Muscle injury and inflammation (myositis) in a rabbit model of an unilateral muscle overuse were examined. It is unknown if the tachykinin system has a functional role in this situation. In this study, therefore, the neurokinin-1 receptor (NK-1R) expression patterns were evaluated. White blood cells, nerve fascicles, fine nerve fibers, and blood vessel walls in myositis areas showed NK-1R immunoreaction. NK-1R mRNA reactions were observable for white blood cells and blood vessel walls of these areas. NK-1R immunoreaction and NK-1R mRNA reactions were also seen for muscle fibers showing degenerative and regenerative features. There were almost no NK-1R immunoreactions in normal muscle tissue. Interestingly, marked NK-1R expressions were seen for myositis areas of both the experimental side and the contralateral nonexperimental side. EIA analyses showed that the concentration of substance P in the muscle tissue was clearly increased bilaterally at the experimental end stage, as compared to the situation for normal muscle tissue. These observations show that the tachykinin system is very much involved in the processes that occur in muscle injury/myositis. The effects can be related to proinflammatory effects and/or tissue repair. The fact that there are also marked NK-1R expressions contralaterally indicate that the tachykinin system has crossover effects. 1. Introduction The tachykinins conform to a group of neuropeptides with marked functional roles. The neuropeptide which is most well known in the group is substance P (SP). SP has pronounced pro-inflammatory effects, including the promotion of extravasation and accumulation of leukocytes at sites of injury [1]. SP is also involved in the so-called neurogenic inflammation [2], wound healing [3], and angiogenesis [4]. SP is on the whole known to have autocrine/paracrine effects [5]. SP has a high affinity for the neurokinin-1 receptor (NK-1R), having its major functions via this receptor [6]. The NK-1R has 407 amino acids and belongs to the G-protein-coupled group of receptors [7]. The NK-1R can play an important role in the modulation of the accumulation of white blood cells that occurs in inflammatory processes [8]. There is frequently an upregulation of tachykinins in situations with inflammation and tissue injury. That includes the situation in, for example, ulcerative colitis [9] and experimentally induced acute pancreatitis and associated lung injury [10]. In the latter situation, the NK-1R is considered to play a key role in the damaging process [11]. It is actually a fact that the upregulation of
References
[1]
T. Patel, S. H. Park, L. M. Lin, F. Chiappelli, and G. T. J. Huang, “Substance P induces interleukin-8 secretion from human dental pulp cells,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, vol. 96, no. 4, pp. 478–485, 2003.
[2]
P. Geppetti, R. Nassini, S. Materazzi, and S. Benemei, “The concept of neurogenic inflammation,” BJU International, Supplement, vol. 101, no. 3, pp. 2–6, 2008.
[3]
T. Nishida, “Neurotrophic mediators and corneal wound healing,” Ocular Surface, vol. 3, no. 4, pp. 194–202, 2005.
[4]
H. Kohara, S. Tajima, M. Yamamoto, and Y. Tabata, “Angiogenesis induced by controlled release of neuropeptide substance P,” Biomaterials, vol. 31, no. 33, pp. 8617–8625, 2010.
[5]
M. Mu？oz, A. Pavón, M. Rosso et al., “Immunolocalization of NK-1 receptor and substance P in human normal placenta,” Placenta, vol. 31, no. 7, pp. 649–651, 2010.
[6]
A. D. Hershey and J. E. Krause, “Molecular characterization of a functional cDNA encoding the rat substance P receptor,” Science, vol. 247, no. 4945, pp. 958–962, 1990.
[7]
H. Ohkubo and S. Nakanishi, “Molecular characterization of the three tachykinin receptors,” Annals of the New York Academy of Sciences, vol. 632, pp. 53–62, 1991.
[8]
T. Cao, E. Pintér, S. Al-Rashed, N. Gerard, J. R. Hoult, and S. D. Brain, “Neurokinin-1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: an in vivo study using neurokinin-1 receptor knockout mice,” Journal of Immunology, vol. 164, no. 10, pp. 5424–5429, 2000.
[9]
M. Jonsson, O. Norrgard, and S. Forsgren, “Presence of a marked nonneuronal cholinergic system in human colon: study of normal colon and colon in ulcerative colitis,” Inflammatory Bowel Diseases, vol. 13, no. 11, pp. 1347–1356, 2007.
[10]
M. Bhatia, A. K. Saluja, B. Hofbauer et al., “Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 8, pp. 4760–4765, 1998.
