Ultramicronized N-palmitoylethanolamine Contributes to Morphine Efficacy Against Neuropathic Pain: Implication of Mast Cells and Glia
- Authors: Micheli L.1, Lucarini E.1, Nobili S.1, Bartolucci G.2, Pallecchi M.3, Toti A.1, Ferrara V.4, Ciampi C.1, Ghelardini C.1, Di Cesare Mannelli L.1
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Affiliations:
- Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
- Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmaceutical and Nutraceutical Sciences Section,, University of Florence
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmaceutical and Nutraceutical Sciences Section, University of Florence
- Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section,, University of Florence
- Issue: Vol 22, No 1 (2024)
- Pages: 88-106
- Section: Neurology
- URL: https://rjsocmed.com/1570-159X/article/view/644235
- DOI: https://doi.org/10.2174/1570159X21666221128091453
- ID: 644235
Cite item
Full Text
Abstract
Background::In the current management of neuropathic pain, in addition to antidepressants and anticonvulsants, the use of opioids is wide, despite their related and well-known issues.
Objective::N-palmitoylethanolamine (PEA), a natural fatty-acid ethanolamide whose anti-inflammatory, neuroprotective, immune-modulating and anti-hyperalgesic activities are known, represents a promising candidate to modulate and/or potentiate the action of opioids.
Methods::This study was designed to evaluate if the preemptive and morphine concomitant administration of ultramicronized PEA, according to fixed or increasing doses of both compounds, delays the onset of morphine tolerance and improves its analgesic efficacy in the chronic constriction injury (CCI) model of neuropathic pain in rats.
Results::Behavioral experiments showed that the preemptive and co-administration of ultramicronized PEA significantly decreased the effective dose of morphine and delayed the onset of morphine tolerance. The activation of spinal microglia and astrocytes, commonly occurring both on opioid treatment and neuropathic pain, was investigated through GFAP and Iba-1 immunofluorescence. Both biomarkers were found to be increased in CCI untreated or morphine treated animals in a PEA-sensitive manner. The increased density of endoneural mast cells within the sciatic nerve of morphine-treated and untreated CCI rats was significantly reduced by ultramicronized PEA. The decrease of mast cell degranulation, evaluated in terms of reduced plasma levels of histamine and N-methyl-histamine metabolite, was mainly observed at intermediate-high doses of ultramicronized PEA, with or without morphine.
Conclusion::Overall, these results show that the administration of ultramicronized PEA in CCI rats according to the study design fully fulfilled the hypotheses of this study.
Keywords
About the authors
Laura Micheli
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
Elena Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
Stefania Nobili
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Author for correspondence.
Email: info@benthamscience.net
Gianluca Bartolucci
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmaceutical and Nutraceutical Sciences Section,, University of Florence
Email: info@benthamscience.net
