FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Veterinary and animal science2019; 8; 100078; doi: 10.1016/j.vas.2019.100078

Serotonin-evoked cytosolic Ca2+ release and opioid receptor expression are upregulated in articular cartilage chondrocytes from osteoarthritic joints in horses.

Abstract: Osteoarthritis is a pain-associated progressive disease and pain mediators, such as opioid receptors, expressed in articular cartilage could represent novel therapeutic targets. Acute and chronic stages of OA indicate different metabolic abilities of the chondrocytes depending on inflammatory state. This study aimed to investigate the response of healthy and osteoarthritic chondrocytes and their expression and release of pain mediators in response to acute inflammation. Interleukin-1 beta (IL-1β) and lipopolysaccharide (LPS) were used to induce an acute inflammatory response in cultured equine chondrocytes harvested from healthy joints (HC) and osteoarthritic joints (OAC), the latter representing acute exacerbation of a chronic inflammatory state. Intracellular Ca release was determined after exposure to serotonin (5-hydroxytryptamine (5-HT), glutamate or ATP. Protein expression levels of F- and G-actin, representing actin rearrangement, and opioid receptors were investigated. Glutamate concentrations in culture media were measured. Cartilage was immunohistochemically stained for µ (MOR), κ (KOR), and δ (DOR) opioid receptors. Upon exposure to acute inflammatory stimuli, OAC showed increased intracellular Ca release after 5-HT stimulation and increased expression of MOR and KOR. When cells were stimulated by inflammatory mediators, glutamate release was increased in both HC and OAC. Immunostaining for MOR was strong in OA cartilage, whereas KOR was less strongly expressed. DOR was not expressed by cultured HC and OAC and immunostaining of OA cartilage equivocal. We show that chondrocytes in different inflammatory stages react differently to the neurotransmitter 5-HT with respect to intracellular Ca release and expression of peripheral pain mediators. Our findings suggest that opioids and neurotransmitters are important in the progression of equine OA. The inflammatory stage of OA (acute chronic) should be taken into consideration when therapeutic strategies are being developed.
© 2019 The Author(s).
Get Full Text
Publication Date: 2019-09-27 PubMed ID: 32734095PubMed Central: PMC7386637DOI: 10.1016/j.vas.2019.100078Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article investigates the differing response of healthy and osteoarthritic cells, notably their expression and release of pain mediators during acute inflammation. The study finds that inflammation stages play a role in these cells’ reactions to pain neurotransmitters, suggesting a need to consider these stages when developing OA therapy strategies.

Research Purpose and Methods

  • The research aims to observe the behavior of both healthy and osteoarthritic chondrocytes (cartilage cells) during an acute inflammatory response. How these cells respond, especially how they express and release pain mediators, is under scrutiny.
  • Chondrocytes from both healthy joints (HC) and osteoarthritic joints (OAC) were put through acute inflammatory simulation using Interleukin-1 beta (IL-1β) and lipopolysaccharide (LPS).
  • The researchers then analyzed the cells’ reaction to different hormones like serotonin (5-hydroxytryptamine (5-HT), glutamate or ATP.

Key Findings

  • The experiments revealed that OAC, indicative of naturally occurring chronic inflammation being acutely exacerbated, displayed an uptick in internal calcium release following 5-HT stimulation. Additionally, there was increased expression of µ (MOR) and κ (KOR) opioid receptors.
  • Under the influence of the inflammatory prods, both HC and OAC amplified their glutamate release.
  • Immunostaining allowed investigators to visualize that MOR was highly expressed in osteoarthritic cartilage, while KOR though present, had less vigorous expression. δ (DOR) opioid receptors weren’t shown by healthy or osteoarthritic cultured specimens.

Research Implications

  • The researchers conclude that different inflammatory stages make chondrocytes more or less sensitive to the neurotransmitter 5-HT in terms of internal calcium release and peripheral pain mediators’ expression.
  • The research suggests that neurotransmitters and opioids play a vital role in the advancement of equine osteoarthritis (OA).
  • It highlights a need to consider the inflammatory stage (acute vs chronic) when creating therapeutic strategies for OA.

