Tendinopathy is a clinical diagnosis of localised tendon pain often confirmed by imaging findings. The pathophysiological cause of the pain is unknown and the sympathetic nervous system (SNS) may be implicated.
To review what is known regarding the role of the SNS in human tendinopathy.
Published data describing sympathetic innervation or an index of sympathetic activity in human tendons were eligible for inclusion.
Bibliographical databases (AMED, Biological Abstracts, CINAHL Plus, EMBASE, MEDLINE, Scopus, SPORTDiscus and Web of Science) were searched for relevant articles. Reference lists from included articles were screened for additional articles.
Studies were scored with a quality assessment tool to identify potential sources of bias. Each question had an explicit decision rule to guide assessment.
Nine case–control and four cross-sectional studies examined sympathetic innervation of tendons. There was evidence suggesting a lack of difference in sympathetic innervation of tendon proper between tendinopathy biopsies and healthy controls. In contrast, the paratendinous tissue showed evidence of increased sympathetic innervation in painful tendons. The most notable increase in SNS markers was seen in abnormal tenocytes from painful tendons. Data from two studies were suitable for meta-analysis. These heterogeneous studies revealed no difference in sympathetic innervation between painful and pain-free tendons. No studies recorded SNS activity in vivo.
Sympathetic innervation in painful tendons depends on tissue type. Abnormal tenocytes may have increased capacity for self-production of sympathetic neurotransmitters. Future insight may be gained by measuring global in vivo sympathetic drive in tendinopathy.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Maffulli N, Wong J, Almekinders LC. Types and epidemiology of tendinopathy. Clin Sports Med. 2003;22(4):675–92.
Rio E, Moseley L, Purdam C, et al. The pain of tendinopathy: physiological or pathophysiological? Sports Med. 2014;44(1):9–23.
Andersson G, Danielson P, Alfredson H, et al. Nerve-related characteristics of ventral paratendinous tissue in chronic Achilles tendinosis. Knee Surg Sports Traumatol Arthrosc. 2007;15(10):1272–9.
Bjur D, Alfredson H, Forsgren S. Presence of the neuropeptide Y1 receptor in tenocytes and blood vessel walls in the human Achilles tendon. Br J Sports Med. 2009;43(14):1136–42.
Bjur D, Danielson P, Alfredson H, et al. Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon. Histol Histopathol. 2008;23(2):197–208.
Danielson P, Alfredson H, Forsgren S. Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man. Microsc Res Tech. 2007;70(4):310–24.
Danielson P, Alfredson H, Forsgren S. In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis. Microsc Res Tech. 2007;70(10):908–11.
Danielson P, Andersson G, Alfredson H, et al. Marked sympathetic component in the perivascular innervation of the dorsal paratendinous tissue of the patellar tendon in arthroscopically treated tendinosis patients. Knee Surg Sports Traumatol Arthrosc. 2008;16(6):621–6.
Sasaki K, Ohki G, Iba K, et al. Innervation pattern at the undersurface of the extensor carpi radialis brevis tendon in recalcitrant tennis elbow. J Orthop Sci. 2013;18(4):528–35.
Tosounidis T, Hadjileontis C, Triantafyllou C, et al. Evidence of sympathetic innervation and α1-adrenergic receptors of the long head of the biceps brachii tendon. J Orthop Sci. 2013;18(2):238–44.
Zeisig E, Ljung BO, Alfredson H, et al. Immunohistochemical evidence of local production of catecholamines in cells of the muscle origins at the lateral and medial humeral epicondyles: of importance for the development of tennis and golfer’s elbow? Br J Sports Med. 2009;43(4):269–75.
Guyton AC, Hall JE. Textbook of medical physiology. 11th ed. Philadelphia: W. B. Saunders; 2006.
Masuo K, Mikami H, Ogihara T, et al. Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens. 1997;10(1):77–83.
Forsgren S. Neuropeptide Y-like immunoreactivity in relation to the distribution of sympathetic nerve fibers in the heart conduction system. J Mol Cell Cardiol. 1989;21(3):279–90.
Kaufman S. Tyrosine hydroxylase. Adv Enzymol Relat Areas Mol Biol. 1995;70:103–220.
Nagatsu T. Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. Essays Biochem. 1995;30:15–35.
Ramos-Vara JA, Miller MA. When tissue antigens and antibodies get along: revisiting the technical aspects of immunohistochemistry: the red, brown, and blue technique. Vet Pathol. 2014;51(1):42–87.
Flaa A, Aksnes TA, Kjeldsen SE, et al. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Metabolism. 2008;57(10):1422–7.
