Microglia and mast cells: new targets for the treatment of chronic pain

Main Article Content

V.I. Romanenko


The article is devoted to the problem of effective ma­nagement of chronic pain. A review of the known mechanisms of development and maintenance of chronic pain and possible me­thods of influence is given. One of the reasons for the lack of chro­nic pain treatment effectiveness in some patients is the use of treatment regimens with drugs acting exclusively on the targets loca­ted in the nerve structures. Today an important role of micro­glia and mast cells in the development and maintenance of chronic pain conditions is well acknowledged. A new class of drugs from the group of acylethanolamides is described. One of the representatives of this group is palmitoylethanolamide. This drug may mo­dulate the activity of microglia and mast cells, thus increasing the pain threshold and the effectiveness of therapy. The use of palmitoylethanolamide in patients with chronic pain can increase the effectiveness of therapy.

Article Details

How to Cite
Romanenko, V. “Microglia and Mast Cells: New Targets for the Treatment of Chronic Pain”. PAIN, JOINTS, SPINE, vol. 11, no. 2, July 2021, pp. 79-85, doi:10.22141/2224-1507.11.2.2021.236566.


Langley P, Müller-Schwefe G, Nicolaou A, Liedgens H, Pergolizzi J, Varrassi G. The societal impact of pain in the European Union: health-related quality of life and healthcare resource utilization. J Med Econ. 2010;13(3):571-581. https://doi.org/10.3111/13696998.2010.516709.

Langley P, Müller-Schwefe G, Nicolaou A, Liedgens H, Pergolizzi J, Varrassi G. The impact of pain on labor force participation, absenteeism and presenteeism in the European Union. J Med Econ. 2010;13(4):662-672. https://doi.org/10.3111/13696998.2010.529379.

Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006 May;10(4):287-333. https://doi.org/10.1016/j.ejpain.2005.06.009.

Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008 Jun;136(3):380-387. https://doi.org/10.1016/j.pain.2007.08.013.

Todd A, McNamara CL, Balaj M, et al. The European epidemic: Pain prevalence and socioeconomic inequalities in pain across 19 European countries. Eur J Pain. 2019 Sep;23(8):1425-1436. https://doi.org/10.1002/ejp.1409.

Miller RE, Miller RJ, Malfait AM. Osteoarthritis joint pain: the cytokine connection. Cytokine. 2014 Dec;70(2):185-193. https://doi.org/10.1016/j.cyto.2014.06.019.

Loeser JD, Treede RD. The Kyoto protocol of IASP Basic Pain Terminology. Pain. 2008 Jul 31;137(3):473-477. https://doi.org/10.1016/j.pain.2008.04.025.

Jay GW, Barkin RL. Neuropathic pain: etiology, pathophysiology, mechanisms, and evaluations. Dis Mon. 2014 Jan;60(1):6-47. https://doi.org/10.1016/j.disamonth.2013.12.001.

Van Laar M, Pergolizzi JV Jr, Mellinghoff HU, et al. Pain treatment in arthritis-related pain: beyond NSAIDs. Open Rheumatol J. 2012;6:320-330. https://doi.org/10.2174/1874312901206010320.

Dimitroulas T, Duarte RV, Behura A, Kitas GD, Raphael JH. Neuropathic pain in osteoarthritis: a review of pathophysiological mechanisms and implications for treatment. Semin Arthritis Rheum. 2014 Oct;44(2):145-154. https://doi.org/10.1016/j.semarthrit.2014.05.011.

Walters ET. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Exp Neurol. 2014 Aug;258:48-61. https://doi.org/10.1016/j.expneurol.2014.02.001.

Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010 Mar;85(3 Suppl):S3-14. https://doi.org/10.4065/mcp.2009.0649.

Paladini A, Fusco M, Cenacchi T, Schievano C, Piroli A, Varrassi G. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016 Feb;19(2):11-24.

Dong H, Zhang X, Qian Y. Mast cells and neuroinflammation. Med Sci Monit Basic Res. 2014 Dec 21;20:200-206. https://doi.org/10.12659/msmbr.893093.

Block L. Glial dysfunction and persistent neuropathic postsurgical pain. Scand J Pain. 2016 Jan;10:74-81. https://doi.org/10.1016/j.sjpain.2015.10.002.

Mika J, Zychowska M, Popiolek-Barczyk K, Rojewska E, Przewlocka B. Importance of glial activation in neuropathic pain. Eur J Pharmacol. 2013 Sep 15;716(1-3):106-119. https://doi.org/10.1016/j.ejphar.2013.01.072.

Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014 Jul;13(7):533-548. https://doi.org/10.1038/nrd4334.

Tiwari V, Guan Y, Raja SN. Modulating the delicate glial-neuronal interactions in neuropathic pain: promises and potential caveats. Neurosci Biobehav Rev. 2014 Sep;45:19-27. https://doi.org/10.1016/j.neubiorev.2014.05.002.

Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005 Dec;6(12):1191-1197. https://doi.org/10.1038/ni1276.

Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP. The resolution of inflammation. Nat Rev Immunol. 2013 Jan;13(1):59-66. https://doi.org/10.1038/nri3362.

Skaper SD, Facci L, Giusti P. Mast cells, glia and neuroinflammation: partners in crime? Immunology. 2014 Mar;141(3):314-327. https://doi.org/10.1111/imm.12170.

Dualé C, Ouchchane L, Schoeffler P, et al. Neuropathic Aspects of Persistent Postsurgical Pain: A French Multicenter Survey With a 6-Month Prospective Follow-Up. Journal of Pain. 2014 Jan;15(1):24.e1-24.e20. https://doi.org/10.1016/j.jpain.2013.08.014.

Martinez V, Ammar SB, Judet T, Bouhassira D, Chauvin M, Fletcher D. Risk factors predictive of chronic postsurgical neuropathic pain: the value of the iliac crest bone harvest model. Pain. 2012 Jul;153(7):1478-1483. https://doi.org/10.1016/j.pain.2012.04.004.

Calvo M, Bennett DL. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol. 2012 Apr;234(2):271-282. https://doi.org/10.1016/j.expneurol.2011.08.018.

Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 2013 Jul;111(1):26-37. https://doi.org/10.1093/bja/aet128.

Beaven MA. Our perception of the mast cell from Paul Ehrlich to now. Eur J Immunol. 2009 Jan;39(1):11-25. https://doi.org/10.1002/eji.200838899.

Gilfillan AM, Austin SJ, Metcalfe DD. Mast Cell Biology: Introduction and Overview. In: Gilfillan AM, Metcalfe DD, editors. Mast Cell Biology. Advances in Experimental Medicine and Biology. Vol 716. Boston, MA: Springer; 2011. 2-12 pp. https://doi.org/10.1007/978-1-4419-9533-9_1.

Skaper SD, Giusti P, Facci L. Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J. 2012 Aug;26(8):3103-3117. https://doi.org/10.1096/fj.11-197194.

Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S73-80. https://doi.org/10.1016/j.jaci.2009.11.017.

Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008 Jul 24;454(7203):428-435. https://doi.org/10.1038/nature07201.

De Vries HE, Blom-Roosemalen MC, van Oosten M, et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol. 1996 Jan;64(1):37-43. https://doi.org/10.1016/0165-5728(95)00148-4.

Huber JD, Witt KA, Hom S, Egleton RD, Mark KS, Davis TP. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2001 Mar;280(3):H1241-1248. https://doi.org/10.1152/ajpheart.2001.280.3.h1241.

Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006 Jan;7(1):41-53. https://doi.org/10.1038/nrn1824.

Beggs S, Liu XJ, Kwan C, Salter MW. Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Mol Pain. 2010 Nov 2;6:74. https://doi.org/10.1186/1744-8069-6-74.

Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol. 2008 Oct;21(5):570-579. https://doi.org/10.1097/aco.0b013e32830edbdf.

Araque A, Sanzgiri RP, Parpura V, Haydon PG. Astrocyte-induced modulation of synaptic transmission. Can J Physiol Pharmacol. 1999 Sep;77(9):699-706.

Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiological Reviews. 2006 Jul;86(3):1009-1031. https://doi.org/10.1152/physrev.00049.2005.

De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain. 2006 May;122(1-2):17-21. https://doi.org/10.1016/j.pain.2006.02.034.

Di Castro MA, Chuquet J, Liaudet N, et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat Neurosci. 2011 Sep 11;14(10):1276-1284. https://doi.org/10.1038/nn.2929.

Chiang CY, Sessle BJ, Dostrovsky JO. Role of astrocytes in pain. Neurochem Res. 2012 Nov;37(11):2419-2431. https://doi.org/10.1007/s11064-012-0801-6.

Watkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol. 2003;521:1-21.

Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36. https://doi.org/10.1038/nrn2533.

Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999 May;22(5):208-215. https://doi.org/10.1016/s0166-2236(98)01349-6.

Guo W, Wang H, Watanabe M, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007 May 30;27(22):6006-6018. https://doi.org/10.1523/jneurosci.0176-07.2007.

Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001 Aug;24(8):450-455. https://doi.org/10.1016/s0166-2236(00)01854-3.

Fu KY, Light AR, Matsushima GK, Maixner W. Microglial reactions after subcutaneous formalin injection into the rat hind paw. Brain Res. 1999 Apr 17;825(1-2):59-67. https://doi.org/10.1016/s0006-8993(99)01186-5.

Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002 Jan 1;22(1):183-192. https://doi.org/10.1523/jneurosci.22-01-00183.2002.

Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of Astrocytic Form and Function. In: Milner R, editor. Astrocytes. Methods and Protocols. Vol 814. Totowa, NJ: Humana Press; 2012. 23-45 pp. https://doi.org/10.1007/978-1-61779-452-0_3.

Santello M, Calì C, Bezzi P. Gliotransmission and the Tripartite Synapse. In: Kreutz MR, Sala C, editors. Synaptic Plasticity. Vienna: Springer; 2012. 307-331 pp. https://doi.org/10.1007/978-3-7091-0932-8_14.

Zorec R, Araque A, Carmignoto G, Haydon PG, Verkhratsky A, Parpura V. Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route. ASN Neuro. 2012 Mar 22;4(2):e00080. https://doi.org/10.1042/an20110061.

Lencesova L, O’Neill A, Resneck WG, Bloch RJ, Blaustein MP. Plasma Membrane-Cytoskeleton-Endoplasmic Reticulum Complexes in Neurons and Astrocytes. J Biol Chem. 2004 Jan 23;279(4):2885-2893. https://doi.org/10.1074/jbc.M310365200.

Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol (Oxf). 2006 May-Jun;187(1-2):321-327. https://doi.org/10.1111/j.1748-1716.2006.01568.x.

Delbro D, Westerlund A, Björklund U, Hansson E. In inflammatory reactive astrocytes co-cultured with brain endothelial cells nicotine-evoked Ca(2+) transients are attenuated due to interleukin-1beta release and rearrangement of actin filaments. Neuroscience. 2009 Mar 17;159(2):770-779. https://doi.org/10.1016/j.neuroscience.2009.01.005.

Esposito E, Cuzzocrea S. Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma. Mini Rev Med Chem. 2013 Feb;13(2):237-255.

Chirchiglia D, Chirchiglia P, Signorelli F. Nonsurgical lumbar radiculopathies treated with ultramicronized palmitoylethanolamide (umPEA): A series of 100 cases. Neurol Neurochir Pol. 2018 Jan-Feb;52(1):44-47. https://doi.org/10.1016/j.pjnns.2017.11.002.

Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-3380. https://doi.org/10.1073/pnas.92.8.3376.

Cerrato S, Brazis P, della Valle MF, Miolo A, Puigdemont A. Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells. Vet Immunol Immunopathol. 2010 Jan 15;133(1):9-15. https://doi.org/10.1016/j.vetimm.2009.06.011.

Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci. 2003 Aug 27;23(21):7767-7775. https://doi.org/10.1523/jneurosci.23-21-07767.2003.

Petrosino S, Palazzo E, de Novellis V, et al. Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology. 2007 Feb;52(2):415-422. https://doi.org/10.1016/j.neuropharm.2006.08.011.

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 Apr 11;300(3):227-236. https://doi.org/10.1016/0014-2999(96)00015-5.

Luongo L, Guida F, Boccella S, et al. Palmitoylethanolamide reduces formalin-induced neuropathic-like behaviour through spinal glial/microglial phenotypical changes in mice. CNS Neurol Disord Drug Targets. 2013 Feb 1;12(1):45-54. https://doi.org/10.2174/1871527311312010009.

Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998 Jul 16;394(6690):277-2781. https://doi.org/10.1038/28393.

Jaggar SI, Hasnie FS, Sellaturay S, Rice ASC. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain. 1998 May;76(1):189-199. https://doi.org/10.1016/s0304-3959(98)00041-4.

Romero TRL, Duarte IDG. N-Palmitoyl-ethanolamine (PEA) Induces Peripheral Antinociceptive Effect by ATP-Sensitive K+-Channel Activation. J Pharmacol Sci. 2012;118(2):156-160. https://doi.org/10.1254/jphs.11150FP.

Skaper SD, Facci L, Fusco M, et al. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacology. 2014 Apr;22(2):79-94. https://doi.org/10.1007/s10787-013-0191-7.

Freitag CM, Miller RJ. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines? Front Cell Neurosci. 2014 Aug 20;8:238. https://doi.org/10.3389/fncel.2014.00238.

Guida G, De Martino M, De Fabiani A, et al. La Palmitoiletanolamide (Normast) en el dolor neuropático crónico por lumbociatalgia de tipo compresivo: estudio clinico multícéntrico. Dolor. Investigación Clínica and Terapéutica. 2010;(25):35-42. (in Spanish).

Cocito D, Peci E, Ciaramitaro P, Merola A, Lopiano L. Short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain. Pain Res Treat. 2014;2014:854560. https://doi.org/10.1155/2014/854560.

Marini I, Bartolucci ML, Bortolotti F, Gatto MR, Bonetti GA. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J Orofac Pain. 2012 Spring;26(2):99-104.

Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Med. 2012 Sep;13(9):1121-1130. https://doi.org/10.1111/j.1526-4637.2012.01432.x.