Cite This Article

APA
Skiöldebrand E, Ley C, Björklund U, Lindahl A, Hansson E. (2019). Serotonin-evoked cytosolic Ca2+ release and opioid receptor expression are upregulated in articular cartilage chondrocytes from osteoarthritic joints in horses. Vet Anim Sci, 8, 100078. https://doi.org/10.1016/j.vas.2019.100078

Publication

Veterinary and animal science
ISSN: 2451-943X
NlmUniqueID: 101694897
Country: Netherlands
Language: English
Volume: 8
Pages: 100078
PII: 100078

Researcher Affiliations

Skiöldebrand, Eva
  • Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
  • Section of Pathology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Ley, Cecilia
  • Section of Pathology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Björklund, Ulrika
  • Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Lindahl, Anders
  • Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
Hansson, Elisabeth
  • Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.

Conflict of Interest Statement

None of the authors has any financial or personal relationship that could inappropriately influence or bias the content of the paper. The authors have no conflict of interest

References

This article includes 42 references
  1. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior.. Anesthesiology 2011 Dec;115(6):1363-81.
    pmc: PMC3698859pubmed: 22020140doi: 10.1097/aln.0b013e318238bba6google scholar: lookup
  2. Anderson JR, Phelan MM, Clegg PD, Peffers MJ, Rubio-Martinez LM. Synovial Fluid Metabolites Differentiate between Septic and Nonseptic Joint Pathologies.. J Proteome Res 2018 Aug 3;17(8):2735-2743.
    pmc: PMC6092013pubmed: 29969035doi: 10.1021/acs.jproteome.8b00190google scholar: lookup
  3. Atkinson JH, Slater MA, Wahlgren DR, Williams RA, Zisook S, Pruitt SD, Epping-Jordan JE, Patterson TL, Grant I, Abramson I, Garfin SR. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity.. Pain 1999 Nov;83(2):137-45.
    pubmed: 10534584doi: 10.1016/s0304-3959(99)00082-2google scholar: lookup
  4. Bendtsen L, Jensen R, Olesen J. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache.. J Neurol Neurosurg Psychiatry 1996 Sep;61(3):285-90.
    pmc: PMC486552pubmed: 8795600doi: 10.1136/jnnp.61.3.285google scholar: lookup
  5. Böhm M, Grässel S. Role of proopiomelanocortin-derived peptides and their receptors in the osteoarticular system: from basic to translational research.. Endocr Rev 2012 Aug;33(4):623-51.
    pmc: PMC3410228pubmed: 22736674doi: 10.1210/er.2011-1016google scholar: lookup
  6. Bonnet CS, Williams AS, Gilbert SJ, Harvey AK, Evans BA, Mason DJ. AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis.. Ann Rheum Dis 2015 Jan;74(1):242-51.
    pmc: PMC4283694pubmed: 24130267doi: 10.1136/annrheumdis-2013-203670google scholar: lookup
  7. Carlton SM, Coggeshall RE. Inflammation-induced changes in peripheral glutamate receptor populations.. Brain Res 1999 Feb 27;820(1-2):63-70.
    pubmed: 10023031doi: 10.1016/s0006-8993(98)01328-6google scholar: lookup
  8. Chabbi-Achengli Y, Coman T, Collet C, Callebert J, Corcelli M, Lin H, Rignault R, Dy M, de Vernejoul MC, Côté F. Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption.. Am J Pathol 2016 Apr;186(4):927-37.
    pubmed: 26968113doi: 10.1016/j.ajpath.2015.11.018google scholar: lookup
  9. Chen C, Xie J, Rajappa R, Deng L, Fredberg J, Yang L. Interleukin-1β and tumor necrosis factor-α increase stiffness and impair contractile function of articular chondrocytes.. Acta Biochim Biophys Sin (Shanghai) 2015 Feb;47(2):121-9.
    pmc: PMC4351355pubmed: 25520178doi: 10.1093/abbs/gmu116google scholar: lookup
  10. Clauw DJ, Hassett AL. The role of centralised pain in osteoarthritis.. Clin Exp Rheumatol 2017 Sep-Oct;35 Suppl 107(5):79-84.
    pubmed: 28967359
  11. Dickenson AH, Chapman V, Green GM. The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord.. Gen Pharmacol 1997 May;28(5):633-8.
    pubmed: 9184794doi: 10.1016/s0306-3623(96)00359-xgoogle scholar: lookup
