High-intensity interval training (HIIT) is considered an effective therapy strategy for improving chronic pain associated with osteoarthritis (OA). Perineuronal nets (PNNs) are specialized extracellular matrix structures in the cerebral cortex that play a crucial role in regulating chronic pain. However, little is unknown whether HIIT could alleviate OA pain sensitization by reducing PNN levels. This study aimed to determine whether HIIT could reduce sensitivity of the affected joint(s) to pain in a chronic pain model in rats with OA. A rat model of interest was induced by intra-articular injection of monosodium iodoacetate (MIA) into the right knee. Thereafter, the mechanical withdrawal thresholds (MWTs) and PNN levels in the contralateral medial prefrontal cortex (mPFC) were measured in rats in the presence or absence of HIIT alone or in combination with injection of chondroitinase-ABC (ChABC) into the contralateral mPFC (inducing the degradation of PNNs), respectively. Results indicated that rats with OA exhibited significant reductions in MWTs, but a significant increase in the PNN levels; that HIIT reversed changes in MWTs and PNN levels in rats with OA, and that pretreatment of ChABC abolished effects of HIIT on MWTs, with PNN levels not changed. We concluded that pain sensitization in rats with OA may correlate with an increase in PNN levels in the mPFC, and that HIIT may increases OA pain-sensitive threshold by reduction of the PNN levels in the mPFC. Keywords: Osteoarthritis, Chronic pain, Pain sensitization, High-intensity interval training, Perineuronal nets.

Department of Rehabilitation Medicine Nanjing 1st Hospital Nanjing Medical University Nanjing China

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Abramoff B, Caldera FE. Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin North Am. 2020;104:293–311. doi: 10.1016/j.mcna.2019.10.007. PubMed DOI

Schaible HG, Ebersberger A, Natura G. Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13:210. doi: 10.1186/ar3305. PubMed DOI PMC

O'Neill TW, Felson DT. Mechanisms of osteoarthritis (OA) pain. Curr Osteoporos Rep. 2018;16:611–616. doi: 10.1007/s11914-018-0477-1. PubMed DOI PMC

Richter F, Natura G, Löser S, Schmidt K, Viisanen H, Schaible HG. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum. 2010;62:3806–3814. doi: 10.1002/art.27715. PubMed DOI

Weisman A, Quintner J, Cohen M, Maharawi Y. Central sensitisation: causes, therapies, and terminology. Lancet Rheumatol. 2021;3:e547–e548. doi: 10.1016/S2665-9913(21)00179-X. PubMed DOI

Hattori T, Shimo K, Niwa Y, Tokiwa Y, Matsubara T. Association of chronic pain with radiologic severity and central sensitization in hip osteoarthritis patients. J Pain Res. 2021;14:1153–1160. doi: 10.2147/JPR.S296273. PubMed DOI PMC

López-Ruiz M, Losilla JM, Monfort J, Portell M, Gutiérrez T, Poca V, Garcia-Fructuoso F, et al. Central sensitization in knee osteoarthritis and fibromyalgia: Beyond depression and anxiety. PLoS One. 2019;14:e0225836. doi: 10.1371/journal.pone.0225836. PubMed DOI PMC

Lluch E, Torres R, Nijs J, Van Oosterwijck J. Evidence for central sensitization in patients with osteoarthritis pain: a systematic literature review. Eur J Pain. 2014;18:1367–1375. doi: 10.1002/j.1532-2149.2014.499.x. PubMed DOI

Ohashi Y, Uchida K, Fukushima K, Inoue G, Takaso M. Mechanisms of peripheral and central sensitization in osteoarthritis pain. Cureus. 2023;15:e35331. doi: 10.7759/cureus.35331. PubMed DOI PMC

Lluch Girbés E, Nijs J, Torres-Cueco R, López Cubas C. Pain treatment for patients with osteoarthritis and central sensitization. Phys Ther. 2013;93:842–851. doi: 10.2522/ptj.20120253. PubMed DOI

Fawcett JW, Oohashi T, Pizzorusso T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci. 2019;20:451–465. doi: 10.1038/s41583-019-0196-3. PubMed DOI

Testa D, Prochiantz A, Di Nardo AA. Perineuronal nets in brain physiology and disease. Semin Cell Dev Biol. 2019;89:125–135. doi: 10.1016/j.semcdb.2018.09.011. PubMed DOI

Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L. Reactivation of ocular dominance plasticity in the adult visual cortex. Science. 2002;298:1248–1251. doi: 10.1126/science.1072699. PubMed DOI

