Effects of melatonin on orofacial pain relief by regulating mitochondrial function in cell viability of peripheral sensory neurons
1Department of Stomatology, The Fifth Affiliated Hospital, Sun Yat-sen University, 519000 Zhuhai, Guangdong, China
2Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-sen University, 519000 Zhuhai, Guangdong, China
3Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 510623 Guangzhou, Guangdong, China
4Guangdong Provincial Key Laboratory of Stomatology, 510080 Guangzhou, Guangdong, China
DOI: 10.22514/sv.2022.075 Vol.18,Issue 6,November 2022 pp.81-93
Submitted: 01 August 2022 Accepted: 28 September 2022
Published: 08 November 2022
Melatonin (MT) is involved in the pain regulation of peripheral neurons, which is relevant to cell viability. This study aimed to examine the cell proliferation, cell cycle, cell apoptosis and intracellular mitochondrial function of ND7/23 and PC-12 cells treated with different physiological concentrations of MT. Our results showed that MT at concentrations of 10−8, 10−10 and 10−12 M inhibited cell proliferation and promoted the apoptosis of two cell lines, with the most significant changes observed at a concentration of 10−12 M. Further, 10−12 M MT promoted mitochondrial respiratory electron transfer and increased mitochondrial function in ND7/23 and PC-12 cells through the non-membrane receptor pathway. Comparatively, 10−8 M MT enhanced the mitochondrial effects of ND7/23 cells but showed opposite effects in PC-12 cells. In summary, MT affected cell viability through the non-membrane receptor pathway in a concentration-dependent manner and might be associated with pain regulations.
Melatonin; ND7/23; Cell viability; Mitochondrial function
Yingying You,Xianping Yi,Hongwen He,Fang Huang. Effects of melatonin on orofacial pain relief by regulating mitochondrial function in cell viability of peripheral sensory neurons. Signa Vitae. 2022. 18(6);81-93.
 De Rossi SS. Orofacial pain: a primer. Dental Clinics of North America. 2013; 57: 383–392.
 Scrivani SJ, Spierings ELH. Classification and differential diagnosis of oral and maxillofacial pain. Oral and Maxillofacial Surgery Clinics of North America. 2016; 28: 233–246.
 Messlinger K, Russo AF. Current understanding of trigeminal ganglion structure and function in headache. Cephalalgia. 2019; 39: 1661–1674.
 Solé L, Tamkun MM. Trafficking mechanisms underlying Nav channel subcellular localization in neurons. Channels. 2020; 14: 1–17.
 Spetea M. Opioid receptors and their ligands in the musculoskeletal system and relevance for pain control. Current Pharmaceutical Design. 2014; 19: 7382–7390.
 Wang T, Xu X, Lin W, Hu D, Shi W, Jia X, et al. Activation of different heterodimers of TLR2 distinctly mediates pain and itch. Neuroscience. 2020; 429: 245–255.
 Ranjbar Ekbatan M, Cairns BE. Attenuation of sensory transmission through the rat trigeminal ganglion by GABA receptor activation. Neuroscience. 2021; 471: 80–92.
 Yudin Y, Rohacs T. Inhibitory Gi/O-coupled receptors in somatosensory neurons: potential therapeutic targets for novel analgesics. Molecular Pain. 2018; 14: 1744806918763646.
 Balderas-Villalobos J, Steele TWE, Eltit JM. Physiological and patholog-ical relevance of selective and nonselective Ca2+ channels in skeletal and cardiac muscle. Ion Channels in Biophysics and Physiology. 2021; 1349: 225–247.
 Li F, Wang F. TRPV1 in pain and itch. Ion Channels in Biophysics and Physiology. 2021; 1349: 249–273.
 Wang LX, Wang ZJ. Animal and cellular models of chronic pain. Advanced Drug Delivery Reviews. 2003; 55: 949–965.
 Haberberger RV, Barry C, Matusica D. Immortalized dorsal root ganglion neuron cell lines. Frontiers in Cellular Neuroscience. 2020; 14: 184.
 Dunn PM, Coote PR, Wood JN, Burgess GM, Rang HP. Bradykinin evoked depolarization of a novel neuroblastoma × DRG neurone hybrid cell line (ND723). Brain Research. 1991; 545: 80–86.
 Zhang Q, Hsia S, Martin-Caraballo M. Regulation of T-type Ca2+ channel expression by herpes simplex virus-1 infection in sensory-like ND7 cells. Journal of NeuroVirology. 2017; 23: 657-670.
 Wood JN, Bevan SJ, Coote PR, Dunn PM, Harmar A, Hogan P, et al. Novel cell lines display properties of nociceptive sensory neurons. Proceedings of the Royal Society. Biological sciences. 1990; 241: 187–194.
 Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E. PC12 cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells. 2020; 9: 958.
 Freeland K, Liu Y, Latchman DS. Distinct signalling pathways mediate the cAMP response element (CRE)-dependent activation of the calcitonin gene-related peptide gene promoter by cAMP and nerve growth factor. Biochemical Journal. 2000; 345: 233–238.
 Zhang YQ, Guo N, Peng G, Wang X, Han M, Raincrow J, et al. Role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain. Pain. 2009; 146: 130–140.
 Ko J, Mizuno Y, Ohki C, Chikama T, Sonoda K, Kiuchi Y. Neuropeptides released from trigeminal neurons promote the stratification of human corneal epithelial cells. Investigative Opthalmology & Visual Science. 2014; 55: 125–133.