[11]
H. Y. Lau, F. L. Wong, and M. Bhatia, “A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury,” Biochemical and Biophysical Research Communications, vol. 327, no. 2, pp. 509–515, 2005.
[12]
D. Renzi, B. Pellegrini, F. Tonelli, C. Surrenti, and A. Calabro, “Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine,” American Journal of Pathology, vol. 157, no. 5, pp. 1511–1522, 2000.
[13]
C. Remr？d, S. Lonne-Rahm, and K. Nordlind, “Study of substance P and its receptor neurokinin-1 in psoriasis and their relation to chronic stress and pruritus,” Archives of Dermatological Research, vol. 299, no. 2, pp. 85–91, 2007.
[14]
Y. Song, S. Forsgren, J. Yu, R. Lorentzon, and P. S. St？l, “Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise,” Plos ONE, vol. 7, no. 12, Article ID e52230, 2012.
[15]
S. Forsgren, L. Renstrom, C. Purdam, and J. E. Gaida, “TNF-alpha in the locomotor system beyond joints: high degree of involvement in myositis in a rabbit model,” International Journal of Rheumatology, vol. 2012, Article ID 637452, 2012.
[16]
C. Spang, A. Scott, P. Danielson, R. Lorentzon, and S. Forsgren, “VGluT2 and NMDAR1 expression in cells in the inflammatory infiltrates in experimentally induced myositis: evidence of local glutamate signaling suggests autocrine/paracrine effects in an overuse injury model,” Inflammation, vol. 35, no. 1, pp. 39–48, 2012.
[17]
U. Hoheisel, A. Kaske, and S. Mense, “Relationship between neuronal activity and substance P-immunoreactivity in the rat spinal cord during acute and persistent myositis,” Neuroscience Letters, vol. 257, no. 1, pp. 21–24, 1998.
[18]
A. Reinert, A. Kaske, and S. Mense, “Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve ending in rat skeletal muscle,” Experimental Brain Research, vol. 121, no. 2, pp. 174–180, 1998.
[19]
R. Ambalavanar, D. Dessem, A. Moutanni et al., “Muscle inflammation induces a rapid increase in calcitonin gene-related peptide (CGRP) mRNA that temporally relates to CGRP immunoreactivity and nociceptive behavior,” Neuroscience, vol. 143, no. 3, pp. 875–884, 2006.
[20]
G. Andersson, S. Forsgren, A. Scott et al., “Tenocyte hypercellularity and vascular proliferation in a rabbit model of tendinopathy: contralateral effects suggest the involvement of central neuronal mechanisms,” British Journal of Sports Medicine, vol. 45, no. 5, pp. 399–406, 2011.
[21]
C. Backman, L. Boquist, J. Friden, R. Lorentzon, and G. Toolanen, “Chronic achilles paratenonitis with tendinosis: an experimental model in the rabbit,” Journal of Orthopaedic Research, vol. 8, no. 4, pp. 541–547, 1990.
[22]
M. Hansson and S. Forsgren, “Immunoreactive atrial and brain natriuretic peptides are co-localized in Purkinje fibres but not in the innervation of the bovine heart conduction system,” Histochemical Journal, vol. 27, no. 3, pp. 222–230, 1995.
[23]
A. C. Cuello, M. Del Fiacco, and G. Paxinos, “The central and peripheral ends of the substance P-containing sensory neurones in the rat trigeminal system,” Brain Research, vol. 152, no. 3, pp. 499–509, 1978.
[24]
G. N. Van Muijen, D. J. Ruiter, and S. O. Warnaar, “Coexpression of intermediate filament polypeptides in human fetal and adult tissues,” Laboratory Investigation, vol. 57, no. 4, pp. 359–369, 1987.
[25]
J. Pettersson, D. Kalbermatten, A. McGrath, and L. N. Novikova, “Biodegradable fibrin conduit promotes long-term regeneration after peripheral nerve injury in adult rats,” Journal of Plastic, Reconstructive and Aesthetic Surgery, vol. 63, no. 11, pp. 1893–1899, 2010.
[26]
A. M. McGrath, M. Brohlin, P. J. Kingham, L. N. Novikov, M. Wiberg, and L. N. Novikova, “Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury,” Neuroscience Letters, vol. 516, no. 2, pp. 171–176, 2012.
[27]
A. Panoskaltsis-Mortari and R. P. Bucy, “In situ hybridization with digoxigenin-labeled RNA probes: facts and artifacts,” BioTechniques, vol. 18, no. 2, pp. 300–307, 1995.
