Anti-hyperalgesic effects of calcitonin on neuropathic pain interacting with its peripheral receptors

Molecular Pain

Megumu Yoshimura¹  Akio Matsuda³  Hiroshi Kuriyama²  Takeshi Ohno⁴  Takayuki Komatsu²  Takeshi Yoshimura²  Mineko Takeda²  Akitoshi Ito² 

[1] Graduate School of Health Sciences, Kumamoto Health Science University, Kumamoto, 861-5598, Japan;Laboratory for Development Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Co. Ltd, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan;Pharmaceuticals Research Center, Asahi Kasei Pharma Co. Ltd, Shizuoka, 410-2321, Japan;Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Co. Ltd, Shizuoka, 410-2321, Japan

关键词: Analgesia;    Na⁺ channel;    CCI model;    Neuropathic pain;    Peripheral nerve excitability;    Calcitonin;    Elcatonin;   

Others  :  863836
DOI  :  10.1186/1744-8069-8-42

 received in 2011-09-29, accepted in 2012-05-12,  发布年份 2012

【 摘 要 】

Background

The polypeptide hormone calcitonin is clinically well known for its ability to relieve neuropathic pain such as spinal canal stenosis, diabetic neuropathy and complex regional pain syndrome. Mechanisms for its analgesic effect, however, remain unclear. Here we investigated the mechanism of anti-hyperalgesic action of calcitonin in a neuropathic pain model in rats.

Results

Subcutaneous injection of elcatonin, a synthetic derivative of eel calcitonin, relieved hyperalgesia induced by chronic constriction injury (CCI). Real-time reverse transcriptase-polymerase chain reaction analysis revealed that the CCI provoked the upregulation of tetrodotoxin (TTX)-sensitive Nav.1.3 mRNA and downregulation of TTX-resistant Nav1.8 and Nav1.9 mRNA on the ipsilateral dorsal root ganglion (DRG), which would consequently increase the excitability of peripheral nerves. These changes were reversed by elcatonin. In addition, the gene expression of the calcitonin receptor and binding site of ¹²⁵I-calcitonin was increased at the constricted peripheral nerve tissue but not at the DRG. The anti-hyperalgesic effect and normalization of sodium channel mRNA by elcatonin was parallel to the change of the calcitonin receptor expression. Elcatonin, however, did not affect the sensitivity of nociception or gene expression of sodium channel, while it suppressed calcitonin receptor mRNA under normal conditions.

Conclusions

These results suggest that the anti-hyperalgesic action of calcitonin on CCI rats could be attributable to the normalization of the sodium channel expression, which might be exerted by an unknown signal produced at the peripheral nerve tissue but not by DRG neurons through the activation of the calcitonin receptor. Calcitonin signals were silent in the normal condition and nerve injury may be one of triggers for conversion of a silent to an active signal.

