Editorial Mediators of Inflammation as Targets for...

Hindawi Publishing CorporationMediators of InflammationVolume 2013, Article ID 783235, 3 pageshttp://dx.doi.org/10.1155/2013/783235

EditorialMediators of Inflammation as Targets forChronic Pain Treatment

Metoda Lipnik-Stangelj

Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana,Korytkova 2, 1000 Ljubljana, Slovenia

Correspondence should be addressed to Metoda Lipnik-Stangelj; [email protected]

Received 2 October 2013; Accepted 2 October 2013

Copyright © 2013 Metoda Lipnik-Stangelj. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Treatment of chronic pain remains an unresolved problemin human medicine which greatly impairs quality of life andprolongs treatment. Solving this problem is difficult due toa number of mechanisms and signalling pathways throughwhich chronic pain is generated [1]. A common underlyingmechanism of chronic pain is the presence of inflammationat the site of the damaged or affected tissue. The releaseof proinflammatory and immunoactive substances such ascytokines, neurotrophic factors, and chemokines initiateslocal actions and can result in a more generalized immuneresponse that leads to the chronic pain condition. Clinicalmanagement of chronic pain, that is, neuropathic pain afternerve injury or cancer pain in tumour invasion representstherefore a real challenge due to our limited understandingof the cellular mechanisms that initiate and maintain chronicpain while many of them are closely overlapping with theprocesses of inflammation, immune response, endocrine andnerve system, and genetic factors as well [2, 3]. This specialissue aims to bring a current knowledge of the role of medi-ators of inflammation in chronic pain, particularly molec-ular mechanisms, signalling molecules, and their role inthe initiation and maintenance of chronic pain, as well as thediagnostic and therapeutic challenges on this field. The briefintroductions of nine published papers are as follows.

The involvement of pro- and anti-inflammatory cytokinesand angiogenic factors in the pain, associated with braintumour progression, is shown in the paper entitled “Cytokinepatterns in brain tumour progression.” R. Albulescu et al.found significant changes in serum levels, with over threefoldup-regulation of cytokines IL-6, IL-1𝛽, TNF-𝛼, and IL-10and up to twofold up-regulation of cytokines IL-8, IL-2, and

GM-CSF, and angiogenic factors VEGF and FGF-2. All thesemolecules are involved in tumour progression, and are alsoinvolved in a generation of pain, associated with disease.While pain is a frequent symptomcaused by glioblastoma, theauthors concluded that determination of selected cytokinescould add to speed and accuracy, making thus possible earlierdiagnostics and onset of therapy.

Activation of N-methyl-D-aspartate (NMDA) receptorleads to development of hyperalgesia. In the study called“posttranslational nitration of tyrosine residues modulates glu-tamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia,” C. Muscoli et al., showed thatthermal hyperalgesia, induced by intrathecal administrationof NMDA, is associated with spinal nitration of GluN1 andGluN2B receptor subunits, glutamine synthase, that normallyconvert glutamate into nontoxic glutamine, and glutamatetransporter. Intrathecal injection of peroxynitrite decompo-sition catalyst FeTM-4-PyP5+ prevents nitration and inhibitsNMDA-mediated thermal hyperalgesia.Their results supportthe hypothesis that nitration of key proteins involved in theregulation of glutamate transmission is a crucial pathwaythrough which peroxynitrite mediates the development andmaintenance of NMDA-mediated thermal hyperalgesia.

Inflammatory conditions, particularly in joint diseases,induce an increase in reactive oxygen substanceswhich have adeleterious role in erosion, osteoarticular degeneration, andpain. L. Di Cesare Mannelli et al. in the psper “Therapeuticeffects of the superoxide dismutase mimetic compound Mn𝐼𝐼Me2DO2A on experimental articular pain in rats” focused on

superoxide dismutases which are decreased in pain con-ditions like joint inflammation, rheumatoid arthritis, and

2 Mediators of Inflammation

osteoarthritis. They tested a superoxide dismutase mimeticcompound 4,10-dimethyl-1,4,7,10 tetraazacyclododecane-1,7-diacetic acid MnII complex (MnIIMe

2DO2A), which has

potently relieved a pain in arthritis models, and they showedthat the effect differed from a direct inhibition of cyclooxyge-nase enzymes. In chronic administration, it involved preven-tion of tissue degenerative alterations induced by the oxida-tive stress and reduction of a persistent inflammatory painvia a direct antioxidant mechanism, while in acute admin-istration, it may decrease the nociceptive nervous fiberactivation induced by the local production of reactive oxygensubstances. Given these properties and the low toxicity ofthe molecule, MnIIMe

2DO2A represents a novel compound

potentially suitable for the treatment of inflammatory andneuropathic pain.

In the paper “Neurovascular unit in chronic pain,” B. M.Radu et al. focused on the role of blood-brain barrier (BBB)and blood-spinal cord barrier (BSCB) during the develop-ment of chronic pain. Reviewing several inflammatory- andnerve-injury-based pain models, they argue that the clari-fication of molecular BBB/BSCB permeabilization events isnecessary for understanding chronic pain mechanisms.Theyproposed that the understanding of chronic painmechanismswould benefit from the extension of research efforts to theneurovascular unit as a whole and reviewed the availableevidence on the interaction between analgesic drugs andthe neurovascular unit. Furthermore, they discussed chronicpain comorbidities, such as neuroinflammatory and neu-rodegenerative diseases, in a view of neurovascular unitchanges, and innovative pharmacological solutions, targetingneurovascular unit components in chronic pain treatment.

