{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:31:31Z","timestamp":1792161091181,"version":"4.4.0"},"reference-count":114,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T00:00:00Z","timestamp":1674604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research"},{"name":"University of Florence"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Persistent pain can be managed with opioids, but their use is limited by the onset of tolerance. Ultramicronized N-palmitoylethanolamine (PEA) in vivo delays morphine tolerance with mechanisms that are still unclear. Since glial cells are involved in opioid tolerance and mast cells (MCs) are pivotal targets of PEA, we hypothesized that a potential mechanism by which PEA delays opioid tolerance might depend on the control of the crosstalk between these cells. Morphine treatment (30 \u03bcM, 30 min) significantly increased MC degranulation of RBL-2H3 cells, which was prevented by pre-treatment with PEA (100 \u03bcM, 18 h), as evaluated by \u03b2-hexosaminidase assay and histamine quantification. The impact of RBL-2H3 secretome on glial cells was studied. Six-hour incubation of astrocytes with control RBL-2H3-conditioned medium, and even more so co-incubation with morphine, enhanced CCL2, IL-1\u03b2, IL-6, Serpina3n, EAAT2 and GFAP mRNA levels. The response was significantly prevented by the secretome from PEA pre-treated RBL-2H3, except for GFAP, which was further upregulated, suggesting a selective modulation of glial signaling. In conclusion, ultramicronized PEA down-modulated both morphine-induced MC degranulation and the expression of inflammatory and pain-related genes from astrocytes challenged with RBL-2H3 medium, suggesting that PEA may delay morphine tolerance, regulating MC-astrocyte crosstalk.<\/jats:p>","DOI":"10.3390\/biom13020233","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T01:30:30Z","timestamp":1674696630000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ultramicronized N-Palmitoylethanolamine Regulates Mast Cell-Astrocyte Crosstalk: A New Potential Mechanism Underlying the Inhibition of Morphine Tolerance"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8435-6017","authenticated-orcid":false,"given":"Alessandra","family":"Toti","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8834-5801","authenticated-orcid":false,"given":"Laura","family":"Micheli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3459-2660","authenticated-orcid":false,"given":"Elena","family":"Lucarini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6455-2723","authenticated-orcid":false,"given":"Clara","family":"Ciampi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4172-2478","authenticated-orcid":false,"given":"Francesco","family":"Margiotta","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Failli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4853-6640","authenticated-orcid":false,"given":"Chiara","family":"Gomiero","sequence":"additional","affiliation":[{"name":"Epitech Group SpA, Via Luigi Einaudi 13, 35030 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0057-6531","authenticated-orcid":false,"given":"Marco","family":"Pallecchi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-8769","authenticated-orcid":false,"given":"Gianluca","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ghelardini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8374-4432","authenticated-orcid":false,"given":"Lorenzo","family":"Di Cesare Mannelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health\u2014NEUROFARBA\u2014Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1037\/a0035514","article-title":"Interdisciplinary Chronic Pain Management: Past, Present, and Future","volume":"69","author":"Gatchel","year":"2014","journal-title":"Am. Psychol."},{"key":"ref_2","first-page":"16","article-title":"Pain after Injury: Some Basic Mechanisms","volume":"84","author":"Yaksh","year":"1997","journal-title":"J. Fla. Med. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1097\/ALN.0b013e3181c6316e","article-title":"Improving Postoperative Pain Management: What Are the Unresolved Issues?","volume":"112","author":"White","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e001566","DOI":"10.1136\/bmjdrc-2020-001566","article-title":"Altered Pain Processing in Patients with Type 1 and 2 Diabetes: Systematic Review and Meta-Analysis of Pain Detection Thresholds and Pain Modulation Mechanisms","volume":"8","author":"Somerville","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/S0140-6736(05)71086-2","article-title":"Pathogenesis and Management of Pain in Osteoarthritis","volume":"365","author":"Dieppe","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.hoc.2018.01.002","article-title":"Cancer Pain Syndromes","volume":"32","author":"Portenoy","year":"2018","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/SPC.0b013e328342f9cc","article-title":"Chemotherapy-Induced Neuropathic Pain","volume":"5","year":"2011","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"576","DOI":"10.3399\/bjgp20X713549","article-title":"Drugs for Chronic Pain","volume":"70","author":"Shaheed","year":"2020","journal-title":"Br. J. Gen. Pract."