Schlereth T, Birklein F. The sympathetic nervous system and pain. Neuromolecular Med. 2008;10(3):141–7.
Alpantaki K, McLaughlin D, Karagogeos D, et al. Sympathetic and sensory neural elements in the tendon of the long head of the biceps. J Bone Joint Surg Am. 2005;87(7):1580–3.
Khan KM, Cook JL, Taunton JE, et al. Overuse tendinosis, not tendinitis part 1: a new paradigm for a difficult clinical problem. Phys Sportsmed. 2000;28(5):38–48.
Lin TW, Cardenas L, Soslowsky LJ. Biomechanics of tendon injury and repair. J Biomech. 2004;37(6):865–77.
Khan KM, Cook JL, Bonar F, et al. Histopathology of common tendinopathies: update and implications for clinical management. Sports Med. 1999;27(6):393–408.
Maffulli N, Khan KM, Puddu G. Overuse tendon conditions: time to change a confusing terminology. Arthroscopy. 1998;14(8):840–3.
Cook JL, Feller JA, Bonar SF, et al. Abnormal tenocyte morphology is more prevalent than collagen disruption in asymptomatic athletes’ patellar tendons. J Orthop Res. 2004;22(2):334–8.
Alfredson H, Thorsen K, Lorentzon R. In situ microdialysis in tendon tissue: high levels of glutamate, but not prostaglandin E2 in chronic Achilles tendon pain. Knee Surg Sports Traumatol Arthrosc. 1999;7(6):378–81.
Khan KM, Bonar F, Desmond PM, et al. Patellar tendinosis (jumper’s knee): findings at histopathologic examination, US, and MR imaging. Victorian Institute of Sport Tendon Study Group. Radiology. 1996;200(3):821–7.
Astrom M, Rausing A. Chronic Achilles tendinopathy: a survey of surgical and histopathologic findings. Clin Orthop Relat Res. 1995;316:151–64.
van Dijk CN, van Sterkenburg MN, Wiegerinck JI, et al. Terminology for Achilles tendon related disorders. Knee Surg Sports Traumatol Arthrosc. 2011;19(5):835–41.
Forde MS, Punnett L, Wegman DH. Prevalence of musculoskeletal disorders in union ironworkers. J Occup Environ Hyg. 2005;2(4):203–12.
Buchbinder R, Green SE, Youd JM, et al. Systematic review of the efficacy and safety of shock wave therapy for lateral elbow pain. J Rheumatol. 2006;33(7):1351–63.
Buchbinder R, Johnston RV, Barnsley L, et al. Surgery for lateral elbow pain. Cochrane Database Syst Rev. 2011;3:CD003525.
Cumpston M, Johnston RV, Wengier L, et al. Topical glyceryl trinitrate for rotator cuff disease. Cochrane Database Syst Rev. 2009;3:CD006355.
Kingma JJ, de Knikker R, Wittink HM, et al. Eccentric overload training in patients with chronic Achilles tendinopathy: a systematic review. Br J Sports Med. 2007;41(6):e3.
Benazzo F, Stennardo G, Valli M. Achilles and patellar tendinopathies in athletes: pathogenesis and surgical treatment. Bull Hosp Jt Dis. 1996;54(4):236–40.
Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med. 2005;15(3):133–5.
Kvist M. Achilles tendon overuse injuries: a clinical and pathophysiological study in athletes [dissertation]. Finland: Turki University; 1991.
van Sterkenburg MN, van Dijk CN. Mid-portion Achilles tendinopathy: why painful? An evidence-based philosophy. Knee Surg Sports Traumatol Arthrosc. 2011;19(8):1367–75.
Rees JD, Maffulli N, Cook J. Management of tendinopathy. Am J Sports Med. 2009;37(9):1855–67.
Malliaras P, Cook J. Patellar tendons with normal imaging and pain: change in imaging and pain status over a volleyball season. Clin J Sport Med. 2006;16(5):388–91.
De Jonge S, Warnaars JL, De Vos RJ, et al. Relationship between neovascularization and clinical severity in Achilles tendinopathy in 556 paired measurements. Scand J Med Sci Sports. 2014;24(5):773–8.
Lichtwark GA, Wilson AM. In vivo mechanical properties of the human Achilles tendon during one-legged hopping. J Exp Biol. 2005;208(Pt 24):4715–25.
Cook JL, Purdam C. Is compressive load a factor in the development of tendinopathy? Br J Sports Med. 2012;46(3):163–8.
Rolf C, Movin T. Etiology, histopathology, and outcome of surgery in achillodynia. Foot Ankle Int. 1997;18(9):565–9.