[28]
P. Danielson, H. Alfredson, and S. Forsgren, “In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis,” Microscopy Research and Technique, vol. 70, no. 10, pp. 908–911, 2007.
[29]
A. Scott, H. Alfredson, and S. Forsgren, “VGIuT2 expression in painful achilles and patellar tendinosis: evidence of local glutamate release by tenocytes,” Journal of Orthopaedic Research, vol. 26, no. 5, pp. 685–692, 2008.
[30]
M. Johansson, M. J？sson, O. Norrgard, and S. Forsgren, “New aspects concerning ulcerative colitis and colonic carcinoma: analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNFreceptor in plasma and mucosa in parallel with histological evaluation of the intestine,” Inflammatory Bowel Diseases, vol. 14, no. 10, pp. 1331–1340, 2008.
[31]
Z. Helyes, K. Elekes, K. Sándor et al., “Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation,” Neuropeptides, vol. 44, no. 5, pp. 399–406, 2010.
[32]
K. Lucas, D. Karamichos, R. Mathew, J. D. Zieske, and J. Stein-Streilein, “Retinal laser burn-induced neuropathy leads to substance P-dependent loss of ocular immune privilege,” Journal of Immunology, vol. 189, no. 3, pp. 1237–1242, 2012.
[33]
H. Qiao, K. Lucas, and J. Stein-Streilein, “Retinal laser burn disrupts immune privilege in the eye,” American Journal of Pathology, vol. 174, no. 2, pp. 414–422, 2009.
[34]
Y. W. Chang, A. Tan, C. Saab, and S. Waxman, “Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn,” Journal of Pain, vol. 11, no. 2, pp. 119–130, 2010.
[35]
J. D. Levine, S. J. Dardick, A. I. Basbaum, and E. Scipio, “Reflex neurogenic inflammation. I. Contribution of the peripheral nervous system to spatially remote inflammatory responses that follow injury,” Journal of Neuroscience, vol. 5, no. 5, pp. 1380–1386, 1985.
[36]
B. L. Kidd, S. C. Cruwys, N. E. Garrett, P. I. Mapp, V. A. Jolliffe, and D. R. Blake, “Neurogenic influences on contralateral responses during experimental rat monoarthritis,” Brain Research, vol. 688, no. 1-2, pp. 72–76, 1995.
[37]
M. Koltzenburg, P. D. Wall, and S. B. McMahon, “Does the right side know what the left is doing?” Trends in Neurosciences, vol. 22, no. 3, pp. 122–127, 1999.
[38]
N. Shenker, R. Haigh, E. Roberts, P. Mapp, N. Harris, and D. Blake, “A review of contralateral responses to a unilateral inflammatory lesion,” Rheumatology, vol. 42, no. 11, pp. 1279–1286, 2003.
[39]
N. G. Shenker, R. C. Haigh, P. I. Mapp, N. Harris, and D. R. Blake, “Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man,” Rheumatology, vol. 47, no. 9, pp. 1417–1421, 2008.
[40]
S. Kelly, J. P. Dunham, and L. F. Donaldson, “Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation,” European Journal of Neuroscience, vol. 26, no. 4, pp. 935–942, 2007.
[41]
O. Hudlicka, L. Graciotti, G. Fulgenzi et al., “The effect of chronic skeletal muscle stimulation on capillary growth in the rat: are sensory nerve fibres involved?” Journal of Physiology, vol. 546, no. 3, pp. 813–822, 2003.
[42]
T. J. Coderre and R. Melzack, “Increased pain sensitivity following heat injury involves a central mechanism,” Behavioural Brain Research, vol. 15, no. 3, pp. 259–262, 1985.
[43]
A. M. Aloisi, C. A. Porro, M. Cavazzuti, P. Baraldi, and G. Carli, “'Mirror pain' in the formalin test: behavioral and 2-deoxyglucose studies,” Pain, vol. 55, no. 2, pp. 267–273, 1993.
[44]
R. Ambalavanar, M. Moritani, A. Moutanni, P. Gangula, C. Yallampalli, and D. Dessem, “Deep tissue inflammation upregulates neuropeptides and evokes nociceptive behaviors which are modulated by a neuropeptide antagonist,” Pain, vol. 120, no. 1-2, pp. 53–68, 2006.
[45]
H. S. Hong, J. Lee, E. Lee et al., “A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells,” Nature Medicine, vol. 15, no. 4, pp. 425–435, 2009.
