Ultramicronized N-palmitoylethanolamine Contributes to Morphine Efficacy Against Neuropathic Pain: Implication of Mast Cells and Glia


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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.

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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Di Cesare Mannelli, L.; D’Agostino, 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
  12. 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
  13. 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
  14. 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
  15. Peritore, A.F.; Siracusa, R.; Fusco, R.; Gugliandolo, E.; D’Amico, 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. D’Amico, 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
  33. Alessio, N.; Belardo, C.; Trotta, M.C.; Paino, S.; Boccella, S.; Gargano, F.; Pieretti, G.; Ricciardi, F.; Marabese, I.; Luongo, L.; Galderisi, U.; D’Amico, 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
  34. D’Aloia, 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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
  44. Henderson, G. The µ-opioid receptor: An electrophysiologist’s perspective from the sharp end. Br. J. Pharmacol., 2015, 172(2), 260-267. doi: 10.1111/bph.12633 PMID: 24640948
  45. 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
  46. 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 receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. J. Clin. Invest., 2014, 124(2), 592-603. doi: 10.1172/JCI70236 PMID: 24382350
  47. 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
  48. Cahill, C.M.; Taylor, A.M.W. Neuroinflammation—a 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
  49. 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.
  50. Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science, 2016, 353(6301), 777-783. doi: 10.1126/science.aag2590
  51. 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
  52. Ferrini, F.; Trang, T.; Mattioli, T.A.M.; Laffray, S.; Del’Guidice, 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
  53. 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
  54. Machelska, H.; Celik, M.Ö. Opioid receptors in immune and glial cells—implications for pain control. Front. Immunol., 2020, 11, 300. doi: 10.3389/fimmu.2020.00300 PMID: 32194554
  55. 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
  56. 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
  57. 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
  58. 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
  59. 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
  60. 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
  61. 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
  62. 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
  63. 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
  64. 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
  65. 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
  66. 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
  67. 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
  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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

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