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      Transient Receptor Potential Vanilloid 1-Immunoreactive Innervation Increases in Fractured Rat Femur

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          Abstract

          Purpose

          Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture.

          Materials and Methods

          We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points.

          Results

          Four weeks after fracture, complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture ( p<0.05).

          Conclusion

          Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.

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          Most cited references18

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          Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain.

          For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release nerve growth factor (NGF), which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that, the earlier therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain. Copyright © 2010 IBRO. All rights reserved.
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            The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund's adjuvant

            Background The present study aims to investigate the role of transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons in chronic pain including thermal hyperalgesia and mechanical allodynia. Chronic inflammatory nociception of rats was produced by intraplantar injection of complete Freund's adjuvant (CFA) and data was collected until day 28 following injection. Results Thermal hyperalgesia was evident from day 1 to day 28 with peak at day 7, while mechanical allodynia persisted from day 1 to day 14 and was greatest at day 7. Intrathecal administration of AMG 9810 at day 7, a selective TRPV1 antagonist, significantly reduced thermal hyperalgesia and mechanical allodynia. TRPV1 expression in DRG detected by Western blotting was increased relative to baseline throughout the observation period. Double labeling of TRPV1 with neuronal marker neurofilament 200 (NF200), calcitonin gene-related peptide (CGRP) or isolectin B4 (IB4) was used to distinguish different subtypes of DRG neurons. TRPV1 expression was increased in the medium-sized myelinated A fiber (NF200 positive) neurons and in small non-peptidergic (IB4 positive) neurons from day 1 to day 14 and was increased in small peptidergic (CGRP positive) neurons from day 1 to day 28. Conclusion TRPV1 expression increases in all three types of DRG neurons after CFA injection and plays a role in CFA-induced chronic inflammatory pain including thermal hyperalgesia and mechanical allodynia.
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              Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs.

              We assessed factors which may affect union in 32 patients with nonunion of a fracture of the diaphysis of the femur and 67 comparable patients whose fracture had united. These included gender, age, smoking habit, the use of non-steroidal anti-inflammatory drugs (NSAIDs) the type of fracture (AO classification), soft-tissue injury (open or closed), the type of nail, the mode of locking, reaming nu non-reaming, infection, failure of the implant, distraction at the fracture site, and the time to full weight-bearing. Patients with severe head injuries were excluded. Both groups were comparable with regard to gender, Injury Severity Score and soft-tissue injury. There was no relationship between the rate of union and the type of implant, mode of locking, reaming, distraction or smoking. There were fewer cases of nonunion in more comminuted fractures (type C) and in patients who were able to bear weight early. There was a marked association between nonunion and the use of NSAIDs after injury (p = 0.000001) and delayed healing was noted in patients who took NSAIDs and whose fractures had united.
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                Author and article information

                Journal
                Yonsei Med J
                Yonsei Med. J
                YMJ
                Yonsei Medical Journal
                Yonsei University College of Medicine
                0513-5796
                1976-2437
                01 January 2014
                29 November 2013
                : 55
                : 1
                : 185-190
                Affiliations
                Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
                Author notes
                Corresponding author: Dr. Seiji Ohtori, Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel: 81-43-226-2117, Fax: 81-43-226-2116, sohtori@ 123456faculty.chiba-u.jp
                Article
                10.3349/ymj.2014.55.1.185
                3874909
                24339305
                a3b06cb3-0bc7-41c9-bb6c-357c50826758
                © Copyright: Yonsei University College of Medicine 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 April 2013
                : 08 May 2013
                : 26 May 2013
                Categories
                Original Article
                Orthopedics & Rehabilitation

                Medicine
                fracture,pain,femur,transient receptor potential vanilloid 1,rat
                Medicine
                fracture, pain, femur, transient receptor potential vanilloid 1, rat

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