Gaida JE, Alfredson L, Kiss ZS, et al. Dyslipidemia in Achilles tendinopathy is characteristic of insulin resistance. Med Sci Sports Exerc. 2009;41(6):1194–7.
Cronin NJ, Peltonen J, Ishikawa M, et al. Achilles tendon length changes during walking in long-term diabetes patients. Clin Biomech (Bristol, Avon). 2010;25(5):476–82.
Giacomozzi C, D’Ambrogi E, Uccioli L, et al. Does the thickening of Achilles tendon and plantar fascia contribute to the alteration of diabetic foot loading? Clin Biomech (Bristol, Avon). 2005;20(5):532–9.
Batista F, Nery C, Pinzur M, et al. Achilles tendinopathy in diabetes mellitus. Foot Ankle Int. 2008;29(5):498–501.
Ardic F, Soyupek F, Kahraman Y, et al. The musculoskeletal complications seen in type II diabetics: predominance of hand involvement. Clin Rheumatol. 2003;22(3):229–33.
Aydeniz A, Gursoy S, Guney E. Which musculoskeletal complications are most frequently seen in type 2 diabetes mellitus? J Int Med Res. 2008;36(3):505–11.
Chammas M, Bousquet P, Renard E, et al. Dupuytren’s disease, carpal tunnel syndrome, trigger finger, and diabetes mellitus. J Hand Surg Am. 1995;20(1):109–14.
Renard E, Jacques D, Chammas M, et al. Increased prevalence of soft tissue hand lesions in type 1 and type 2 diabetes mellitus: various entities and associated significance. Diabetes Metab. 1994;20(6):513–21.
Yosipovitch G, Yosipovitch Z, Karp M, et al. Trigger finger in young patients with insulin dependent diabetes. J Rheumatol. 1990;17(7):951–2.
Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain. 2000;16(2 Suppl):S12–20.
Wong HY. Neural mechanisms of joint pain. Ann Acad Med Singapore. 1993;22(4):646–50.
Chabal C, Jacobson L, Russell LC, et al. Pain response to perineuromal injection of normal saline, epinephrine, and lidocaine in humans. Pain. 1992;49(1):9–12.
Torebjork E, Wahren L, Wallin G, et al. Noradrenaline-evoked pain in neuralgia. Pain. 1995;63(1):11–20.
Green PG, Luo J, Heller PH, et al. Further substantiation of a significant role for the sympathetic nervous system in inflammation. Neuroscience. 1993;55(4):1037–43.
Donnerer J, Amann R, Lembeck F. Neurogenic and non-neurogenic inflammation in the rat paw following chemical sympathectomy. Neuroscience. 1991;45(3):761–5.
Helme RD, Andrews PV. The effect of nerve lesions on the inflammatory response to injury. J Neurosci Res. 1985;13(3):453–9.
Khalil Z, Helme RD. Sympathetic neurons modulate plasma extravasation in the rat through a non-adrenergic mechanism. Clin Exp Neurol. 1989;26:45–50.
Lam FY, Ferrell WR. Neurogenic component of different models of acute inflammation in the rat knee joint. Ann Rheum Dis. 1991;50(11):747–51.
Hansen J, Thomas GD, Jacobsen TN, et al. Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle. Am J Physiol. 1994;266(6 Pt 2):H2508–14.
Wallin BG, Victor RG, Mark AL. Sympathetic outflow to resting muscles during static handgrip and postcontraction muscle ischemia. Am J Physiol. 1989;256(1 Pt 2):H105–10.
Anderson EA, Sinkey CA, Lawton WJ, et al. Elevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordings. Hypertension. 1989;14(2):177–83.
Paavola M, Kannus P, Paakkala T, et al. Long-term prognosis of patients with achilles tendinopathy: an observational 8-year follow-up study. Am J Sports Med. 2000;28(5):634–42.
Anesini C, Borda E. Modulatory effect of the adrenergic system upon fibroblast proliferation: participation of beta 3-adrenoceptors. Auton Autacoid Pharmacol. 2002;22(3):177–86.
Burniston JG, Tan LB, Goldspink DF. beta2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol (1985). 2005;98(4):1379–86.
Kryger GS, Chong AK, Costa M, et al. A comparison of tenocytes and mesenchymal stem cells for use in flexor tendon tissue engineering. J Hand Surg Am. 2007;32(5):597–605.
Mano T, Iwase S, Toma S. Microneurography as a tool in clinical neurophysiology to investigate peripheral neural traffic in humans. Clin Neurophysiol. 2006;117(11):2357–84.
