosci 1988,8:3208–3220.
[4]Reichling DB,Levine JD.Heat transduction in rat sensory neurons by calcium-dependent activation of a cation channel[J]. Proc Natl Acad Sci 1997,94: 7006–7011.
[5] Cesare P, McNaughton P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin[J]. Proc Natl Acad Sci 1996,93:15435–15439.
[6] Niemeyer BA, Suzuki E, Scott K, et al. The Drosophila light-activated conductance is composed of the two channels TRP and TRPL[J]. Cell 1996,85:651–659.
[7] Scott K, Sun Y, Beckingham K, et al. Calmodulin regulation of Drosophila light-activated channels and receptor function mediates termination of the light response in vivo[J]. Cell 1999,91:375–383.
[8] Vriens J,Owsianik G,Voets T,et al. Invertebrate TRP proteins as functional modelsfor mammalian channels[J]. Pflugers Arch 2004,449(3): 213-226.
[9] Xu H,Blair NT,Clapham DE.Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism [J]. Neurosci. 2005,25:8924–8937.
[10] Macpherson LJ, Geierstanger BH, Viswanath V, et al.The pungency of garlic:activate- ion of TRPA1 and TRPV1 in response to allicin[J]. Curr Biol 2005,15 :929–934.
[11] Macpherson LJ, Hwang SW, Miyamoto T, et al.More than cool: promiscuous relation- ships of menthol and other sensory compounds[J]. Mol Cell Neurosci 2006, 32 : 335–343.
[12] Yoshida T, Inoue R, Morii T, et al. Nitric oxide activates TRP channels by cysteine S- nitrosylation[J]. Nat Chem Biol 2006, 2: 596 - 607.
[13] Trevisani M, Smart D, Gunthorpe MJ, et al. Ethanol elicits and potentiates nociceptorresponses via the vanilloid receptor-1. Nat Neurosci 2002,5:546–551.
[14] Ahern GP, Brooks IM, Miyares RL, et al. Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling[J]. Neurosci 2005,25:5109–5116.
[15] Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat- activated ion channel in the pain pathway[J]. Nature 1997,389: 816–824.
[16] Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. [J] Neuron 1998,21 :531–543.
[17] Behrendt HJ, Germann T, Gillen C, et al.Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay[J]. Br J Pharmacol 2004, 141: 737–745.
[18] Roberts JC, Davis JB, Benham CD. [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution [J] . Brain Res 2004,995:176–183.
[19] Doly S, Fischer J, Salio C, et al. The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes[J]. Neurosci Lett 2004,357:123–126.
[20] Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells[J]. Proc Natl Acad Sci 2001,98:13396–13401.
[21] Inoue K, Koizumi S, Fuziwara S, et al. Functional vanilloid receptors in cultured normal human epidermal keratinocytes[J]. Biochem Biophys Res Commun 2002, 291: 124–129.
[22] Mezey E, Toth ZE, Cortright DN, et al., Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human[J]. Proc Natl Acad Sci 2000, 97: 3655–3660.
[23] Toth A, Boczan J, Kedei N, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res 2005,135:162–168.
[24] Sanchez JF, Krause JE, Cortright DN. The distribution and regulation of vanilloid receptor VR1 and VR1 5' splice variant RNA expression in rat[J]. Neuroscience 2001,107:373–381.
[25] Tóth A, Boczán J, Kedei N, et al. Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain[J]. Brain Res Mol Brain Res 2005,135: 162-168.
[26] Caterina MJ. Transient Receptor Potential Ion Channels as Participants in Thermo- sensation and Thermoregulation[J]. Am J Physiol Regul Integr Comp Physiol 2007,292 (1):64-72.
[27] Caterina M, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor[J]. Science 2000,288:306-313.
[28] Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflamm- atory thermal hyperalgesia[J]. Nature 2000,405:183–187.
[29] T Moriyama, T Iida, K Kobayashi, et al.Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity[J]. Neurosci 2003,23:6058–6062.
