Levels of bioactive endogenous lipids and health-related quality of life in Chronic Idiopathic Axonal Polyneuropathy
Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain.
Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA.
Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons.
Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.
- Hanewinckel R, Drenthen J, van Oijen M, Hofman A, van Doorn PA, Ikram MA. Prevalence of polyneuropathy in the general middle-aged and elderly population. Neurology. 2016;87:1892–8. doi: 10.1212/WNL.0000000000003293
- Lindh J, Tondel M, Persson B, Vrethem M. Health-related quality of life in patients with cryptogenic polyneuropathy compared with the general population. Disabil Rehabil. 2011;33:617–23. doi: 10.3109/09638288.2010.505996
- Gwathmey KG, Pearson KT. Diagnosis and management of sensory polyneuropathy. BMJ. 2019;365:l1108. doi: 10.1136/bmj.l1108
- Lindh J, Tondel M, Osterberg A, Vrethem M. Cryptogenic polyneuropathy: clinical and neurophysiological findings. J Peripher Nerv Syst. 2005;10:31–7. doi: 10.1111/j.1085-9489.2005.10106.x
- Cocito D, Paolasso I, Pazzaglia C, Tavella A, Poglio F, Ciaramitaro P, et al. Pain affects the quality of life of neuropathic patients. Neurol Sci. 2006;27:155–60. doi: 10.1007/s10072-006-0660-5
- Boyd D, Butler M, Carr D, Cohen M, Devor M, Dworkin R, et al. IASP. International Association for the Study of Pain (IASP) terminology. Available from: https://wwwiasp-painorg/terminology?navItemNumber=576#Neuropathicpain. 2021.
- Bouhassira D. Neuropathic pain: definition, assessment and epidemiology. Rev Neurol (Paris). 2019;175:16–25. doi: 10.1016/j.neurol.2018.09.016
- Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971–9. doi: 10.1126/science.150.3699.971
- Dinakar P. Principles of pain management. In: Robert B. Daroff, Joseph Jankovic, John C. Mazziotta, Scott L Pomeroy. Bradley’s neurology in clinical practice. 7th ed. ClinicalKey: Elsevier Inc; 2016, pp. 720–41.
- Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci. 2014;17:164–74. doi: 10.1038/nn.3612
- Skaper SD, Facci L, Barbierato M, Zusso M, Bruschetta G, Impellizzeri D, et al. N-palmitoylethanolamine and neuroinflammation: a novel therapeutic strategy of resolution. Mol Neurobiol. 2015;52:1034–42. doi: 10.1007/s12035-015-9253-8
- Iannotti FA, Di Marzo V, Petrosino S. Endocannabinoids and endocannabinoid-related mediators: targets, metabolism and role in neurological disorders. Prog Lipid Res. 2016;62:107–28. doi: 10.1016/j.plipres.2016.02.002
- Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V. The cannabinoid system and pain. Neuropharmacology. 2017;124:105–20. doi: 10.1016/j.neuropharm.2017.06.015
- Khasabova IA, Yao X, Paz J, Lewandowski CT, Lindberg AE, Coicou L, et al. JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. Pharmacol Res. 2014;90:67–75. doi: 10.1016/j.phrs.2014.09.008
- 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;21:5330. doi: 10.3390/ijms21155330
- 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;67:15–9. doi: 10.1124/mol.104.006353
- Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998;394:277–81. doi: 10.1038/28393
- Zhang X, Young HA. PPAR and immune system – what do we know? Int Immunopharmacol. 2002;2:1029–44. doi: 10.1016/S1567-5769(02)00057-7
- Wang X, Miyares RL, Ahern GP. Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J Physiol. 2005;564:541–7. doi: 10.1113/jphysiol.2004.081844
- Piomelli D, Hohmann AG, Seybold V, Hammock BD. A lipid gate for the peripheral control of pain. J Neurosci. 2014;34:15184–91. doi: 10.1523/JNEUROSCI.3475-14.2014
- Berdyshev AG, Kosiakova HV, Onopchenko OV, Panchuk RR, Stoika RS, Hula NM. N-Stearoylethanolamine suppresses the pro-inflammatory cytokines production by inhibition of NF-kappaB translocation. Prostaglandins Other Lipid Mediat. 2015;121:91–6. doi: 10.1016/j.prostaglandins.2015.05.001
- Dalle Carbonare M, Del Giudice E, Stecca A, Colavito D, Fabris M, D’Arrigo A, et al. A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story. J Neuroendocrinol. 2008;20:26–34. doi: 10.1111/j.1365-2826.2008.01689.x
- Staud R. Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol. 2011;25:155–64. doi: 10.1016/j.berh.2010.01.010
- Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain. 2009;145:96–104. doi: 10.1016/j.pain.2009.05.020
- Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75:196–208. doi: 10.1002/ana.24065
- Uceyler N, Zeller D, Kahn A-K, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136:1857–67.