 Bao L, Jin S, Zhang C, Wang L, Xu Z, Zhang F, et al. Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron. 2003; 37: 121–133.
 Reiter RJ, Rosales-Corral S, Sharma R. Circadian disruption, melatonin rhythm perturbations and their contributions to chaotic physiology. Advances in Medical Sciences. 2020; 65: 394–402.
 Moriya T, Horie N, Mitome M, Shinohara K. Melatonin influences the proliferative and differentiative activity of neural stem cells. Journal of Pineal Research. 2007; 42: 411–418.
 He Y, Fan W, Xu Y, Liu YL, He H, Huang F. Distribution and colocalization of melatonin 1a-receptor and NADPH-d in the trigeminal system of rat. PeerJ. 2019; 7: e6877.
 Dubocovich ML. Luzindole (N-0774): a novel melatonin receptor antagonist. The Journal of Pharmacology and Experimental Therapeutics. 1988; 246: 902–910.
 Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid & Redox Signal. 2008; 10: 179–206.
 Llorens J, Li AA, Ceccatelli S, Suñol C. Strategies and tools for preventing neurotoxicity: to test, to predict and how to do it. NeuroToxicology. 2012; 33: 796–804.
 Lisek M, Boczek T, Stragierowicz J, Wawrzyniak J, Guo F, Klimczak M, et al. Hexachloronaphthalene (HxCN) impairs the dopamine pathway in an in vitro model of PC12 cells. Chemosphere. 2022; 287: 132284.
 Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nature Neuroscience. 2015; 18: 145–153.
 Noseda R, Hernández A, Valladares L, Mondaca M, Laurido C, Soto-Moyano R. Melatonin-induced inhibition of spinal cord synaptic potentiation in rats is MT2 receptor-dependent. Neuroscience Letters. 2004; 360: 41–44.
 Areti A, Komirishetty P, Akuthota M, Malik RA, Kumar A. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. Journal of Pineal Research. 2017; 62: e12393.
 Perissin L, Boccalon S, Scaggiante B, Petrelli L, Ortolani F, Porro CA. Diurnal changes of tonic nociceptive responses in mice: evidence for a proalgesic role of melatonin. Pain. 2004; 110: 250–258.
 Ilari S, Giancotti LA, Lauro F, Dagostino C, Gliozzi M, Malafoglia V, et al. Antioxidant modulation of sirtuin 3 during acute inflammatory pain: the ROS control. Pharmacological Research. 2020; 157: 104851.
 Flatters SJL. The contribution of mitochondria to sensory processing and pain. Progress in Molecular Biology and Translational Science. 2015; 131: 119–146.
 Areti A, Ganesh Yerra V, Komirishetty P, Kumar A. Potential therapeutic benefits of maintaining mitochondrial health in peripheral neuropathies. Current Neuropharmacology. 2016; 14: 593–609.
 García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA, et al. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. Journal of Pineal Research. 2014; 56: 225–237.
 Cui P, Luo Z, Zhang H, Su Y, Li A, Li H, et al. Effect and mechanism of melatonin’s action on the proliferation of human umbilical vein endothelial cells. Journal of Pineal Research. 2006; 41: 358–362.
 Cui P, Yu M, Luo Z, Dai M, Han J, Xiu R, et al. Intracellular signaling pathways involved in cell growth inhibition of human umbilical vein endothelial cells by melatonin. Journal of Pineal Research. 2008; 44: 107–114.
 Mendivil-Perez M, Soto-Mercado V, Guerra-Librero A, Fernandez-Gil BI, Florido J, Shen Y, et al. Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function. Journal of Pineal Research. 2017; 63: e12415.
 Liu Y, Zhang Z, Lv Q, Chen X, Deng W, Shi K, et al. Effects and mechanisms of melatonin on the proliferation and neural differentiation of PC12 cells. Biochemical and Biophysical Research Communications. 2016; 478: 540–545.
 Martín-Renedo J, Mauriz JL, Jorquera F, Ruiz-Andrés O, González P, González-Gallego J. Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. Journal of Pineal Research. 2008; 45: 532–540.
 Cucina A, Proietti S, D’Anselmi F, Coluccia P, Dinicola S, Frati L, et al. Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. Journal of Pineal Research. 2009; 46: 172–180.
 Wiesenberg I, Missbach M, Carlberg C. The potential role of the transcription factor RZR/ROR as a mediator of nuclear melatonin signaling. Restorative Neurology and Neuroscience. 1998; 12: 143–150.
 Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Medicine. 2007; 8: 34–42.
 Zhao A, Zhao K, Xia Y, Lyu J, Chen Y, Li S. Melatonin inhibits embryonic rat H9c2 cells growth through induction of apoptosis and cell cycle arrest via PI3K-AKT signaling pathway. Birth Defects Research. 2021; 113: 1171–1181.
 Lin PH, Tung YT, Chen HY, Chiang YF, Hong HC, Huang KC, et al. Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation. Journal of Pineal Research. 2020; 68: e12620.
 Kasahara A, Scorrano L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends in Cell Biology. 2014; 24: 761–770.
 Chang C, Huang T, Chen H, Huang T, Lin L, Chang Y, et al. Protective effect of melatonin against oxidative stress-induced apoptosis and enhanced autophagy in human retinal pigment epithelium cells. Oxidative Medicine and Cellular Longevity. 2018; 2018: 1–12.
 Wang S, Liu W, Wen A, Yang B, Pang X. Luzindole and 4P-PDOT block the effect of melatonin on bovine granulosa cell apoptosis and cell cycle depending on its concentration. PeerJ. 2021; 9: e10627.
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