Marco Pallecchi
Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmaceutical and Nutraceutical Sciences Section, University of Florence
Email: info@benthamscience.net
Alessandra Toti
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
Valentina Ferrara
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section,, University of Florence
Email: info@benthamscience.net
Clara Ciampi
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
Carla Ghelardini
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
Lorenzo Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA Pharmacology and Toxicology Section, University of Florence
Email: info@benthamscience.net
References
- Treede, R.D.; Jensen, T.S.; Campbell, J.N.; Cruccu, G.; Dostrovsky, J.O.; Griffin, J.W.; Hansson, P.; Hughes, R.; Nurmikko, T.; Serra, J. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology, 2008, 70(18), 1630-1635. doi: 10.1212/01.wnl.0000282763.29778.59 PMID: 18003941
- Colloca, L.; Ludman, T.; Bouhassira, D.; Baron, R.; Dickenson, A.H.; Yarnitsky, D.; Freeman, R.; Truini, A.; Attal, N.; Finnerup, N.B.; Eccleston, C.; Kalso, E.; Bennett, D.L.; Dworkin, R.H.; Raja, S.N. Neuropathic pain. Nat. Rev. Dis. Primers, 2017, 3(1), 17002. doi: 10.1038/nrdp.2017.2 PMID: 28205574
- Smith, B.H.; Hébert, H.L.; Veluchamy, A. Neuropathic pain in the community: Prevalence, impact, and risk factors. Pain, 2020, 161(Suppl. 1), S127-S137. doi: 10.1097/j.pain.0000000000001824 PMID: 33090746
- Finnerup, N.B.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpää, M.; Hansson, P.; Jensen, T.S.; Kamerman, P.R.; Lund, K.; Moore, A.; Raja, S.N.; Rice, A.S.C.; Rowbotham, M.; Sena, E.; Siddall, P.; Smith, B.H.; Wallace, M. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol., 2015, 14(2), 162-173. doi: 10.1016/S1474-4422(14)70251-0 PMID: 25575710
- Serrano, A.; Carnaval, T.; Videla Cés, S. Combination therapy for neuropathic pain: A review of recent evidence. J. Clin. Med., 2021, 10(16), 3533. doi: 10.3390/jcm10163533 PMID: 34441829
- Nudell, Y.; Dym, H.; Sun, F.; Benichou, M.; Malakan, J.; Halpern, L.R. Pharmacologic management of neuropathic pain. Oral Maxillofac. Surg. Clin. North Am., 2022, 34(1), 61-81. doi: 10.1016/j.coms.2021.09.002 PMID: 34802616
- Sommer, C.; Klose, P.; Welsch, P.; Petzke, F.; Häuser, W. Opioids for chronic non‐cancer neuropathic pain. An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks duration. Eur. J. Pain, 2020, 24(1), 3-18. doi: 10.1002/ejp.1494 PMID: 31705717
- Kuehl, F.A., Jr; Jacob, T.A.; Ganley, O.H.; Ormond, R.E.; Meisinger, M.A.P. The identification of N-(2-hydroxyethyl)-palmitoile as a naturally occuring anti-inflammatory agent. J. Am. Chem. Soc., 1957, 79(20), 5577-5578. doi: 10.1021/ja01577a066
- Aloe, L.; Leon, A.; Levi-Montalcini, R. A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions, 1993, 39(S1), C145-C147. doi: 10.1007/BF01972748 PMID: 7505999
- Di Cesare Mannelli, L.; Corti, F.; Micheli, L.; Zanardelli, M.; Ghelardini, C. Delay of morphine tolerance by palmitoylethanolamide. BioMed Res. Int., 2015, 2015, 1-12. doi: 10.1155/2015/894732 PMID: 25874232