},{"key":"ref_9","first-page":"229","article-title":"Influence of Morphine on TLR4\/NF-KB Signaling Pathway of MCF-7 Cells","volume":"119","author":"Ghasemi","year":"2018","journal-title":"Bratisl. Lek. Listy"},{"key":"ref_10","first-page":"219","article-title":"The Pharmacological Basis of Opioids","volume":"12","author":"Ghelardini","year":"2015","journal-title":"Clin. Cases Miner. Bone Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1097\/00002820-199808000-00011","article-title":"Side Effects of Morphine Administration in Cancer Patients","volume":"21","author":"Vanegas","year":"1998","journal-title":"Cancer Nurs."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1208\/s12248-008-9056-1","article-title":"Opioid Tolerance Development: A Pharmacokinetic\/Pharmacodynamic Perspective","volume":"10","author":"Dumas","year":"2008","journal-title":"AAPS J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.bbi.2008.07.005","article-title":"Attenuation of Morphine Tolerance by Minocycline and Pentoxifylline in Naive and Neuropathic Mice","volume":"23","author":"Mika","year":"2009","journal-title":"Brain Behav. Immun."},{"key":"ref_14","unstructured":"Davis, M. (2009). Modulation of Microglia Can Attenuate Neuropathic Pain Symptoms and Enhance Morphine Effectiveness. J. Pain Palliat. Care Pharmacother., 23."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mahmoud, S., Gharagozloo, M., Simard, C., and Gris, D. (2019). Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release. Cells, 8.","DOI":"10.3390\/cells8020184"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1113\/JP270988","article-title":"Role of Astrocyte-Synapse Interactions in CNS Disorders","volume":"595","author":"Caldwell","year":"2017","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/978-3-030-27480-1_10","article-title":"Glycogen in Astrocytes and Neurons: Physiological and Pathological Aspects","volume":"23","author":"Duran","year":"2019","journal-title":"Adv. Neurobiol."},{"key":"ref_18","first-page":"894732","article-title":"Delay of Morphine Tolerance by Palmitoylethanolamide","volume":"2015","author":"Corti","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0168-0102(00)00226-1","article-title":"The Involvement of Glial Cells in the Development of Morphine Tolerance","volume":"39","author":"Song","year":"2001","journal-title":"Neurosci. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejphar.2007.01.013","article-title":"Minocycline and Pentoxifylline Attenuate Allodynia and Hyperalgesia and Potentiate the Effects of Morphine in Rat and Mouse Models of Neuropathic Pain","volume":"560","author":"Mika","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.bbi.2007.07.014","article-title":"A Novel Role of Minocycline: Attenuating Morphine Antinociceptive Tolerance by Inhibition of P38 MAPK in the Activated Spinal Microglia","volume":"22","author":"Cui","year":"2008","journal-title":"Brain Behav. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/sj.npp.1300315","article-title":"Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats","volume":"29","author":"Raghavendra","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"D\u2019aloia, A., Molteni, L., Gullo, F., Bresciani, E., Artusa, V., Rizzi, L., Ceriani, M., Meanti, R., Lecchi, M., and Coco, S. (2021). Palmitoylethanolamide Modulation of Microglia Activation: Characterization of Mechanisms of Action and Implication for Its Neuroprotective Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063054"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.tvjl.2005.10.003","article-title":"Palmitoylethanolamide, Endocannabinoids and Related Cannabimimetic Compounds in Protection against Tissue Inflammation and Pain: Potential Use in Companion Animals","volume":"173","author":"Re","year":"2007","journal-title":"Vet. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3389\/fphar.2019.00821","article-title":"Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer\u2019s Disease","volume":"10","author":"Beggiato","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/bcp.13020","article-title":"Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy","volume":"82","author":"Gabrielsson","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","first-page":"353","article-title":"Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis","volume":"20","author":"Artukoglu","year":"2017","journal-title":"Pain Physician"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rankin, L., and Fowler, C.J. (2020). The Basal Pharmacology of Palmitoylethanolamide. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217942"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00300","DOI":"10.1002\/prp2.300","article-title":"The Anti-Inflammatory Compound Palmitoylethanolamide Inhibits Prostaglandin and Hydroxyeicosatetraenoic Acid Production by a Macrophage Cell Line","volume":"5","author":"Gabrielsson","year":"2017","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_30","first-page":"328797","article-title":"Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism","volume":"2013","author":"Pacini","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"i4","DOI":"10.1093\/bja\/aeu090","article-title":"Morphine Stimulates Cancer Progression and Mast Cell Activation and Impairs Survival in Transgenic Mice with Breast Cancer","volume":"113","author":"Nguyen","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/BF01967614","article-title":"Histamine Release from Isolated Rat Mast Cells: Effect of Morphine and Related Drugs and Their Interaction with Compound 48\/80","volume":"11","author":"Grosman","year":"1981","journal-title":"Agents Actions"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1182\/blood-2013-04-498105","article-title":"Mast Cell Activation Contributes to Sickle Cell Pathobiology and Pain in Mice","volume":"122","author":"Vincent","year":"2013","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0014-2999(96)00015-5","article-title":"N-(2-Hydroxyethyl) Hexadecanamide Is Orally Active in Reducing Edema Formation and Inflammatory Hyperalgesia by down-Modulating Mast Cell Activation","volume":"300","author":"Mazzari","year":"1996","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"389","DOI":"10.3233\/JAD-170699","article-title":"Palmitoylethanolamide Blunts Amyloid-\u039242-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures","volume":"61","author":"Beggiato","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","first-page":"51","article-title":"La Lign\u00e9e Mastocytaire RBL: Mod\u00e8le Exp\u00e9rimental in Vitro et Application En Pharmacologie Clinique","volume":"44","author":"Blank","year":"2004","journal-title":"Rev. Fr. Allergol. Immunol. Clin."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1083\/jcb.85.3.890","article-title":"Preparation of Separate Astroglial and Oligodendroglial Cell Cultures from Rat Cerebral Tissue","volume":"85","author":"McCarthy","year":"1980","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1006\/abbi.1993.1311","article-title":"Characterization of the Cellular Reduction of 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT): Subcellular Localization, Substrate Dependence, and Involvement of Mitochondrial Electron Transport in MTT Reduction","volume":"303","author":"Berridge","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/j.1600-0765.2011.01436.x","article-title":"The Antimicrobial Peptide LL-37 Is Anti-Inflammatory and Proapoptotic in Human Periodontal Ligament Cells","volume":"47","author":"Nilsson","year":"2012","journal-title":"J. Periodontal Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1016\/j.yexcr.2012.07.010","article-title":"Establishment and Characterization of Mouse Bone Marrow-Derived Mast Cell Hybridomas","volume":"318","author":"Kawahara","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Micheli, L., Lucarini, E., Toti, A., Ferrara, V., Ciampi, C., Parisio, C., Bartolucci, G., Mannelli, L.D.C., and Ghelardini, C. (2022). Effects of Ultramicronized N-Palmitoylethanolamine Supplementation on Tramadol and Oxycodone Analgesia and Tolerance Prevention. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020403"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1186\/s13046-021-02127-x","article-title":"VEGF-A\/VEGFR-1 Signalling and Chemotherapy-Induced Neuropathic Pain: Therapeutic Potential of a Novel Anti-VEGFR-1 Monoclonal Antibody","volume":"40","author":"Micheli","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9524","DOI":"10.3390\/molecules20069524","article-title":"Pretreatment with Relaxin Does Not Restore NO-Mediated Modulation of Calcium Signal in Coronary Endothelial Cells Isolated from Spontaneously Hypertensive Rats","volume":"20","author":"Nistri","year":"2015","journal-title":"Molecules"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s00011-009-0028-4","article-title":"RBL-2H3 Cells Are an Imprecise Model for Mast Cell Mediator Release","volume":"58","author":"Passante","year":"2009","journal-title":"Inflamm. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00011-009-0074-y","article-title":"The RBL-2H3 Cell Line: Its Provenance and Suitability as a Model for the Mast Cell","volume":"58","author":"Passante","year":"2009","journal-title":"Inflamm. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s00011-016-0917-2","article-title":"A Novel Eremophilane Lactone Inhibits Fc\u03b5RI-Dependent Release of pro-Inflammatory Mediators: Structure-Dependent Bioactivity","volume":"65","author":"Qian","year":"2016","journal-title":"Inflamm. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s00441-022-03687-w","article-title":"Systematic Comparisons of Various Markers for Mast Cell Activation in RBL-2H3 Cells","volume":"390","author":"Rujitharanawong","year":"2022","journal-title":"Cell Tissue Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3389\/fphar.2018.00473","article-title":"N-Palmitoylethanolamine Supplementation for Long-Lasting, Low-Dosed Morphine Antinociception","volume":"9","author":"Micheli","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Micheli, L., Lucarini, E., Nobili, S., Bartolucci, G., Pallecchi, A., Toti, A., Ferrara, V., Ciampi, C., Ghelardini, C., and Di Cesare Mannelli, L. (2022). Ultramicronized N-Palmitoylethanolamine Contributes to Morphine Efficacy against Neuropathic Pain: Implication of Mast Cells and Glia. Curr. Neuropharmacol., 21.","DOI":"10.2174\/1570159X21666221128091453"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1186\/s12974-019-1671-5","article-title":"Palmitoylethanolamide Counteracts Substance P-Induced Mast Cell Activation in Vitro by Stimulating Diacylglycerol Lipase Activity","volume":"16","author":"Petrosino","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"569","DOI":"10.3389\/fimmu.2014.00569","article-title":"Mast Cell Mediators: Their Differential Release and the Secretory Pathways Involved","volume":"5","author":"Moon","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/j.1365-2044.2004.03757.x","article-title":"Mast Cell Tryptase: A Review of Its Physiology and Clinical Significance","volume":"59","author":"Payne","year":"2004","journal-title":"Anaesthesia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fncel.2019.00110","article-title":"Mast Cell Neural Interactions in Health and Disease","volume":"13","author":"Mittal","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6891","DOI":"10.4049\/jimmunol.1000126","article-title":"Meningeal Mast Cells Affect Early T Cell Central Nervous System Infiltration and Blood-Brain Barrier Integrity through TNF: A Role for Neutrophil Recruitment?","volume":"184","author":"Sayed","year":"2010","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1515\/revneuro-2017-0007","article-title":"Mast Cells in Neuropathic Pain: An Increasing Spectrum of Their Involvement in Pathophysiology","volume":"28","author":"Kaur","year":"2017","journal-title":"Rev. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1152\/jn.00593.2001","article-title":"Sensitization to Mechanical Stimulation by Inflammatory Mediators and by Mild Burn in Canine Visceral Nociceptors in Vitro","volume":"87","author":"Koda","year":"2002","journal-title":"J. Neurophysiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/imm.12170","article-title":"Mast Cells, Glia and Neuroinflammation: Partners in Crime?","volume":"141","author":"Skaper","year":"2014","journal-title":"Immunology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1186\/1744-8069-7-42","article-title":"Central Nervous System Mast Cells in Peripheral Inflammatory Nociception","volume":"7","author":"Xanthos","year":"2011","journal-title":"Mol. Pain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.bbi.2011.09.016","article-title":"Mast Cell Degranulation Distinctly Activates Trigemino-Cervical and Lumbosacral Pain Pathways and Elicits Widespread Tactile Pain Hypersensitivity","volume":"26","author":"Levy","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lian, Q., Cheng, Y., Zhong, C., and Wang, F. (2015). Inhibition of the IgE-Mediated Activation of RBL-2H3 Cells by TIPP, a Novel Thymic Immunosuppressive Pentapeptide. Int. J. Mol. Sci., 16.","DOI":"10.3390\/ijms16012252"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fu, H., Cheng, H., Cao, G., Zhang, X., Tu, J., Sun, M., Mou, X., Shou, Q., and Ke, Y. (2016). The Inhibition of Mast Cell Activation of Radix Paeoniae Alba Extraction Identified by TCRP Based and Conventional Cell Function Assay Systems. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155930"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Okahashi, N., Nakata, M., Hirose, Y., Morisaki, H., Kataoka, H., Kuwata, H., and Kawabata, S. (2020). Streptococcal H2O2 Inhibits IgE-Triggered Degranulation of RBL-2H3 Mast Cell\/Basophil Cell Line by Inducing Cell Death. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231101"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1097\/ALN.0b013e31828351aa","article-title":"Role of Meningeal Mast Cells in Intrathecal Morphine-Evoked Granuloma Formation","volume":"118","author":"Yaksh","year":"2013","journal-title":"Anesthesiology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1046\/j.1399-6576.2003.00237.x","article-title":"Screening for Mast Cell Tryptase and Serum IgE Antibodies in 18 Patients with Anaphylactic Shock during General Anaesthesia","volume":"47","author":"Dybendal","year":"2003","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/j.1398-9995.2007.01345.x","article-title":"Codeine Induces Human Mast Cell Chemokine and Cytokine Production: Involvement of G-Protein Activation","volume":"62","author":"Sheen","year":"2007","journal-title":"Allergy"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.4049\/jimmunol.1302520","article-title":"Does \u03b2-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of \u03b2-Hexosaminidase in Mast Cell Granules","volume":"193","author":"Fukuishi","year":"2014","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Alanazi, S., Grujic, M., Lampinen, M., Rollman, O., Sommerhoff, C.P., Pejler, G., and Melo, F.R. (2020). Mast Cell \u03b2-Tryptase Is Enzymatically Stabilized by DNA. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145065"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00418-018-1659-8","article-title":"Tryptase as a Polyfunctional Component of Mast Cells","volume":"149","author":"Atiakshin","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/jat.3738","article-title":"Searching for Tryptase in the RBL-2H3 Mast Cell Model: Preparation for Comparative Mast Cell Toxicology Studies with Zebrafish","volume":"39","author":"Shim","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"113014","DOI":"10.1016\/j.biopha.2022.113014","article-title":"Propofol Pretreatment Alleviates Mast Cell Degranulation by Inhibiting SOC to Protect the Myocardium from Ischemia\u2013Reperfusion Injury","volume":"150","author":"Li","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/ALN.0000000000002730","article-title":"Mast Cell Degranulation and Fibroblast Activation in the Morphine-Induced Spinal Mass: Role of Mas-Related G Protein-Coupled Receptor Signaling","volume":"131","author":"Yaksh","year":"2019","journal-title":"Anesthesiology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.3389\/fimmu.2018.01873","article-title":"The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets","volume":"9","author":"Thangam","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1002\/eji.200535464","article-title":"Histamine Modulates Mast Cell Degranulation through an Indirect Mechanism in a Model IgE-Mediated Reaction","volume":"36","author":"Carlos","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_74","first-page":"787","article-title":"Role of TNF in Mast Cell Neuroinflammation and Pain","volume":"29","author":"Gu","year":"2015","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1177\/039463200702000303","article-title":"Anti-Chemokine Therapy for Inflammatory Diseases","volume":"20","author":"Castellani","year":"2016","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/eji.1830230329","article-title":"RANTES and Related Chemokines Activate Human Basophil Granulocytes through Different G Protein-coupled Receptors","volume":"23","author":"Bischoff","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1073\/pnas.92.8.3376","article-title":"Mast Cells Express a Peripheral Cannabinoid Receptor with Differential Sensitivity to Anandamide and Palmitoylethanolamide","volume":"92","author":"Facci","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.vetimm.2009.06.011","article-title":"Effects of Palmitoylethanolamide on Immunologically Induced Histamine, PGD2 and TNFalpha Release from Canine Skin Mast Cells","volume":"133","author":"Cerrato","year":"2010","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/vde.12456","article-title":"Ultramicronized Palmitoylethanolamide Counteracts