[46]
S. M. Carlton, S. Zhou, and R. E. Coggeshall, “Localization and activation of substance P receptors in unmyelinated axons of rat glabrous skin,” Brain Research, vol. 734, no. 1-2, pp. 103–108, 1996.
[47]
I. J. Lever, A. D. Grant, S. Pezet, N. P. Gerard, S. D. Brain, and M. Malcangio, “Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback,” Neuropharmacology, vol. 45, no. 8, pp. 1101–1110, 2003.
[48]
A. M. Harrington, J. M. Hutson, and B. R. Southwell, “Immunohistochemical localization of substance P NK1 receptor in guinea pig distal colon,” Neurogastroenterology and Motility, vol. 17, no. 5, pp. 727–737, 2005.
[49]
T. Yamaza, M. A. Kido, B. Wang et al., “Distribution of substance P and neurokinin-1 receptors in the peri-implant epithelium around titanium dental implants in rats,” Cell and Tissue Research, vol. 335, no. 2, pp. 407–415, 2009.
[50]
A. Spreca, M. Grazia Rambotti, M. Rende et al., “Immunocytochemical localization of S-100b protein in degenerating and regenerating rat sciatic nerves,” Journal of Histochemistry and Cytochemistry, vol. 37, no. 4, pp. 441–446, 1989.
[51]
J. Hu, S. Zou, Z. Tang, D. Wang, J. Li, and Z. Gao, “Response of Schwann cells in the inferior alveolar nerve to distraction osteogenesis: an ultrastructural and immunohistochemical study,” International Journal of Oral and Maxillofacial Surgery, vol. 32, no. 3, pp. 318–324, 2003.
[52]
T. Duobles, T. D. S. Lima, B. D. F. A. Levy, and G. Chadi, “S100β and fibroblast growth factor-2 are present in cultured Schwann cells and may exert paracrine actions on the peripheral nerve injury,” Acta Cirurgica Brasileira, vol. 23, no. 6, pp. 555–560, 2008.
[53]
M. C. Brown and V. J. Hardman, “A reassessment of the accuracy of reinnervation by motoneurons following crushing or freezing of the sciatic or lumbar spinal nerves of rats,” Brain, vol. 110, no. 3, pp. 695–705, 1987.
[54]
A. Sipka, K. Langner, H. M. Seyfert, and H. J. Schuberth, “Substance P alters the in vitro LPS responsiveness of bovine monocytes and blood-derived macrophages,” Veterinary Immunology and Immunopathology, vol. 136, no. 3-4, pp. 219–226, 2010.
[55]
K. O. De Swert, K. R. Bracke, T. Demoor, G. G. Brusselle, and G. F. Joos, “Role of the tachykinin NK1 receptor in a murine model of cigarette smoke-induced pulmonary inflammation,” Respiratory Research, vol. 10, article 37, 2009.
[56]
P. W. Mantyh, “Neurobiology of substance P and the NK1 receptor,” Journal of Clinical Psychiatry, vol. 63, supplement 11, pp. 6–10, 2002.
[57]
T. Goto, T. Yamaza, M. A. Kido, and T. Tanaka, “Light- and electron-microscopic study of the distribution of axons containing substance P and the localization of neurokinin-1 receptor in bone,” Cell and Tissue Research, vol. 293, no. 1, pp. 87–93, 1998.
[58]
D. Roosterman, G. S. Cottrell, F. Schmidlin, M. Steinhoff, and N. W. Bunnett, “Recycling and resensitization of the neurokinin 1 receptor: influence of agonist concentration and Rab GTPases,” Journal of Biological Chemistry, vol. 279, no. 29, pp. 30670–30679, 2004.
[59]
E. F. Grady, A. M. Garland, P. D. Gamp, M. Lovett, D. G. Payan, and N. W. Bunnett, “Delineation of the endocytic pathway of substance P and its seven- transmembrane domain NK1 receptor,” Molecular Biology of the Cell, vol. 6, no. 5, pp. 509–524, 1995.
[60]
S. Harrison and P. Geppetti, “Substance P,” International Journal of Biochemistry and Cell Biology, vol. 33, no. 6, pp. 555–576, 2001.
[61]
K. Maghni, M. C. Michoud, M. Alles et al., “Airway smooth muscle cells express functional neurokinin-1 receptors and the nerve-derived preprotachykinin-A gene: regulation by passive sensitization,” American Journal of Respiratory Cell and Molecular Biology, vol. 28, no. 1, pp. 103–110, 2003.
[62]
C. Young, M. Y. Lin, P. J. Wang, and Y. Z. Shen, “Immunocytochemical studies on desmin and vimentin in neuromuscular disorders,” Journal of the Formosan Medical Association, vol. 93, no. 10, pp. 829–835, 1994.
