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TNF-Α and Neuropathic Pain Leung and Cahill Journal of Neuroinflammation 2010, 7:27 JOURNAL OF http://www.jneuroinflammation.com/content/7/1/27 NEUROINFLAMMATION REVIEW Open Access TNF-αReview and neuropathic pain - a review Lawrence Leung*1,2,3 and Catherine M Cahill1,4,5 Abstract Tumor necrosis factor alpha (TNF-α) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-α at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-α therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-α with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain. Introduction stimuli (allodynia). It is a pathological type of pain that Despite intense research over the last 30 years, debate is persists despite resolution of the inciting damage to the still ongoing regarding the nature of neuropathic pain, nerve and the surrounding tissues. From a behavioral including controversy as to whether such pain is periph- standpoint, nociception is an adaptive tool for better sur- eral or central in origin, and as to whether its etiology is vival, while neuropathic pain is considered maladaptive. inflammatory or non-inflammatory. Increasing evidence The prevalence of neuropathic pain ranges from 1% in has provided better understanding of the roles of both UK [5] to 1.5% in the US [6] to 17.9% in Canada [7]. Weir immune and pro-inflammatory mediators (e.g., the inter- Mitchell [8] is often credited with the first descriptive leukins, TNF-α, complement components, ATP and the account of neuropathic pain from nerve injuries seen in chemokines) in the mechanisms of both peripheral and the US Civil War, using terms that range from "burning", central neuropathic pain [1-4]. This review will concen- "mustard red hot", "red-hot file rasping the skin" to "with trate on current knowledge and experimental models intensity ranging from most trivial burning to a state of regarding the role of TNF-α, among other cytokines, in torture". Clinically, the top three most common types of neuropathic pain; with an appraisal of available potential neuropathic pain are post-herpetic neuralgia, trigeminal therapeutic targets related to TNF-α and directions for neuralgia and diabetic neuropathy [9]. Neuropathic pain future developments in this area. is among the most difficult types of chronic pain to treat, which not only significantly impairs patients' quality of Neuropathic pain as an example of an inflammatory pain life [10] but also adds to the burden of direct and indirect model medical cost for our society [10,11]. Conceptually, neuro- Neuropathic pain is characterized by disproportionate pathic pain consequent to peripheral nerve injury results hypersensitivity to stimuli (hyperalgesia), abnormal pins- from an increased excitability of the neurons as a result of and-needles or electric-shock-like sensations (hyper- sensitization. The debate is still on-going as to whether pathia) and, finally, nociceptive responses to non-noxious this sensitization occurs in the peripheral or central com- partments of the nervous system, or both. Experimen- * Correspondence: [email protected] tally, various animal models of peripheral neuropathic 1 Centre for Neurosciences Studies, 18, Stuart Street, Queen's University, pain have been developed: chronic constriction injury Kingston, Ontario K7L 3N6, Canada Full list of author information is available at the end of the article (CCI) of the sciatic nerve with loose ligatures [12-15]; © 2010 Leung and Cahill; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com- BioMed Central mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited. Leung and Cahill Journal of Neuroinflammation 2010, 7:27 Page 2 of 11 http://www.jneuroinflammation.com/content/7/1/27 partial sciatic nerve injury with tight ligatures [15-17]; pain [47,68]. In particular, tumor necrosis factor alpha total sciatic nerve ligation [15,18]; sciatic nerve transac- (TNF-α) [69,70], interleukin-1 (IL-1) [47,71,72] and inter- tion [19-21] and axotomy of lumbar roots entering the leukin-6 (IL-6) [49,73] have been associated with the sciatic nerve [22,23]. Despite the various degrees and development of neuropathic pain in various animal mod- modes of nerve damage in these models, there is a com- els [74]. In this review, we shall limit our scope to TNF-α. mon sequel--post-injury inflammatory changes leading to mast cell degranulation [24], and recruitment of both Tumor necrosis factor alpha (TNF-α): a neuropathic