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      Peripheral and central substance P expression in rat CFA-induced TMJ synovitis pain

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          Abstract

          Synovitis contributes to temporomandibular joint (TMJ) pain, nevertheless, the detailed nociceptive mechanism remains unclear. In this study, a rat model of TMJ synovitis was induced by intra-articular injection with complete Freund’s adjuvant (CFA). After CFA-induced synovitis, pain behaviors were observed. Then, TMJ, trigeminal ganglion, and trigeminal nucleus caudalis (TNC) tissues were collected, and immunohistochemistry was used to detect the expression of substance P (SP) and protein gene product 9.5 (PGP9.5) in the synovium tissue. Furthermore, the gene expression level of SP and PGP9.5 in synovium was detected by reverse transcription-polymerase chain reaction (RT-PCR). Afterwards, the expression of SP in the trigeminal ganglion and TNC and c-fos in the TNC was detected by immunohistochemistry. Compared with the control group, the expression of SP and PGP9.5 nerve fibers density and gene levels of them in the synovium tissue were significantly increased in CFA-induced TMJ synovitis rats. Similarly, SP expression in the trigeminal ganglion and TNC, and c-fos expression in the TNC were also obviously increased in CFA-induced TMJ synovitis rats. Collectively, CFA-induced rat TMJ synovitis resulted in obvious pain. This nociceptive reaction could be attributed to the augmented quantity of SP and PGP9.5 positive-stained nerve fibers distributed in the inflammatory synovium as well as enhanced SP expression in the trigeminal ganglion and TNC tissue. c-fos expression in the rat TNC illustrates CFA-induced TMJ synovitis can evoke the acute pain.

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          Most cited references35

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          Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia.

          Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate inflammatory as well as neuropathic pain and hyperalgesia. Direct receptor-mediated actions of cytokines on afferent nerve fibers have been reported as well as cytokine effects involving further mediators. The final outcome of cytokine action greatly depends on whether they act in the central of in the peripheral nervous system. Here we summarize recent findings on the peripheral mechanisms of action of three prototypic proinflammatory cytokines, interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha, with regards to pain and hyperalgesia.
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            Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis.

            Normal adult articular cartilage is thought to be avascular and aneural. To describe neurovascular structures at the osteochondral junction and in osteophytes in tibiofemoral osteoarthritis (OA) displaying a range of severity of cartilage changes. Articular surfaces were obtained from 40 patients at total knee joint replacement surgery for tibiofemoral OA (TKR) and seven patients post mortem (PM). Antibodies directed against CD34 (vascular endothelium), protein gene product 9.5 (pan-neuronal marker), substance P and calcitonin gene-related peptide (sensory nerves) and C-flanking peptide of neuropeptide Y (sympathetic nerves) were used to localise blood vessels and nerves by immunohistochemistry. Severity of OA cartilage changes was graded histologically. TKR and PM samples displayed a range of OA cartilage changes including tidemark breaching by vascular channels. Sympathetic and sensory nerves were both present within vascular channels in the articular cartilage, in both mild and severe OA. Perivascular and free nerve fibres, and nerve trunks were observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Sensory and sympathetic nerves displayed similar distributions in each region studied. Vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity.
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              The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology

              The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo-chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions.
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                Author and article information

                Journal
                Mol Pain
                Mol Pain
                MPX
                spmpx
                Molecular Pain
                SAGE Publications (Sage CA: Los Angeles, CA )
                1744-8069
                30 July 2019
                2019
                : 15
                : 1744806919866340
                Affiliations
                [1 ]State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
                [2 ]Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
                Author notes
                [*]Jin Ke, State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, Hubei, China. Email: kejin@ 123456whu.edu.cn
                [*]Xing Long, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, Hubei, China. Email: longxing@ 123456whu.edu.cn
                Author information
                https://orcid.org/0000-0001-5794-1117
                Article
                10.1177_1744806919866340
                10.1177/1744806919866340
                6685108
                31322474
                be8950f5-b07f-4ba2-b94e-ae195f3def16
                © The Author(s) 2019

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 21 April 2019
                : 20 June 2019
                : 30 June 2019
                Funding
                Funded by: National Natural Science Foundation of China, FundRef http://doi.org/10.13039/501100001809;
                Award ID: 81600889
                Award ID: 8177041189
                Award ID: 81870789
                Categories
                Research Article
                Custom metadata
                January-December 2019

                Molecular medicine
                synovitis,trigeminal ganglion,trigeminal nucleus caudalis,substance p,c-fos,complete freund’s adjuvant

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