- Di Cesare Mannelli, L.; DAgostino, G.; Pacini, A.; Russo, R.; Zanardelli, M.; Ghelardini, C.; Calignano, A. Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy: pain relief and neuroprotection share a PPAR-alpha-mediated mechanism. Mediators Inflamm., 2013, 2013, 1-12. doi: 10.1155/2013/328797 PMID: 23533304
- Di Cesare Mannelli, L.; Pacini, A.; Corti, F.; Boccella, S.; Luongo, L.; Esposito, E.; Cuzzocrea, S.; Maione, S.; Calignano, A.; Ghelardini, C. Antineuropathic profile of N-palmitoylethanolamine in a rat model of oxaliplatin-induced neurotoxicity. PLoS One, 2015, 10(6), e0128080. doi: 10.1371/journal.pone.0128080 PMID: 26039098
- Di Cesare Mannelli, L.; Micheli, L.; Lucarini, E.; Ghelardini, C. Ultramicronized N-palmitoylethanolamine supplementation for long-lasting, low-dosed morphine antinociception. Front. Pharmacol., 2018, 9, 473. doi: 10.3389/fphar.2018.00473 PMID: 29910726
- Skaper, S.D.; Facci, L.; Barbierato, M.; Zusso, M.; Bruschetta, G.; Impellizzeri, D.; Cuzzocrea, S.; Giusti, P. N-palmitoylethanolamine and neuroinflammation: A novel therapeutic strategy of resolution. Mol. Neurobiol., 2015, 52(2), 1034-1042. doi: 10.1007/s12035-015-9253-8 PMID: 26055231
- Peritore, A.F.; Siracusa, R.; Fusco, R.; Gugliandolo, E.; DAmico, R.; Cordaro, M.; Crupi, R.; Genovese, T.; Impellizzeri, D.; Cuzzocrea, S.; Di Paola, R. Ultramicronized palmitoylethanolamide and paracetamol, a new association to relieve hyperalgesia and pain in a sciatic nerve injury model in rat. Int. J. Mol. Sci., 2020, 21(10), 3509. doi: 10.3390/ijms21103509 PMID: 32429243
- Clayton, P.; Hill, M.; Bogoda, N.; Subah, S.; Venkatesh, R. Palmitoylethanolamide: A natural compound for health management. Int. J. Mol. Sci., 2021, 22(10), 5305. doi: 10.3390/ijms22105305 PMID: 34069940
- Ardizzone, A.; Fusco, R.; Casili, G.; Lanza, M.; Impellizzeri, D.; Esposito, E.; Cuzzocrea, S. Effect of ultra-micronized-palmitoylethanolamide and acetyl-l-carnitine on experimental model of inflammatory pain. Int. J. Mol. Sci., 2021, 22(4), 1967. doi: 10.3390/ijms22041967 PMID: 33671213
- Petrosino, S.; Palazzo, E.; de Novellis, V.; Bisogno, T.; Rossi, F.; Maione, S.; Di Marzo, V. Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology, 2007, 52(2), 415-422. doi: 10.1016/j.neuropharm.2006.08.011 PMID: 17011598
- Congiu, M.; Micheli, L.; Santoni, M.; Sagheddu, C.; Muntoni, A.L.; Makriyannis, A.; Malamas, M.S.; Ghelardini, C.; Di Cesare Mannelli, L.; Pistis, M. N-Acylethanolamine acid amidase inhibition potentiates morphine analgesia and delays the development of tolerance. Neurotherapeutics, 2021, 18(4), 2722-2736. doi: 10.1007/s13311-021-01116-4 PMID: 34553321
- McGrath, J.C.; Lilley, E. Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP. Br. J. Pharmacol., 2015, 172(13), 3189-3193. doi: 10.1111/bph.12955 PMID: 25964986
- Bennett, G.J.; Xie, Y.K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 1988, 33(1), 87-107. doi: 10.1016/0304-3959(88)90209-6 PMID: 2837713
- Leighton, G.E. Rodriguez, R.E.; Hill, R.G.; Hughes, J. κ-Opioid agonists produce antinociception after i.v. and i.c.v. but not intrathecal administration in the rat. Br. J. Pharmacol., 1988, 93(3), 553-560. doi: 10.1111/j.1476-5381.1988.tb10310.x PMID: 2836010
- Di Cesare Mannelli, L.; Pacini, A.; Bonaccini, L.; Zanardelli, M.; Mello, T.; Ghelardini, C. Morphologic features and glial activation in rat oxaliplatin-dependent neuropathic pain. J. Pain, 2013, 14(12), 1585-1600. doi: 10.1016/j.jpain.2013.08.002 PMID: 24135431