- Stensson N, Ghafouri B, Gerdle B, Ghafouri N. Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain – a case control study. Lipids Health Dis. 2017;16:112. doi: 10.1186/s12944-017-0505-7
- Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2008;10:R43.
- Lindh J, Soderkvist P, Fredrikson M, Hosseininia S, Tondel M, Persson B, Vrethem M. Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case-control study. Brain Behav. 2011;1:135–41. doi: 10.1002/brb3.26
- Persson B, Vrethem M, Murgia N, Lindh J, Hallsten A-L, Fredrikson M, Tondel M. Urinary 2,5-hexanedione excretion in cryptogenic polyneuropathy compared to the general Swedish population. J Occup Med Toxicol. 2013;8:21. doi: 10.1186/1745-6673-8-21
- Tondel M, Lindh J, Jonsson P, Vrethem M, Persson B. Occupational determinants of cryptogenic polyneuropathy. Neuroepidemiology. 2006;26:187–94. doi: 10.1159/000092405
- Vrethem M, Lindh J, Tondel M, Persson B, Dahle C. IgA antibodies against tissue transglutaminase, endomysium and gliadin in idiopathic polyneuropathy. Acta Neurol Scand. 2013;127:109–15.
- Prineas J. Polyneuropathies of undetermined cause. Acta Neurol Scand Suppl. 1970;44:3–72. doi: 10.1111/j.1600-0404.1970.tb07459.x
- Lindh J. Cryptogenic polyneuropathy: clinical, environmental, and genetic studies. Institutionen för klinisk och experimentell medicin, Neurologi. Linköping: Linköping University; 2011, p. 122.
- Stensson N, Ghafouri N, Träff H, Anderson CD, Gerdle B, Ghafouri B. Identification of lipid mediators in peripheral human tissues using an integrative in vivo microdialysis approach. OMICS International in Henderson, Nevada, USA. 2016.
- Balvers MGJ, Verhoeckx KCM, Witkamp RF. Development and validation of a quantitative method for the determination of 12 endocannabinoids and related compounds in human plasma using liquid chromatography–tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:1583–90. doi: 10.1016/j.jchromb.2009.04.010
- Baggelaar MP, Maccarrone M, van der Stelt M. 2-Arachidonoylglycerol: a signaling lipid with manifold actions in the brain. Prog Lipid Res. 2018;71:1–17. doi: 10.1016/j.plipres.2018.05.002
- Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.
- Veress G, Meszar Z, Muszil D, Avelino A, Matesz K, Mackie K, Nagy I. Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct Funct. 2013;218:733–50. doi: 10.1007/s00429-012-0425-2
- Di Cesare ML, 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;2013:328797. doi: 10.1155/2013/328797
- Waldfogel JM, Nesbit, SA, Dy SM, Sharma R, Zhang A, Wilson LM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review. Neurology. 2017;88:1958–67. doi: 10.1212/WNL.0000000000003882
- Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett. 1997;221:157–60. doi: 10.1016/S0304-3940(96)13308-5
- Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6:713–37. doi: 10.1016/j.nurt.2009.08.002
- Mulpuri Y, Marty VN, Munier JJ, Mackie K, Schmidt BL, Seltzman HH, Spigelman I. Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacology. 2018;139:85–97. doi: 10.1016/j.neuropharm.2018.07.002
- Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182. doi: 10.1002/14651858.CD012182.pub2
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