  12. dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ. Actin binding proteins: regulation of cytoskeletal microfilaments.. Physiol Rev 2003 Apr;83(2):433-73.
    pubmed: 12663865doi: 10.1152/physrev.00026.2002google scholar: lookup
  13. Elvenes J, Andjelkov N, Figenschau Y, Seternes T, Bjørkøy G, Johansen O. Expression of functional mu-opioid receptors in human osteoarthritic cartilage and chondrocytes.. Biochem Biophys Res Commun 2003 Nov 7;311(1):202-7.
    pubmed: 14575714doi: 10.1016/j.bbrc.2003.09.191google scholar: lookup
  14. Fishbain D. Evidence-based data on pain relief with antidepressants.. Ann Med 2000 Jul;32(5):305-16.
    pubmed: 10949061doi: 10.3109/07853890008995932google scholar: lookup
  15. Hansson E, Skiöldebrand E. Coupled cell networks are target cells of inflammation, which can spread between different body organs and develop into systemic chronic inflammation.. J Inflamm (Lond) 2015;12:44.
    pmc: PMC4514450pubmed: 26213498doi: 10.1186/s12950-015-0091-2google scholar: lookup
  16. Hinoi E, Takarada T, Ueshima T, Tsuchihashi Y, Yoneda Y. Glutamate signaling in peripheral tissues.. Eur J Biochem 2004 Jan;271(1):1-13.
    pubmed: 14686914doi: 10.1046/j.1432-1033.2003.03907.xgoogle scholar: lookup
  17. Hinoi E, Takarada T, Yoneda Y. Glutamate signaling system in bone.. J Pharmacol Sci 2004 Mar;94(3):215-20.
    pubmed: 15037805doi: 10.1254/jphs.94.215google scholar: lookup
  18. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: key role in nociception and inflammation.. Pain 2000 May;86(1-2):69-74.
    pubmed: 10779662doi: 10.1016/s0304-3959(99)00311-5google scholar: lookup
  19. Ley C, Svala E, Nilton A, Lindahl A, Eloranta ML, Ekman S, Skiöldebrand E. Effects of high mobility group box protein-1, interleukin-1β, and interleukin-6 on cartilage matrix metabolism in three-dimensional equine chondrocyte cultures.. Connect Tissue Res 2011;52(4):290-300.
    pubmed: 21117899doi: 10.3109/03008207.2010.523803google scholar: lookup
  20. Lindegaard C, Gleerup KB, Thomsen MH, Martinussen T, Jacobsen S, Andersen PH. Anti-inflammatory effects of intra-articular administration of morphine in horses with experimentally induced synovitis.. Am J Vet Res 2010 Jan;71(1):69-75.
    pubmed: 20043783doi: 10.2460/ajvr.71.1.69google scholar: lookup
  21. Lindegaard C, Thomsen MH, Larsen S, Andersen PH. Analgesic efficacy of intra-articular morphine in experimentally induced radiocarpal synovitis in horses.. Vet Anaesth Analg 2010 Mar;37(2):171-85.
    pubmed: 20230568doi: 10.1111/j.1467-2995.2009.00521.xgoogle scholar: lookup
  22. Millan MJ. Descending control of pain.. Prog Neurobiol 2002 Apr;66(6):355-474.
    pubmed: 12034378doi: 10.1016/s0301-0082(02)00009-6google scholar: lookup
  23. MOORE S, STEIN WH. A modified ninhydrin reagent for the photometric determination of amino acids and related compounds.. J Biol Chem 1954 Dec;211(2):907-13.
    pubmed: 13221596
  24. Negrete R, García Gutiérrez MS, Manzanares J, Maldonado R. Involvement of the dynorphin/KOR system on the nociceptive, emotional and cognitive manifestations of joint pain in mice.. Neuropharmacology 2017 Apr;116:315-327.
    doi: 10.1016/j.neuropharm.2016.08.026pubmed: 27567942google scholar: lookup
  25. Parreno J, Nabavi Niaki M, Andrejevic K, Jiang A, Wu PH, Kandel RA. Interplay between cytoskeletal polymerization and the chondrogenic phenotype in chondrocytes passaged in monolayer culture.. J Anat 2017 Feb;230(2):234-248.
    pmc: PMC5244456pubmed: 27807861doi: 10.1111/joa.12554google scholar: lookup
  26. Patetsos E, Horjales-Araujo E. Treating chronic pain with SSRIs: What do we know?. Pain research & management : the journal of the Canadian Pain Society = journal de la societe Canadienne Pour Le Traitement de la douleur 2016;2016.
  27. Perkins NR, Reid SW, Morris RS. Profiling the New Zealand Thoroughbred racing industry. 2. Conditions interfering with training and racing.. N Z Vet J 2005 Feb;53(1):69-76.
    pubmed: 15731837doi: 10.1080/00480169.2005.36471google scholar: lookup