the Effects of Compound 48\/80 in a Canine Skin Organ Culture Model","volume":"28","author":"Abramo","year":"2017","journal-title":"Vet. Dermatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"34","DOI":"10.2174\/1871527311312010008","article-title":"Non-Neuronal Cell Modulation Relieves Neuropathic Pain: Efficacy of the Endogenous Lipid Palmitoylethanolamide","volume":"12","author":"Bettoni","year":"2013","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1046\/j.1365-3164.2001.00214.x","article-title":"Clinical and Histological Evaluation of an Analogue of Palmitoylethanolamide, PLR 120 (Comicronized Palmidrol INN) in Cats with Eosinophilic Granuloma and Eosinophilic Plaque: A Pilot Study","volume":"12","author":"Scarampella","year":"2001","journal-title":"Vet. Dermatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"C145","DOI":"10.1007\/BF01972748","article-title":"A Proposed Autacoid Mechanism Controlling Mastocyte Behaviour","volume":"39","author":"Aloe","year":"1993","journal-title":"Agents Actions"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.tins.2005.10.001","article-title":"Glia: Novel Counter-Regulators of Opioid Analgesia","volume":"28","author":"Watkins","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"366","DOI":"10.2174\/1570159X15666171128144441","article-title":"Targeting Cytokines for Morphine Tolerance: A Narrative Review","volume":"17","author":"Liu","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1002\/jnr.24731","article-title":"Deep Proteomics and Phosphoproteomics Reveal Novel Biological Pathways Perturbed by Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Human Astrocytes","volume":"100","author":"Dozio","year":"2022","journal-title":"J. Neurosci. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.biopsych.2021.06.009","article-title":"Astrocyte-Derived Extracellular Vesicle-Mediated Activation of Primary Ciliary Signaling Contributes to the Development of Morphine Tolerance","volume":"90","author":"Ma","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1007\/s13311-021-01116-4","article-title":"N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance","volume":"18","author":"Congiu","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0169-328X(95)00165-O","article-title":"Primary Astroglial Cultures Derived from Several Rat Brain Regions Differentially Express \u03bc, \u03b4 and \u03ba Opioid Receptor MRNA","volume":"34","author":"Ruzicka","year":"1995","journal-title":"Mol. Brain Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5607\/en.2018.27.2.120","article-title":"Expression of \u039c-Opioid Receptor in CA1 Hippocampal Astrocytes","volume":"27","author":"Nam","year":"2018","journal-title":"Exp. Neurobiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6713","DOI":"10.1007\/s12035-018-0878-2","article-title":"Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis","volume":"55","author":"Sil","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.bbi.2011.02.006","article-title":"Effects of Palmitoylethanolamide on Release of Mast Cell Peptidases and Neurotrophic Factors after Spinal Cord Injury","volume":"25","author":"Esposito","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fncel.2017.00216","article-title":"Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration","volume":"11","author":"Kempuraj","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pain.2005.02.003","article-title":"Interleukin-1 Antagonizes Morphine Analgesia and Underlies Morphine Tolerance","volume":"115","author":"Shavit","year":"2005","journal-title":"Pain"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1213\/ANE.0b013e3182025b15","article-title":"Etanercept Restores the Antinociceptive Effect of Morphine and Suppresses Spinal Neuroinflammation in Morphine-Tolerant Rats","volume":"112","author":"Shen","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"9980","DOI":"10.1523\/JNEUROSCI.22-22-09980.2002","article-title":"The Role of Spinal Neuroimmune Activation in Morphine Tolerance\/Hyperalgesia in Neuropathic and Sham-Operated Rats","volume":"22","author":"Raghavendra","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.neulet.2012.09.034","article-title":"Melanocortin 4 Receptor Antagonists Attenuates Morphine Antinociceptive Tolerance, Astroglial Activation and Cytokines Expression in the Spinal Cord of Rat","volume":"529","author":"Niu","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.cyto.2019.03.007","article-title":"Chemokines CCL2 and CCL7, but Not CCL12, Play a Significant Role in the Development of Pain-Related Behavior and Opioid-Induced Analgesia","volume":"119","author":"Kwiatkowski","year":"2019","journal-title":"Cytokine"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.bbrc.2017.04.058","article-title":"Effect of ApoA4 on SERPINA3 Mediated by Nuclear Receptors NR4A1 and NR1D1 in Hepatocytes","volume":"487","author":"Zhang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1158\/0008-5472.CAN-11-4088","article-title":"S-Glutathionylated Serine Proteinase Inhibitors as Plasma Biomarkers in Assessing Response to Redox-Modulating Drugs","volume":"72","author":"Grek","year":"2012","journal-title":"Cancer Res."