Wallin BG, Charkoudian N. Sympathetic neural control of integrated cardiovascular function: insights from measurement of human sympathetic nerve activity. Muscle Nerve. 2007;36(5):595–614.
Esler M, Jennings G, Korner P, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11(1):3–20.
Kopin IJ. Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev. 1985;37(4):333–64.
Grassi G, Bolla G, Seravalle G, et al. Comparison between reproducibility and sensitivity of muscle sympathetic nerve traffic and plasma noradrenaline in man. Clin Sci (Lond). 1997;92(3):285–9.
Esler M, Jennings G, Lambert G, et al. Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions. Physiol Rev. 1990;70(4):963–85.
Parati G, Pomidossi G, Ramirez A, et al. Variability of the haemodynamic responses to laboratory tests employed in assessment of neural cardiovascular regulation in man. Clin Sci (Lond). 1985;69(5):533–40.
Parati G, Pomidossi G, Casadei R, et al. Comparison of the cardiovascular effects of different laboratory stressors and their relationship with blood pressure variability. J Hypertens. 1988;6(6):481–8.
Grassi G, Vailati S, Bertinieri G, et al. Heart rate as marker of sympathetic activity. J Hypertens. 1998;16(11):1635–9.
Rittner HL, Machelska H, Stein C. Leukocytes in the regulation of pain and analgesia. J Leukoc Biol. 2005;78(6):1215–22.
Whiting P, Rutjes AW, Reitsma JB, et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;10(3):25.
von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9.
Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–84.
Lievense AM, Bierma-Zeinstra SM, Verhagen AP, et al. Influence of obesity on the development of osteoarthritis of the hip: a systematic review. Rheumatology. 2002;41(10):1155–62.
Lian O, Dahl J, Ackermann PW, et al. Pronociceptive and antinociceptive neuromediators in patellar tendinopathy. Am J Sports Med. 2006;34(11):1801–8.
Ljung BO, Forsgren S, Friden J. Sympathetic and sensory innervations are heterogeneously distributed in relation to the blood vessels at the extensor carpi radialis brevis muscle origin of man. Cells Tissues Organs. 1999;165(1):45–54.
Schubert TEO, Weidler C, Lerch K, et al. Achilles tendinosis is associated with sprouting of substance P positive nerve fibres. Ann Rheum Dis. 2005;64(7):1083–6.
Vallbo AB, Hagbarth KE, Torebjork HE, et al. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59(4):919–57.
Kalawy H, Stålnacke BM, Fahlström M, et al. New objective findings after whiplash injuries: high blood flow in painful cervical soft tissue: an ultrasound pilot study. Scand J Pain. 2013;4(4):173–9.
Bjur D, Danielson P, Alfredson H, et al. Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy). Cell Tissue Res. 2008;331(2):385–400.
Danielson P, Alfredson H, Forsgren S. Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon tendinosis. Microsc Res Tech. 2006;69(10):808–19.
Dean BJF, Franklin SL, Carr AJ. The peripheral neuronal phenotype is important in the pathogenesis of painful human tendinopathy: a systematic review. Clin Orthop Relat Res. 2013;471(9):3036–46.
Inoue M, Katayama K, Hojo T, et al. The effects of electrical acupuncture to patellar tendon and electrical stimulation to femoral nerve on the blood flow of the patellar tendon in rat. Tairyoku Kagaku. 2001;50(1):119–28.
Ackermann PW, Ahmed M, Kreicbergs A. Early nerve regeneration after Achilles tendon rupture: a prerequisite for healing? A study in the rat. J Orthop Res. 2002;20(4):849–56.
Ackermann PW, Li J, Finn A, et al. Autonomic innervation of tendons, ligaments and joint capsules: a morphologic and quantitative study in the rat. J Orthop Res. 2001;19(3):372–8.
Wall ME, Faber JE, Yang X, et al. Norepinephrine-induced calcium signaling and expression of adrenoceptors in avian tendon cells. Am J Physiol Cell Physiol. 2004;287(4):C912–8.
No sources of funding were used to assist in the preparation of this review. The authors had no potential conflicts of interest that are directly relevant to the content of this review.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Jewson, J.L., Lambert, G.W., Storr, M. et al. The Sympathetic Nervous System and Tendinopathy: A Systematic Review. Sports Med 45, 727–743 (2015). https://doi.org/10.1007/s40279-014-0300-9
- Tyrosine Hydroxylase
- Sympathetic Nervous System
- Sympathetic Activity
- Electronic Supplementary Material Table
- Muscle Sympathetic Nerve Activity