Chen H, He D, Lasek AW. Repeated binge drinking increases perineuronal nets in the insular cortex. Alcohol Clin Exp Res. 2015;39:1930–1938. doi: 10.1111/acer.12847. PubMed DOI PMC

Xue YX, Xue LF, Liu JF, He J, Deng JH, Sun SC, Han HB, et al. Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories. J Neurosci. 2014;34:6647–6658. doi: 10.1523/JNEUROSCI.5390-13.2014. PubMed DOI PMC

Tansley S, Gu N, Guzmán AU, Cai W, Wong C, Lister KC, Muñoz-Pino E, et al. Microglia-mediated degradation of perineuronal nets promotes pain. Science. 2022;377:80–86. doi: 10.1126/science.abl6773. PubMed DOI

Potter LE, Paylor JW, Suh JS, Tenorio G, Caliaperumal J, Colbourne F, Baker G, et al. Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis. J Neuroinflammation. 2016;13:142. doi: 10.1186/s12974-016-0609-4. PubMed DOI PMC

Xu Y, Jiang Y, Wang L, Huang J, Wen J, Lv H, Wu X, et al. Thymosin Alpha-1 Inhibits Complete Freund's Adjuvant-Induced Pain and Production of Microglia-Mediated Pro-inflammatory Cytokines in Spinal Cord. Neurosci Bull. 2019;35:637–648. doi: 10.1007/s12264-019-00346-z. PubMed DOI PMC

Hsieh TH, Lee HHC, Hameed MQ, Pascual-Leone A, Hensch TK, Rotenberg A. Trajectory of parvalbumin cell impairment and loss of cortical inhibition in traumatic brain injury. Cereb Cortex. 2017;27:5509–5524. doi: 10.1093/cercor/bhw318. PubMed DOI PMC

Bressel E, Wing JE, Miller AI, Dolny DG. High-intensity interval training on an aquatic treadmill in adults with osteoarthritis: effect on pain, balance, function, and mobility. J Strength Cond Res. 2014;28:2088–2096. doi: 10.1519/JSC.0000000000000258. PubMed DOI

Keogh JW, Grigg J, Vertullo CJ. Is high-intensity interval cycling feasible and more beneficial than continuous cycling for knee osteoarthritic patients? Results of a randomised control feasibility trial. PeerJ. 2018;6:e4738. doi: 10.7717/peerj.4738. PubMed DOI PMC

Baliki MN, Mansour AR, Baria AT, Apkarian AV. Functional reorganization of the default mode network across chronic pain conditions. PLoS One. 2014;9:e106133. doi: 10.1371/journal.pone.0106133. PubMed DOI PMC

Ong WY, Stohler CS, Herr DR. Role of the prefrontal cortex in pain processing. Mol Neurobiol. 2019;56:1137–1166. doi: 10.1007/s12035-018-1130-9. PubMed DOI PMC

Mascio G, Notartomaso S, Martinello K, Liberatore F, Bucci D, Imbriglio T, Battaglia G, et al. A progressive build-up of perineuronal nets in the somatosensory cortex is associated with the development of chronic pain in mice. J Neurosci. 2022;42:3037–3048. doi: 10.1523/JNEUROSCI.1714-21.2022. PubMed DOI PMC

Takiguchi M, Akaike T, Shindo K, Sakuyama R, Koganemaru R, Funakoshi K. Chondroitin sulfate expression around motoneurons changes after complete spinal transection of neonatal rats. Neurosci Lett. 2022;766:136324. doi: 10.1016/j.neulet.2021.136324. PubMed DOI

Arbat-Plana A, Cobianchi S, Herrando-Grabulosa M, Navarro X, Udina E. Endogenous modulation of TrkB signaling by treadmill exercise after peripheral nerve injury. Neuroscience. 2017;340:188–200. doi: 10.1016/j.neuroscience.2016.10.057. PubMed DOI

Sánchez-Ventura J, Giménez-Llort L, Penas C, Udina E. Voluntary wheel running preserves lumbar perineuronal nets, enhances motor functions and prevents hyperreflexia after spinal cord injury. Exp Neurol. 2021;336:113533. doi: 10.1016/j.expneurol.2020.113533. PubMed DOI

Abaei M, Sagar DR, Stockley EG, Spicer CH, Prior M, Chapman V, Auer DP. Neural correlates of hyperalgesia in the monosodium iodoacetate model of osteoarthritis pain. Mol Pain. 2016:12. doi: 10.1177/1744806916642445. PubMed DOI PMC