[30] Calixto JB, Kassuya CA, Andre E, et al. Contribution of natural products to the disco- very of the transient receptor potential (TRP) channels family and their functions [J]. Pharmacol Ther 2005,106:179–208.
[31] Tominaga M, Caterina MJ. Thermosensation and pain[J]. Neurobiol 2004,61: 3–12.
[32] Tominaga M, Tominaga T. Structure and function of TRPV1[J]. Pflugers Arch 2005 ,451:143–150.
[33] Ji RR, Samad TA, Jin SX, et al. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia[J]. Neuron 2002,36:57–68.
[34] Zhang X, Huang J, McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels[J]. EMBO 2005,24:4211–4223.
[35] Mohapatra DP, Nau C. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway[J]. Biol Chem 2003,278:50080–50090.
[36] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by proteinkinase C[J]. Nature 2000,408: 985–990.
[37] Bhave G, .t. Gereau RW. Posttranslational mechanisms of peripheralsensitization [J]. Neurobiol 2004,61:88–106.
[38] Shin J, Cho H, Hwang SW, et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia[J]. Proc Natl Acad Sci 2002,99:10150–10155.
[39] Amadesi S, Cottrell GS, Divino L, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice[J]. Physiol 2006,575:555–571.
[40] Bolcskei K, Helyes Z, Szabo A, et al. Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using genedeficient mice[J]. Pain 2005,117:368–376.
[41] Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/ capsaicin sensitization model[J]. NeuroReport 1999,10:1511–1516.
[42] Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway[J]. Annu Rev Neurosci 2001,24:487–517.
[43] Szabo A, Helyes Z, Sandor K, et al. Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice[J]. Pharmacol Exp Ther 2005,314:111–119.
[44] Christoph T, Grunweller A, Mika J, et al. Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo[J]. Biochem Biophys Res Commun 2006,350:238–243.
[45] Fukuoka T, Tokunaga A, Tachibana T, et al. VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation[J]. Pain 2002,99: 111–120.
[46] Wu G, Ringkamp M, Hartke TV,et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers[J]. Neurosci 2001,21: 140.
[47] Ghilardi JR, Rohrich H, Lindsay TH, et al.Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 2005, 25:3126–3131.
[48] Sevcik MA, Luger NM, Mach DB, et al.Bone cancer pain: the effects of the bisphosp-honate alendronate on pain, skeletal remodeling, tumor growth and tumornecrosis.Pain 2004,111:169–180.
[49] Boyle WJ, Simonet WS, Lacey DL.Osteoclast differentiation and activation. Nature 2003,423:337–342.
[50] Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998,21:531–543.
[51] Numazaki M, Tominaga T, Toyooka H, et al. Direct phosphorylation of capsaicin receptor VR1 by protein kinase C; epsilon and identification of two target serine residues. J Biol Chem2002,277:13375–13378.
[52] Moriyama T,Higashi T, Togashi K,et al.Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 2005,1:3.
[53] Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature 2000, 408:985–990.
[54] Yamamoto H, Kawamata T, Ninomiya T, et al. Endothelin-1 enhances capsaicin -evoked intracellular Ca2+ response via activation of endothelin a receptor in a protein kinase C epsilon-dependent manner in dorsal root ganglion neurons. Neuroscience 2006, 137:949–960.
[55] Van Buren JJ, Bhat S, Rotello R, et al. Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain 2005,1:17.
[56] Zhang X, Huang J, McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO 2005,24:4211–4223.
[57] Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch 2005,451 :143–150
[58] Sabino MA, Ghilardi JR, Jongen JL, et al. Simultaneous reduction in cancer pain,bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res 2002,62:7343–7349.
[59] Peters CM, Lindsay TH, Pomonis JD,et al. Endothelin and the tumorigenic component of bone cancer pain. Neuroscience 2004,126:1043–1052.