【 授权许可】

   
2012 Ito et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Munson PL: Physiology and pharmacology of thyrocalciotonin. In Handbook of physiology. vol. 7 edition. Edited by Aurbach GD. American Physiological Society, Washington D.C; 1976:443-464.
• [2]Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FA, Martin TJ: Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization. J Clin Invest 1986, 78:355-360.
• [3]Suzuki H, Nakamura I, Takahashi N, Ikuhara T, Matsuzaki K, Isogai Y, Hori M, Suda T: Calcitonin-induced changes in the cytoskeleton are mediated by a signal pathway associated with protein kinase A in osteoclasts. Endocrinology 1996, 137:4685-4690.
• [4]Silva OL, Becker KL: Salmon calcitonin in the treatment of hypercalcemia. Arch Intern Med 1973, 132:337-339.
• [5]Jiménez FE, Albizuri JMA, Alier JMA, Soto JJM, Canales AG: Effectiveness and safety of medium- and long-term elcatonin use in the prevention and treatment of bone mass loss. Curr Ther Res 1995, 56:385-399.
• [6]Orimo H, Morii H, Inoue T, Yamamoto K, Minaguchi H, Ishii Y, Murota K, Fujimaki E, Watanabe R, Harata S, Honjo H, Fujita T: Effect of elcatonin on involutional osteoporosis. J Bone Miner Metab 1996, 14:73-78.
• [7]Reginster JY, Denis D, Deroisy R, Lecart MP, de Longueville M, Zegels B, Sarlet N, Noirfalisse P, Franchimont P: Long-term (3 years) prevention of trabecular postmenopausal bone loss with low-dose intermittent nasal salmon calcitonin. J Bone Miner Res 1994, 9:69-73.
• [8]Pontiroli AE, Pajetta E, Scaglia L, Rubinacci A, Resmini G, Arrigoni M, Pozza G: Analgesic effect of intranasal and intramuscular salmon calcitonin in post-menopausal osteoporosis: a double-blind, double-placebo study. Aging Milano 1994, 6:459-463.
• [9]de Tran QH, Duong S, Finlayson RJ: Lumbar spinal stenosis: a brief review of the nonsurgical management. Can J Anaesth 2010, 57:694-703.
• [10]Quatraro A, Minei A, De Rosa N, Giugliano D: Calcitonin in painful diabetic neuropathy. Lancet 1992, 339:746-747.
• [11]Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ: Treatment of reflex sympathetic dystrophy (CRPS type 1): a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001, 21:511-526.
• [12]Visser EJ, Kwei PL: Salmon calcitonin in the treatment of post herpetic neuralgia. Anaesth Intensive Care 2006, 34:668-671.
• [13]Matayoshi S, Shimodozono M, Hirata Y, Ueda T, Horio S, Kawahira K: Use of calcitonin to prevent complex regional pain syndrome type I in severe hemiplegic patients after stroke. Disabil Rehabil 2009, 31:1773-1779.
• [14]Ito A, Kumamoto E, Takeda M, Shibata K, Sagai H, Yoshimura M: Mechanisms for ovariectomy-induced hyperalgesia and its relief by calcitonin: participation of 5-HT1A-like receptor on C-afferent terminals in substantia gelatinosa of the rat spinal cord. J Neurosci 2000, 20:6302-6308.
• [15]Shibata K, Takeda M, Ito A, Takeda M, Sagai H: Ovariectomy-induced hyperalgesia and antinociceptive effect of elcatonin, a synthetic eel calcitonin. Pharmacol Biochem Behav 1998, 60:371-376.
• [16]Takayama B, Kikuchi S, Konno S, Sekiguchi M: An immunohistochemical study of the antinociceptive effect of calcitonin in ovariectomized rats. BMC Musculoskelet Disord 2008, 15:164.
• [17]Dib-Hajj SD, Black JA, Waxman SG: Voltage-gated sodium channels: therapeutic targets for pain. Pain Med 2009, 10:1260-1269.
• [18]Wada S, Martin TJ, Findlay DM: Homologous regulation of the calcitonin receptor in mouse osteoclast-like cells and human breast cancer T47D cells. Endocrinology 1995, 136:2611-2621.
• [19]Dib-Hajj SD, Black JA, Felts P, Waxman SG: Downregulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc Natl Acad Sci USA 1996, 93:14950-14954.
• [20]Waxman SG, Kocsis JD, Black JA: Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol 1994, 72:466-470.
• [21]Decosterd I, Ji RR, Abdi S, Tate S, Woolf CJ: The pattern of expression of the voltage-gated sodium channels Na(v)1.8 and Na(v)1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models. Pain 2002, 96:269-277.
• [22]Sleeper AA, Cummins TR, Dib-Hajj SD, Hormuzdiar W, Tyrrell L, Waxman SG, Black JA: Changes in expression of two tetrodotoxin-resistant sodium channels and their currents in dorsal root ganglion neurons after sciatic nerve injury but not rhizotomy. J Neurosci 2000, 20:7279-7289.
• [23]Carroll SL, Miller ML, Frohnert PW, Kim SS, Corbett JA: Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 1997, 17:1642-1659.
• [24]Costa B, Trovato AE, Colleoni M, Giagnoni G, Zarini E, Croci T: Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain 2005, 116:52-61.
• [25]Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB: Potent analgesic effects of GDNF in neuropathic pain states. Science 2000, 290:124-127.
• [26]Leffler A, Cummins TR, Dib-Hajj SD, Hormuzdiar WN, Black JA, Waxman SG: GDNF and NGF reverse changes in repriming of TTX-sensitive Na(+) currents following axotomy of dorsal root ganglion neurons. J Neurophysiol 2002, 88:650-658.
• [27]Henderson CE, Phillips HS, Pollock RA, Davies AM, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen RA, Simpson LC: GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 1994, 266:1062-1064.
• [28]Matsuoka I, Meyer M, Thoenen H: Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: comparison of Schwann cells with other cell types. J Neurosci 1991, 11:3165-3177.
• [29]Ito A, Takeda M, Furue H, Shibata K, Hori M, Sagai H, Sakurada T, Yoshimura M: Administration of estrogen shortly after ovariectomy mimics the anti-nociceptive action and change in 5-HT1A-like receptor expression induced by calcitonin in ovariectomized rats. Bone 2004, 35:697-703.
• [30]Takeyama M, Ikawa K, Nagano T, Mori K: Elcatonin raises levels of vasoactive intestinal peptide in human plasma. J Pharm Pharmacol 1996, 48:657-659.
• [31]Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33:87-107.
• [32]Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32:77-88.
• [33]Gibson UE, Heid CA, Williams PM: A novel method for real time quantitative RT-PCR. Genome Res 1996, 6:995-1001.
• [34]Heid CA, Stevens J, Livak KJ, Williams PM: Real time quantitative PCR. Genome Res 1996, 6:986-994.