pain- macrophages [25] and polymorphonuclear neutrophils related cytokine [26]. However, in CCI models thermal hyperalgesia still In 1891, the success story of William Coley in using occurs when ligatures are loosely placed around the sci- supernatant extract of heat-killed mixtures of Streptococ- atic nerve without actual mechanical damage [27]. This cus pyogenes and Serratia marcescens bacteria to treat finding supports the hypothesis that it is the inflamma- tumors may in fact be the first discovery of tumor necro- tory microenvironment [28] and the release of mediators sis factor [75]. It was not until 1975 that an endotoxin-like [29], rather than the nerve injury per se, that is pivotal for substance was described in activated macrophages with the development of neuropathic pain. Clatworthy et al. tumor-regression activity and was given the name of [30] further demonstrated that suppression of the inflam- tumor necrosis factor alpha, TNF-α [76]. TNF-α belongs matory response with dexamethasone reduces thermal to a superfamily of ligand/receptor proteins called the hyperalgesia, while enhancing the inflammatory response tumor necrosis factor/tumor necrosis factor receptor using Freud's adjuvant was seen to aggravate the level of superfamily proteins (TNF/TNFR SFP). TNF-α possess a pain hypersensitivity. His work set the stage for continu- trimeric symmetry with a structural motif called the TNF ing research on immune and pro-inflammatory media- homology domain (THD), which is shared with all other tors in neuropathic pain over the next two decades. An members of the TNF proteins. This THD binds to the updated list of such mediators, by no means exhaustive, cysteine-rich domains (CRDs) of the TNF receptors includes the eicosanoids [31-34], bradykinins [35,36], (TNFRs), and variations of these CRDs lead to heteroge- serotonin [37-39], ATP/ADP [40-42], neurotrophins [43- neity of the TNFRs [77]. TNFRs are either constitutively 46], cytokines [47-52], chemokines [53,54], and reactive expressed (TNFR1, p55-R) or inducible (TNFR2, p75-R) oxygen species [21,55,56]. These mediators are not exclu- [78]. In the context of neuropathic pain, using the stan- sive to cells of immune/inflammatory origin, but are also dard model of chronic constriction injury (CCI) of sciatic produced by Schwann cells [57-59] and spinal glial cells nerve in rats, TNF-α has been detected at the injury site [42,60-63], thereby potentially mediating the mechanisms and shows temporal up-regulation [79-81]; here TNF-α is of neuropathic pain. located mainly in macrophages [82] and Schwann cells [70,83] by immuno-reactive staining. Similarly, there is Cytokines in neuropathic pain local up-regulation of both TNFR1 and TNFR2 as injured Cytokines are low molecular weight glycoproteins that neurons undergo Wallerian degeneration, albeit at differ- are secreted mainly, but not exclusively, by immunologi- ential rates [84]. Similar results are found in humans, cal cells such as T-cells, macrophages and neutrophils. where nerve biopsies from patients with painful neuropa- Other cells that secrete cytokines include keratinocytes thy show higher levels of TNF-α expression, especially in and dendritic cells of the skin [64] and Schwann cells and Schwann cells [85]. Intra-sciatic injection of TNF-α in glial cells of the central nervous system [65,66]. They act rats reproduces pain hypersensitivity that is similar to as intercellular mediators regulating the functions and that of neuropathic pain in humans [69,86], and this is differentiation of neighboring cells and are produced in reversible with neutralizing antibodies to TNFR [86], in response to disease, inflammation, or tissue damage. particular TNFR1 [50]. TNF-α enhances the tetrodo- Cytokine synthesis is prompt and their actions are often toxin-resistant (TTX-R) Na+ current in cultured DRG localized with a relatively short half-life. This distin- cells from wild-type but not from TNFR1-knockout mice, guishes them from hormones which are constantly pro- and such current is abolished by a p38-MAPK inhibitor; duced with longer-lasting and more distant effects. The implying that TNF acts via TNFR1 and activates TTX-R first cytokine was discovered by Beeson in 1948 [67] as a Na+ channels via the p38 MAPK system [87]. Further pyrogenic compound extracted from ploymorphonuclear studies using TNFR1/TNFR2 knock-out mice have sug- leucocytes, later known as IL-1β.
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