  28. Pritchard S, Guilak F. Effects of interleukin-1 on calcium signaling and the increase of filamentous actin in isolated and in situ articular chondrocytes.. Arthritis Rheum 2006 Jul;54(7):2164-74.
    pubmed: 16802354doi: 10.1002/art.21941google scholar: lookup
  29. Robson MJ, Quinlan MA, Blakely RD. Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery.. ACS Chem Neurosci 2017 May 17;8(5):932-942.
    pubmed: 28345868doi: 10.1021/acschemneuro.6b00412google scholar: lookup
  30. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O'Donnell D, Kieffer BL, Basbaum AI. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.. Cell 2009 Jun 12;137(6):1148-59.
    pmc: PMC3683597pubmed: 19524516doi: 10.1016/j.cell.2009.04.019google scholar: lookup
  31. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control.. Pain Physician 2011 May-Jun;14(3):249-58.
    pubmed: 21587328
  32. Sheehy JG, Hellyer PW, Sammonds GE, Mama KR, Powers BE, Hendrickson DA, Magnusson KR. Evaluation of opioid receptors in synovial membranes of horses.. Am J Vet Res 2001 Sep;62(9):1408-12.
    pubmed: 11560269doi: 10.2460/ajvr.2001.62.1408google scholar: lookup
  33. Shen H, Aeschlimann A, Reisch N, Gay RE, Simmen BR, Michel BA, Gay S, Sprott H. Kappa and delta opioid receptors are expressed but down-regulated in fibroblast-like synoviocytes of patients with rheumatoid arthritis and osteoarthritis.. Arthritis Rheum 2005 May;52(5):1402-10.
    pubmed: 15880345doi: 10.1002/art.21141google scholar: lookup
  34. Skiöldebrand E, Thorfve A, Björklund U, Johansson P, Wickelgren R, Lindahl A, Hansson E. Biochemical alterations in inflammatory reactive chondrocytes: evidence for intercellular network communication.. Heliyon 2018 Jan;4(1):e00525.
    pmc: PMC5857518pubmed: 29560438doi: 10.1016/j.heliyon.2018.e00525google scholar: lookup
  35. Stein C, Hassan AH, Lehrberger K, Giefing J, Yassouridis A. Local analgesic effect of endogenous opioid peptides.. Lancet 1993 Aug 7;342(8867):321-4.
    pubmed: 8101583doi: 10.1016/0140-6736(93)91471-wgoogle scholar: lookup
  36. Szafranski JD, Grodzinsky AJ, Burger E, Gaschen V, Hung HH, Hunziker EB. Chondrocyte mechanotransduction: effects of compression on deformation of intracellular organelles and relevance to cellular biosynthesis.. Osteoarthritis Cartilage 2004 Dec;12(12):937-46.
    pubmed: 15564060doi: 10.1016/j.joca.2004.08.004google scholar: lookup
  37. van Loon JP, de Grauw JC, Brunott A, Weerts EA, van Weeren PR. Upregulation of articular synovial membrane μ-opioid-like receptors in an acute equine synovitis model.. Vet J 2013 Apr;196(1):40-6.
    pubmed: 22939088doi: 10.1016/j.tvjl.2012.07.030google scholar: lookup
  38. van Loon JP, de Grauw JC, van Dierendonck M, L'ami JJ, Back W, van Weeren PR. Intra-articular opioid analgesia is effective in reducing pain and inflammation in an equine LPS induced synovitis model.. Equine Vet J 2010 Jul;42(5):412-9.
    pubmed: 20636777doi: 10.1111/j.2042-3306.2010.00077.xgoogle scholar: lookup
  39. van Loon JP, Menke ES, L'ami JJ, Jonckheer-Sheehy VS, Back W, René van Weeren P. Analgesic and anti-hyperalgesic effects of epidural morphine in an equine LPS-induced acute synovitis model.. Vet J 2012 Aug;193(2):464-70.
    pubmed: 22342215doi: 10.1016/j.tvjl.2012.01.015google scholar: lookup
  40. Wen ZH, Chang YC, Jean YH. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis.. Osteoarthritis Cartilage 2015 Nov;23(11):2009-16.
    pubmed: 26521747doi: 10.1016/j.joca.2015.03.017google scholar: lookup
  41. Wu L, Zhang S, Shkhyan R, Lee S, Gullo F, Eliasberg CD, Petrigliano FA, Ba K, Wang J, Lin Y, Evseenko D. Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration.. JCI Insight 2017 Jan 12;2(1):e88553.
    pmc: PMC5214705pubmed: 28097228doi: 10.1172/jci.insight.88553google scholar: lookup
  42. Zhang GH, Yoon YW, Lee KS, Min SS, Hong SK, Park JY, Han HC. The glutamatergic N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the joint contribute to the induction, but not maintenance, of arthritic pain in rats.. Neurosci Lett 2003 Nov 20;351(3):177-80.
    pubmed: 14623135doi: 10.1016/j.neulet.2003.08.009google scholar: lookup