Wang X, Song J, Xia P, Lin Q, Chen A, Cheng K, Li X, et al. High intensity interval training attenuates osteoarthritis-associated hyperalgesia in rats. J Physiol Sci. 2023;73:8. doi: 10.1186/s12576-023-00866-4. PubMed DOI PMC

Anderson MD, Paylor JW, Scott GA, Greba Q, Winship IR, Howland JG. ChABC infusions into medial prefrontal cortex, but not posterior parietal cortex, improve the performance of rats tested on a novel, challenging delay in the touchscreen TUNL task. Learn Mem. 2020;27:222–235. doi: 10.1101/lm.050245.119. PubMed DOI PMC

Christensen SL, Hansen RB, Storm MA, Olesen J, Hansen TF, Ossipov M, Izarzugaza JMG, et al. Von Frey testing revisited: Provision of an online algorithm for improved accuracy of 50% thresholds. Eur J Pain. 2020;24:783–790. doi: 10.1002/ejp.1528. PubMed DOI

Marino S, Idris AI. Analysis of signaling pathways by western blotting and immunoprecipitation. Methods Mol Biol. 2019;1914:131–143. doi: 10.1007/978-1-4939-8997-3_7. PubMed DOI

Donaldson JG.Immunofluorescence Staining Curr Protoc Cell Biol 2015694.3.1–4.3.710.1002/0471143030.cb0403s69 PubMed DOI

Hussaini HM, Seo B, Rich AM. Immunohistochemistry and immunofluorescence. Methods Mol Biol. 2023;2588:439–450. doi: 10.1007/978-1-0716-2780-8_26. PubMed DOI

Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. doi: 10.1126/science.288.5472.1765. PubMed DOI

Sánchez-Ventura J, Lane MA, Udina E. The role and modulation of spinal perineuronal nets in the healthy and injured spinal cord. Front Cell Neurosci. 2022;16:893857. doi: 10.3389/fncel.2022.893857. PubMed DOI PMC

Suttkus A, Holzer M, Morawski M, Arendt T. The neuronal extracellular matrix restricts distribution and internalization of aggregated Tau-protein. Neuroscience. 2016;313:225–235. doi: 10.1016/j.neuroscience.2015.11.040. PubMed DOI

Li X, Ren D, Luo B, Liu Z, Li N, Zhou T, Fei E. Perineuronal Nets Alterations Contribute to Stress-Induced Anxiety-Like Behavior. Mol Neurobiol. 2024;61:411–422. doi: 10.1007/s12035-023-03596-1. PubMed DOI

Roura-Martínez D, Díaz-Bejarano P, Ucha M, Paiva RR, Ambrosio E, Higuera-Matas A. Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration. Neuropharmacology. 2020;180:108290. doi: 10.1016/j.neuropharm.2020.108290. PubMed DOI

Frischknecht R, Chang KJ, Rasband MN, Seidenbecher CI. Neural ECM molecules in axonal and synaptic homeostatic plasticity. Prog Brain Res. 2014;214:81–100. doi: 10.1016/B978-0-444-63486-3.00004-9. PubMed DOI

Favuzzi E, Marques-Smith A, Deogracias R, Winterflood CM, Sánchez-Aguilera A, Mantoan L, Maeso P, et al. Activity-dependent gating of parvalbumin interneuron function by the perineuronal net protein brevican. Neuron. 2017;95:639–655.e610. doi: 10.1016/j.neuron.2017.06.028. PubMed DOI

Schmidt S, Arendt T, Morawski M, Sonntag M. Neurocan contributes to perineuronal net development. Neuroscience. 2020;442:69–86. doi: 10.1016/j.neuroscience.2020.06.040. PubMed DOI

Smith CC, Mauricio R, Nobre L, Marsh B, Wüst RC, Rossiter HB, Ichiyama RM. Differential regulation of perineuronal nets in the brain and spinal cord with exercise training. Brain Res Bull. 2015;111:20–26. doi: 10.1016/j.brainresbull.2014.12.005. PubMed DOI

Smith-Ryan AE, Blue MNM, Anderson KC, Hirsch KR, Allen KD, Huebner JL, Muehlbauer MJ, et al. Metabolic and physiological effects of high intensity interval training in patients with knee osteoarthritis: A pilot and feasibility study. Osteoarthr Cartil Open. 2020;2:100083. doi: 10.1016/j.ocarto.2020.100083. PubMed DOI PMC