- Di Cesare Mannelli, L.; Maresca, M.; Micheli, L.; Farina, C.; Scherz, M.W.; Ghelardini, C. A rat model of FOLFOX-induced neuropathy: Effects of oral dimiracetam in comparison with duloxetine and pregabalin. Cancer Chemother. Pharmacol., 2017, 80(6), 1091-1103. doi: 10.1007/s00280-017-3449-8 PMID: 29026967
- Di, C.M.L.; Micheli, L.; Zanardelli, M.; Ghelardini, C. Low dose native type II collagen prevents pain in a rat osteoarthritis model. BMC Musculoskelet. Disord., 2013, 14(1), 228. doi: 10.1186/1471-2474-14-228 PMID: 23915264
- Maresca, M.; Micheli, L.; Cinci, L.; Bilia, A.R.; Ghelardini, C.; Di, C.M.L. Pain relieving and protective effects of Astragalus hydroalcoholic extract in rat arthritis models. J. Pharm. Pharmacol., 2017, 69(12), 1858-1870. doi: 10.1111/jphp.12828 PMID: 28960309
- Ito, D.; Imai, Y.; Ohsawa, K.; Nakajima, K.; Fukuuchi, Y.; Kohsaka, S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res. Mol. Brain Res., 1998, 57(1), 1-9. doi: 10.1016/S0169-328X(98)00040-0 PMID: 9630473
- Ben Saad, R.; Harbaoui, M.; Ben Romdhane, W.; Zouari, N.; Giang, K.N.; Ben Hsouna, A.; Brini, F. Overexpression of triticum durum TdAnn12 gene confers stress tolerance through scavenging reactive oxygen species in transgenic tobacco. Funct. Plant Biol., 2019, 46(10), 885-895. doi: 10.1071/FP18316 PMID: 31196377
- Micheli, L.; Lucarini, E.; Toti, A.; Ferrara, V.; Ciampi, C.; Parisio, C.; Bartolucci, G.; Di Cesare Mannelli, L.; Ghelardini, C. Effects of ultramicronized N-palmitoylethanolamine supplementation on tramadol and oxycodone analgesia and tolerance prevention. Pharmaceutics, 2022, 14(2), 403. doi: 10.3390/pharmaceutics14020403 PMID: 35214131
- Yawn, B.P.; Wollan, P.C.; Weingarten, T.N.; Watson, J.C.; Hooten, W.M.; Melton, L.J., III The prevalence of neuropathic pain: Clinical evaluation compared with screening tools in a community population. Pain Med., 2009, 10(3), 586-593. doi: 10.1111/j.1526-4637.2009.00588.x PMID: 20849570
- DiBonaventura, M.; Sadosky, A.; Concialdi, K.; Hopps, M.; Kudel, I.; Parsons, B.; Cappelleri, J.C.; Hlavacek, P.; Alexander, A.; Stacey, B.R.; Markman, J.D.; Farrar, J.T. The prevalence of probable neuropathic pain in the US: Results from a multimodal general-population health survey. J. Pain Res., 2017, 10, 2525-2538. doi: 10.2147/JPR.S127014 PMID: 29138590
- DAmico, R.; Impellizzeri, D.; Cuzzocrea, S.; Di Paola, R. Aliamides update: Palmitoylethanolamide and its formulations on management of peripheral neuropathic pain. Int. J. Mol. Sci., 2020, 21(15), 5330. doi: 10.3390/ijms21155330 PMID: 32727084
- Alessio, N.; Belardo, C.; Trotta, M.C.; Paino, S.; Boccella, S.; Gargano, F.; Pieretti, G.; Ricciardi, F.; Marabese, I.; Luongo, L.; Galderisi, U.; DAmico, M.; Maione, S.; Guida, F. Vitamin D deficiency induces chronic pain and microglial phenotypic changes in mice. Int. J. Mol. Sci., 2021, 22(7), 3604. doi: 10.3390/ijms22073604 PMID: 33808491
- DAloia, A.; Molteni, L.; Gullo, F.; Bresciani, E.; Artusa, V.; Rizzi, L.; Ceriani, M.; Meanti, R.; Lecchi, M.; Coco, S.; Costa, B.; Torsello, A. Palmitoylethanolamide modulation of microglia activation: Characterization of mechanisms of action and implication for its neuroprotective effects. Int. J. Mol. Sci., 2021, 22(6), 3054. doi: 10.3390/ijms22063054 PMID: 33802689