Citations

This article has been cited 4 times.
  1. Cai L, Huang N, Zhang X, Wu S, Wang L, Ke Q. Long non-coding RNA plasmacytoma variant translocation 1 and growth arrest specific 5 regulate each other in osteoarthritis to regulate the apoptosis of chondrocytes. Bioengineered 2022 May;13(5):13680-13688.
    doi: 10.1080/21655979.2022.2063653pubmed: 35706414google scholar: lookup
  2. Hansson E, Skiöldebrand E. Bupivacaine in combination with sildenafil (Viagra) and vitamin D3 have anti-inflammatory effects in osteoarthritic chondrocytes. Curr Res Pharmacol Drug Discov 2021;2:100066.
    doi: 10.1016/j.crphar.2021.100066pubmed: 34909684google scholar: lookup
  3. Chow L, Kawahisa-Piquini G, Bass L, Hendrickson D, Patel A, Rockow M, Dow S, Pezzanite LM. Correlation of fecal microbiome dysregulation to synovial transcriptome in an equine model of obesity associated osteoarthritis. Ann Transl Med 2024 Dec 24;12(6):112.
    doi: 10.21037/atm-24-109pubmed: 39817240google scholar: lookup
  4. Costa GL, Tabbì M, Bruschetta G, Spadola F, Leonardi F, Bruno F, Iannelli NM, Licata P, Macrì F, Passino ES, Macrì D, Interlandi C. Analgesic efficacy of tapentadol in chronic joint disorders in horses: plasma serotonin concentration and adrenocortical response as biomarkers of pain-induced stress. Front Vet Sci 2024;11:1505398.
    doi: 10.3389/fvets.2024.1505398pubmed: 39742317google scholar: lookup
Subscribe to our newsletter
Join 99,780 horse owners like you who receive our email updates on horse health and nutrition.