title: The peripheral neuronal phenotype is important in the pathogenesis of painful human tendinopathy: a systematic review.
abstract: BACKGROUND
  The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients.
  
  
  OBJECTIVE
  The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms.
  
  
  METHODS
  We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text.
  
  
  RESULTS
  Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain.
  
  
  CONCLUSIONS
  The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process.
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Oxford, OX3 7LD, UK. benjamin.dean@ndorms.ox.ac.uk
authors.forename: Benjamin John Floyd
authors.initials: BJ
authors.lastname: Dean
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Franklin
authors.forename: Andrew Jonathan
authors.initials: AJ
authors.lastname: Carr
mesh_terms: D006801:Humans; D009474:Neurons / Q000473:pathology*; D010146:Pain / Q000209:etiology* / Q000473:pathology; D010641:Phenotype; D017006:Rotator Cuff / Q000473:pathology*; D052256:Tendinopathy / Q000209:etiology* / Q000473:pathology