- Maione, S.; Costa, B.; Di Marzo, V. Endocannabinoids: A unique opportunity to develop multitarget analgesics. Pain, 2013, 154(Suppl. 1), S87-S93. doi: 10.1016/j.pain.2013.03.023 PMID: 23623250
- Lo Verme, J.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol., 2005, 67(1), 15-19. doi: 10.1124/mol.104.006353 PMID: 15465922
- Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol., 2007, 152(7), 1092-1101. doi: 10.1038/sj.bjp.0707460 PMID: 17876302
- De Petrocellis, L.; Davis, J.B.; Di Marzo, V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett., 2001, 506(3), 253-256. doi: 10.1016/S0014-5793(01)02934-9 PMID: 11602256
- Di, M.A.R.Z.O. V.; Melck, D.; Orlando, P.; Bisogno, T.; Zagoory, O.; Bifulco, M.; Vogel, Z.; de Petrocellis, L. Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells. Biochem. J., 2001, 358(1), 249-255. doi: 10.1042/bj3580249 PMID: 11485574
- Ho, W-S.V.; Barrett, D.A.; Randall, M.D. Entourage effects of N -palmitoylethanolamide and N -oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br. J. Pharmacol., 2008, 155(6), 837-846. doi: 10.1038/bjp.2008.324 PMID: 18695637
- Petrosino, S.; Schiano Moriello, A.; Cerrato, S.; Fusco, M.; Puigdemont, A.; De Petrocellis, L.; Di Marzo, V. The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br. J. Pharmacol., 2016, 173(7), 1154-1162. doi: 10.1111/bph.13084 PMID: 25598150
- Skaper, S.D.; Di Marzo, V. Endocannabinoids in nervous system health and disease: The big picture in a nutshell. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2012, 367(1607), 3193-3200. doi: 10.1098/rstb.2012.0313 PMID: 23108539
- Deuis, J.R.; Dvorakova, L.S.; Vetter, I. Methods used to evaluate pain behaviors in rodents. Front. Mol. Neurosci., 2017, 10, 284. doi: 10.3389/fnmol.2017.00284 PMID: 28932184
- Henderson, G. The µ-opioid receptor: An electrophysiologists perspective from the sharp end. Br. J. Pharmacol., 2015, 172(2), 260-267. doi: 10.1111/bph.12633 PMID: 24640948
- Iwai, S.; Kiguchi, N.; Kobayashi, Y.; Fukazawa, Y.; Saika, F.; Ueno, K.; Yamamoto, C.; Kishioka, S. Inhibition of morphine tolerance is mediated by painful stimuli via central mechanisms. Drug Discov. Ther., 2012, 6(1), 31-37. doi: 10.5582/ddt.2012.v6.1.31 PMID: 22460426
- Xu, J.T.; Zhao, J.Y.; Zhao, X.; Ligons, D.; Tiwari, V.; Atianjoh, F.E.; Lee, C.Y.; Liang, L.; Zang, W.; Njoku, D.; Raja, S.N.; Yaster, M.; Tao, Y.X. Opioid receptortriggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. J. Clin. Invest., 2014, 124(2), 592-603. doi: 10.1172/JCI70236 PMID: 24382350
- Williams, J.T.; Ingram, S.L.; Henderson, G.; Chavkin, C.; von Zastrow, M.; Schulz, S.; Koch, T.; Evans, C.J.; Christie, M.J. Regulation of µ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev., 2013, 65(1), 223-254. doi: 10.1124/pr.112.005942 PMID: 23321159
- Cahill, C.M.; Taylor, A.M.W. Neuroinflammationa co-occurring phenomenon linking chronic pain and opioid dependence. Curr. Opin. Behav. Sci., 2017, 13, 171-177. doi: 10.1016/j.cobeha.2016.12.003 PMID: 28451629
- DeLeo, J.A.; Tanga, F.Y.; Tawfik, V.L. Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist, 2004, 10, 40-52.
- Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science, 2016, 353(6301), 777-783. doi: 10.1126/science.aag2590
- Salter, M.W.; Stevens, B. Microglia emerge as central players in brain disease. Nat. Med., 2017, 23(9), 1018-1027. doi: 10.1038/nm.4397 PMID: 28886007
- Ferrini, F.; Trang, T.; Mattioli, T.A.M.; Laffray, S.; DelGuidice, T.; Lorenzo, L.E.; Castonguay, A.; Doyon, N.; Zhang, W.; Godin, A.G.; Mohr, D.; Beggs, S.; Vandal, K.; Beaulieu, J.M.; Cahill, C.M.; Salter, M.W.; De Koninck, Y. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat. Neurosci., 2013, 16(2), 183-192. doi: 10.1038/nn.3295 PMID: 23292683
- Vacca, V.; Marinelli, S.; Luvisetto, S.; Pavone, F. Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and µ opioid receptor expression in neuropathic mice. Brain Behav. Immun., 2013, 32, 40-50. doi: 10.1016/j.bbi.2013.01.088 PMID: 23402794
- Machelska, H.; Celik, M.Ö. Opioid receptors in immune and glial cellsimplications for pain control. Front. Immunol., 2020, 11, 300. doi: 10.3389/fimmu.2020.00300 PMID: 32194554
- Hutchinson, M.R.; Bland, S.T.; Johnson, K.W.; Rice, K.C.; Maier, S.F.; Watkins, L.R. Opioid-induced glial activation: Mechanisms of activation and implications for opioid analgesia, dependence, and reward. Sci. World J., 2007, 7, 98-111. doi: 10.1100/tsw.2007.230 PMID: 17982582
- Wang, X.; Loram, L.C.; Ramos, K.; de Jesus, A.J.; Thomas, J.; Cheng, K.; Reddy, A.; Somogyi, A.A.; Hutchinson, M.R.; Watkins, L.R.; Yin, H. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc. Natl. Acad. Sci. USA, 2012, 109(16), 6325-6330. doi: 10.1073/pnas.1200130109 PMID: 22474354
- Eidson, L.N.; Murphy, A.Z. Inflammatory mediators of opioid tolerance: Implications for dependency and addiction. Peptides, 2019, 115, 51-58. doi: 10.1016/j.peptides.2019.01.003 PMID: 30890355
- Berta, T.; Liu, Y.C.; Xu, Z.Z.; Ji, R.R. Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience, 2013, 247, 376-385. doi: 10.1016/j.neuroscience.2013.05.018 PMID: 23707980
- Taves, S.; Berta, T.; Chen, G.; Ji, R.R. Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast., 2013, 2013, 1-10. doi: 10.1155/2013/753656 PMID: 24024042
- Matejuk, A.; Ransohoff, R.M. Crosstalk between astrocytes and microglia: An overview. Front. Immunol., 2020, 11, 1416. doi: 10.3389/fimmu.2020.01416 PMID: 32765501
- Mazzari, S.; Canella, R.; Petrelli, L.; Marcolongo, G.; Leon, A.N. -(2-Hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur. J. Pharmacol., 1996, 300(3), 227-236. doi: 10.1016/0014-2999(96)00015-5 PMID: 8739213
- Costa, B.; Comelli, F.; Bettoni, I.; Colleoni, M.; Giagnoni, G. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB1, TRPV1 and PPARγ receptors and neurotrophic factors. Pain, 2008, 139(3), 541-550. doi: 10.1016/j.pain.2008.06.003 PMID: 18602217
- Iuvone, T.; Affaitati, G.; De Filippis, D.; Lopopolo, M.; Grassia, G.; Lapenna, D.; Negro, L.; Costantini, R.; Vaia, M.; Cipollone, F.; Ialenti, A.; Giamberardino, M.A. Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis. Pain, 2016, 157(1), 80-91. doi: 10.1097/j.pain.0000000000000220 PMID: 25974242