Pain perception displays large interindividual variabilityin the population that affects selection of analgesics andtheir dosing. In the comprehensive paper “Pharmacogeneticsof chronic pain and its treatment,” S. Svetlık et al. reviewedthe most recognized pharmacogenetic areas and variables inthe treatment of chronic pain. They focused on the impactof genetic variability of drug metabolizing enzymes, trans-porters, receptors, and pathways involved in chronic painperception and on the efficacy and safety of analgesicsand other drugs used for chronic pain treatment. Althoughseveral candidate genes have been identified in the literature,there is only limited clinical evidence substantiating for thepenetration of the testing for these candidate biomarkers intothe clinical practice. While the pain-perception regulationand modulation are still not fully understood, the authorshave concluded that more complex knowledge of genetic andepigenetic background for analgesia will be needed prior tothe clinical use of the candidate genetic biomarkers.

In autoimmune diseases of the nervous system, theneuropathic pain is frequently presented. In the reviewarticle “Neuropathic pain in animal models of nervous systemautoimmune diseases,” D. H. Tian et al. focused on neuro-pathic pain, associated with multiple sclerosis and Guillain-Barre syndrome, as well as with experimental autoimmuneencephalomyelitis and experimental autoimmune neuritis, inanimal models which enable investigations of behaviouralchanges, underlying mechanisms, and potential pharma-cotherapeutic approaches for neuropathic pain, associated

with these diseases. In this review, the symptoms, mecha-nisms, and clinical therapeutic options in these conditionsare examined, and the value of experimental autoimmuneencephalomyelitis and experimental autoimmune neuritisanimal models for the study of neuropathic pain in multiplesclerosis and Guillain-Barre syndrome is highlighted.

In the paper “Chronic pain treatment: the influence oftricyclic antidepressants on serotonin release and uptake inmast cells,” I. Ferjan M. Lipnik-Stangeli discussed the role ofserotonin (5-HT), tricyclic antidepressants, and mast cells inthe generation of chronic pain in the periphery and centralnerve system.They showed that, besides inhibition of the painstimuli in the central nerve system, 5-HTmight be associatedalso by an increased pain transmission from the periphery,where mast cells play an important role. The authors demon-strated that tricyclic antidepressants are able to influencemast cell-derived 5-HT levels via at least three differentmechanisms: secretion of 5-HT, uptake of exogenous 5-HT, and reuptake of secreted 5-HT. They concluded thatanalgesic effect of tricyclic antidepressants involved differentmechanisms of action.

Current evidence indicates lines of the prominent role ofgonadal hormones in affecting pain occurrence and intensity.In the review article “Testosterone-induced effects on lipids andinflammation,” S. Vodo et al. described interesting aspectson the generation of chronic pain, influenced by andro-gen hormones, particularly testosterone, and lipids, whosealtered metabolism is often accompanied by the release ofinterleukins and lipid-derived pro-inflammatory mediators,and based on interactions which are often not consideredin chronic pain mechanisms. Also important is the abilityof pain as well as pain therapies to affect gonadal hormonemetabolism. The authors concluded that lower testosteronelevels are associated with an increased metabolic risk, sys-temic inflammation, and chronic pain.

In the paper “Inflammatory pain and corticosteroneresponse in infant rats: effect of 5-HT1A agonist buspirone priorto gestational stress,” hypothalamo-pituitary-adrenal axis andserotonin system interactions in the chronic pain are dis-cussed. I. P. Butkevich et al. presented the effect of buspironeon the dynamics of the inflammatory pain-like behaviour andstress response of corticosterone during the formalin test inthe infant male rat offspring and evaluated the correlationbetween pain-like and hormonal parameters.They concludedthat maternal buspirone, applicated before the stress dur-ing gestation, may enhance an adaptive mechanism of theinflammatory nociceptive system through activation of thehypothalamo-pituitary-adrenal axis peripheral link.

Acknowledgment

I would like to thank all authors and reviewers for theircontribution and support to this special issue. A special thankis due to the Associate Editors, Mila Vlaskovska, MarshallDevor, Gila Moalem-Taylor, and Anna Maria Aloisi, for theircommitment, support, and excellent work.

Metoda Lipnik-Stangelj

Mediators of Inflammation 3

References

[1] M. Devor, “Neuropathic pain: what do we do with all thesetheories?” Acta Anaesthesiologica Scandinavica, vol. 45, no. 9,pp. 1121–1127, 2001.

[2] P. J. Austin andG.Moalem-Taylor, “Theneuro-immune balancein neuropathic pain: involvement of inflammatory immunecells, immune-like glial cells and cytokines,” Journal of Neuroim-munology, vol. 229, no. 1-2, pp. 26–50, 2010.

[3] A. M. Aloisi and M. Bonifazi, “Sex hormones, central nervoussystem and pain,”Hormones and Behavior, vol. 50, no. 1, pp. 1–7,2006.

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