[63]
A. Gallanti, A. Prelle, M. Moggio et al., “Desmin and vimentin as markers of regeneration in muscle diseases,” Acta Neuropathologica, vol. 85, no. 1, pp. 88–92, 1992.
[64]
H. W. Koon, D. Shih, I. Karagiannides et al., “Substance P modulates colitis-asscociated fibrosis,” American Journal of Pathology, vol. 177, no. 5, pp. 2300–2309, 2010.
[65]
H. Vinet-Oliphant, X. Alvarez, E. Buza et al., “Neurokinin-1 receptor (NK1-R) expression in the brains of SIV-infected rhesus macaques: implications for substance P in NK1-R immune cell trafficking into the CNS,” American Journal of Pathology, vol. 177, no. 3, pp. 1286–1297, 2010.
[66]
H. Wu, C. Guan, X. Qin et al., “Upregulation of substance P receptor expression by calcitonin gene-related peptide, a possible cooperative action of two neuropeptides involved in airway inflammation,” Pulmonary Pharmacology and Therapeutics, vol. 20, no. 5, pp. 513–524, 2007.
[67]
T. M. O'Connor, J. O'Connell, D. I. O'Brien et al., “Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis,” Journal of Clinical Immunology, vol. 23, no. 5, pp. 425–435, 2003.
[68]
Y. Zhang, A. Berger, C. D. Milne, and C. J. Paige, “Tachykinins in the immune system,” Current Drug Targets, vol. 7, no. 8, pp. 1011–1020, 2006.
[69]
M. Nowicki, B. Mi？kowiak, and D. Ostalska-Nowicka, “Detection of substance P and its mRNA in human blast cells in childhood lymphoblastic leukaemia using immunocytochemistry and in situ hybridisation,” Folia Histochemica et Cytobiologica, vol. 41, no. 1, pp. 33–36, 2003.
[70]
J. P. Lai, S. D. Douglas, and W. Z. Ho, “Human lymphocytes express substance P and its receptor,” Journal of Neuroimmunology, vol. 86, no. 1, pp. 80–86, 1998.
[71]
A. Schmassmann, B. Waser, B. Flogerzi, and J. C. Reubi, “Expression of functional neurokinin-1 receptors in regenerative glands during gastric wound healing in rodents,” Gastroenterology, vol. 126, no. 3, pp. 784–795, 2004.
[72]
J. R. Scott, P. Muangman, and N. S. Gibran, “Making sense of hypertrophic scar: a role for nerves,” Wound Repair and Regeneration, vol. 15, no. 1, pp. S27–S31, 2007.
[73]
P. Burssens, A. Steyaert, R. Forsyth, E. J. Van Ovost, Y. De Paepe, and R. Verdenk, “Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing,” Foot and Ankle International, vol. 26, no. 10, pp. 832–839, 2005.
[74]
A. E. Steyaert, P. J. Burssens, C. W. Vercruysse, G. G. Vanderstraeten, and R. M. Verbeeck, “The effects of substance P on the biomechanic properties of ruptured rat Achilles' tendon,” Archives of Physical Medicine and Rehabilitation, vol. 87, no. 2, pp. 254–258, 2006.
[75]
O. Carlsson, N. Schizas, J. Li, and P. W. Ackermann, “Substance P injections enhance tissue proliferation and regulate sensory nerve ingrowth in rat tendon repair,” Scandinavian Journal of Medicine and Science in Sports, vol. 21, no. 4, pp. 562–569, 2011.
[76]
G. Andersson, L. J. Backman, A. Scott, R. Lorentzon, S. Forsgren, and P. Danielson, “Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model,” British Journal of Sports Medicine, vol. 45, no. 13, pp. 1017–1022, 2011.
[77]
M. Dib, Z. Zsengeller, A. Mitsialis et al., “A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury,” American Journal of Physiology, vol. 297, no. 4, pp. L687–L697, 2009.
[78]
T. Goode, J. O'Connell, D. O'Brien, T. Goode, C. Bredin, and F. Shanahan, “The role of substance P in inflammatory disease,” Journal of Cell Physiology, vol. 201, pp. 167–180, 2004.
[79]
M. Gad, A. E. Pedersen, N. N. Kristensen, C. D. F. Fernandez, and M. H. Claesson, “Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis,” Inflammatory Bowel Diseases, vol. 15, no. 8, pp. 1174–1182, 2009.