- Skaper, S.D.; Facci, L.; Giusti, P. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol. Neurobiol., 2013, 48(2), 340-352. doi: 10.1007/s12035-013-8487-6 PMID: 23813098
- Petrosino, S.; Schiano Moriello, A.; Verde, R.; Allarà, M.; Imperatore, R.; Ligresti, A.; Mahmoud, A.M.; Peritore, A.F.; Iannotti, F.A.; Di Marzo, V. Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity. J. Neuroinflammation, 2019, 16(1), 274. doi: 10.1186/s12974-019-1671-5 PMID: 31878942
- Zuo, Y.; Perkins, N.M.; Tracey, D.J.; Geczy, C.L. Inflammation and hyperalgesia induced by nerve injury in the rat: A key role of mast cells. Pain, 2003, 105(3), 467-479. doi: 10.1016/S0304-3959(03)00261-6 PMID: 14527707
- Smith, F.M.; Haskelberg, H.; Tracey, D.J.; Moalem-Taylor, G. Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation, 2007, 14(6), 317-325. doi: 10.1159/000125048 PMID: 18401194
- Obara, I.; Telezhkin, V.; Alrashdi, I.; Chazot, P.L. Histamine, histamine receptors, and neuropathic pain relief. Br. J. Pharmacol., 2020, 177(3), 580-599. doi: 10.1111/bph.14696 PMID: 31046146
- Abramo, F.; Lazzarini, G.; Pirone, A.; Lenzi, C.; Albertini, S.; della Valle, M.F.; Schievano, C.; Vannozzi, I.; Miragliotta, V. Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model. Vet. Dermatol., 2017, 28(5), 456-e104. doi: 10.1111/vde.12456 PMID: 28585337
- Cerrato, S.; Brazis, P.; della Valle, M.F.; Miolo, A.; Puigdemont, A. Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFα release from canine skin mast cells. Vet. Immunol. Immunopathol., 2010, 133(1), 9-15. doi: 10.1016/j.vetimm.2009.06.011 PMID: 19625089
- Schweiger, V.; Martini, A.; Bellamoli, P.; Donadello, K.; Schievano, C.; Balzo, G.D.; Sarzi-Puttini, P.; Parolini, M.; Polati, E. Ultramicronized palmitoylethanolamide (um-PEA) as add-on treatment in fibromyalgia syndrome (FMS): Retrospective observational study on 407 patients. CNS Neurol. Disord. Drug Targets, 2019, 18(4), 326-333. doi: 10.2174/1871527318666190227205359 PMID: 30827269
- Papetti, L.; Sforza, G.; Tullo, G.; Alaimo di Loro, P.; Moavero, R.; Ursitti, F.; Ferilli, M.A.N.; Tarantino, S.; Vigevano, F.; Valeriani, M. Tolerability of palmitoylethanolamide in a pediatric population suffering from migraine: A pilot study. Pain Res. Manag., 2020, 2020, 1-7. doi: 10.1155/2020/3938640 PMID: 32377286
- Cruccu, G.; Stefano, G.D.; Marchettini, P.; Truini, A. Micronized palmitoylethanolamide: A post hoc analysis of a controlled study in patients with low back pain - sciatica. CNS Neurol. Disord. Drug Targets, 2019, 18(6), 491-495. doi: 10.2174/1871527318666190703110036 PMID: 31269891
- Scaturro, D.; Asaro, C.; Lauricella, L.; Tomasello, S.; Varrassi, G.; Letizia Mauro, G. Combination of rehabilitative therapy with ultramicronized palmitoylethanolamide for chronic low back pain: An observational study. Pain Ther., 2020, 9(1), 319-326. doi: 10.1007/s40122-019-00140-9 PMID: 31863365
Supplementary files
