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Acute local inflammation elicits sprouting of sensory axons in the rat supraspinatus tendon
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Inflammation activates nociceptive nerve endings and can elicit local sprouting of axons. We hypothesized that axon sprouting might be one factor behind the emergence of painful inflammatory conditions in the shoulder. Here we examine the distribution of sensory and sympathetic axons in the rat subacromial space under normal conditions and after local induction of inflammation with carrageenan. Furthermore, we measured the neuropeptide content in the supraspinatus tendon. In normal rats protein gene product 9.5- (POP 9.5-), substance P- (SP-), calcitonin gene related peptide- (CGRP-), neuropeptide Y- (NPY-) and tyrosine hydroxylase- (TH-) like immunoreactive (LI) axon profiles occurred in the subacromial space and around the glenohumeral joint. In the supraspinatus tendon axon profiles were limited to the tendon-muscle junction. After carrageenan injection inflammatory cells invaded the tendon and the subacromial bursa with a maximum at 2-3 weeks. Moreover, the tendon and the bursa showed signs of sprouting of PGP-9.5-, SP- and CGRP-LI axons, but not NPY- and TH-LI axons. The tendon was also invaded by blood vessels. The occurrence of axon profiles had a maximum at 2 weeks after injection and then subsided. Also, these axons were GAP-43-LI indicating collateral sprouting of nociceptive nerve fibres. There was no significant increase in the concentration of the neuropeptides SP and CGRP in the supraspinatus tendon. No inflammatory reaction or sprouting of nerve fibres was seen in saline-injected controls. We conclude that an acute inflammation in the subacromial space of the rat shoulder region can elicit a transient local sprouting of sensory axons in the tendon stroma and associated aberrant blood vessels.

Keyword [en]
inflanunation, carrageenan, protein gene product 9.5, calcitonin gene related peptide, neuropeptide Y, substance P, tyrosine hydroxylase, GAP-43, radioimmunoassay
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-80044OAI: diva2:545127
Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2012-08-17Bibliographically approved
In thesis
1. Subacromial inflammation: Clinical and experimental studies
Open this publication in new window or tab >>Subacromial inflammation: Clinical and experimental studies
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Shoulder pain and disability are common clinical problems. One major cause is subacromial inflammation and impingement of the supraspinatus tendon. These patients are usually offered conservative treatment or arthroscopic subacromial decompression (ASD). However, in some patients pain and a deficient shoulder function persist in spite of conservative and surgical treatment. This reflects the fact that the pathophysiology of this important disease is not fully understood. The general aim of the present thesis was to generate new lmowledge contributing to the understanding of subacromial inflammation through a combination of clinical and experimental studies.

Ketoprofen is a non-steroid antiinflammatory drug with effects on peripherally as well as centrally generated pain. In a randomized, double-blind, prospective study on impingement patients treated with ASD, postoperative administration of ketoprofen showed short-term, but not long-term positive effects on pain, range of movement and satisfaction.

The status of the rotator cuff was found not to influence the postoperative results after ASD. Patients with an intact, partially ruptured or totally ruptured (<2cm) supraspinatus tendon did equally well, both 3 and 6 years after surgery. The results suggest that the presence of an inflamed bursa is more important for the symptoms than the cuff lesion.

In search for an experimental model we found that the shoulder region of the rat shows macroanatomical similarities to the human shoulder. Analysis of the innervation of the rat shoulder showed that the suprascapular nerve and some branches projecting to the subacromial space contain numerous C- and Ao-fibers. Many of these appeared to be polymodally nociceptive units or postganglionic sympathetic units as revealed by capsaicin and chemical sympathectomy. Such fibers are relevant for inflanunatory states.

In the normal rat substance P- (SP), calcitonin gene-related peptide- (CGRP) immunoreactive putative nociceptive fibers and neuropeptide Y- (NPY) and tyrosine hydroxylase- (TH) immunoreactive putative sympathetic fibers were widely distributed in the subacromial space. After induction of an acute subacromial inflammation with carrageenan, the presence of SP- and/or CGRP-immunoreactive fibers in the supraspinatus tendon was increased, with a maximum at two weeks. The results of labeling with the growth-associated protein GAP-43 indicated a de novo sprouting of nociceptive fibers in the tendon. But, radioimmunoassay measurements showed that the content of SP, CGRP and NPY in the supraspinatus tendon were normal or subnormal.

These results called for examination of subacromial tissue biopsies from  impingement patients. Innnunohistochemical analysis showed an increase of SP- and/or CGRP- immunoreactive nerve fibers and of NPY-immunoreactive nerve fibers in tendon tissue. The presence of corresponding neuropeptides was also elevated, as determined by RIA. The analysis also revealed an increase of SP and/or CGRP-immunoreactive nerve fibers and an elevated concentration of corresponding neuropeptides in bursal tissue.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 87 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 658
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-25660 (URN)10036 (Local ID)91-721-9759-5 (ISBN)10036 (Archive number)10036 (OAI)
Public defence
2001-02-16, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-17Bibliographically approved

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Hoe-Hansen, CarstenNorlin, RolfTheodorsson, ElvarHildebrand, Claes
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