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Park, J., Masaki, T., Mezaki, Y., Yokoyama, H., Nakamura, M., Maehashi, H., Fujimi, T.J., Gouraud, S.S., Nagatsuma, K., and Nakagomi, M. (2017). Alpha-1 Antichymotrypsin Is Involved in Astrocyte Injury in Concert with Arginine-Vasopressin during the Development of Acute Hepatic Encephalopathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189346"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/0197-4580(96)00111-X","article-title":"Synthesis and Secretion of Active Alpha 1-Antichymotrypsin by Murine Primary Astrocytes","volume":"17","author":"Kanemaru","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/j.1471-4159.2004.02900.x","article-title":"Duration of A1-Antichymotrypsin Gene Activation by IL-1 Is Determined by Efficiency of IkB\u03b1 Resynthesis in Primary Human Astrocytes","volume":"92","author":"Kiss","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nm.3852","article-title":"The Serine Protease Inhibitor SerpinA3N Attenuates Neuropathic Pain by Inhibiting T Cell\u2013Derived Leukocyte Elastase","volume":"21","author":"Strochlic","year":"2015","journal-title":"Nat. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1038\/npp.2014.70","article-title":"A Molecular Profile of Cocaine Abuse Includes the Differential Expression of Genes That Regulate Transcription, Chromatin, and Dopamine Cell Phenotype","volume":"39","author":"Bannon","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"6391","DOI":"10.1523\/JNEUROSCI.6221-11.2012","article-title":"Genomic Analysis of Reactive Astrogliosis","volume":"32","author":"Zamanian","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s12017-019-08581-3","article-title":"A Transcriptomic Analysis of Neuropathic Pain in Rat Dorsal Root Ganglia Following Peripheral Nerve Injury","volume":"22","author":"Sun","year":"2020","journal-title":"Neuromol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/ana.20003","article-title":"Altered Expression of the Glutamate Transporter EAAT2b in Neurological Disease","volume":"55","author":"Maragakis","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.pneurobio.2011.01.005","article-title":"GFAP in Health and Disease","volume":"93","author":"Middeldorp","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.neulet.2013.12.071","article-title":"The Dual Role of Astrocyte Activation and Reactive Gliosis","volume":"565","author":"Pekny","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"573256","DOI":"10.3389\/fimmu.2020.573256","article-title":"Protective Functions of Reactive Astrocytes Following Central Nervous System Insult","volume":"11","author":"Linnerbauer","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1111\/j.1471-4159.1993.tb09814.x","article-title":"Glial Fibrillary Acidic Protein and the Mesolimbic Dopamine System: Regulation by Chronic Morphine and Lewis-Fischer Strain Differences in the Rat Ventral Tegmental Area","volume":"61","author":"Guitart","year":"1993","journal-title":"J. Neurochem."},{"key":"ref_112","unstructured":"European Medicines Agency (2023, January 12). Guideline Bioanalytical Method Validation. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-bioanalytical-method-validation_en.pdf."},{"key":"ref_113","unstructured":"(2022, January 12). ICH Q2(R2) Validation of Analytical Procedures. Available online: https:\/\/www.ema.europa.eu\/en\/ich-q2r2-validation-analytical-procedures."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1021\/ac020361s","article-title":"Strategies for the Assessment of Matrix Effect in Quantitative Bioanalytical Methods Based on HPLC\u2212MS\/MS","volume":"75","author":"Matuszewski","year":"2003","journal-title":"Anal. Chem."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:15:13Z","timestamp":1760120113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,25]]},"references-count":114,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020233"],"URL":"https:\/\/doi.org\/10.3390\/biom13020233","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,25]]}}}