Abstract
Background
Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options.
Methods
A literature review was performed to assess the role of pro-inflammatory and antiinflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized.
Results and conclusions
In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition.
1 Introduction
Neuropathic pain refers to pain caused by pathology of the central or peripheral nervous system. It is a clinical diagnosis, typically described as shock-like or burning pain, often with hyperalgesia and allodynia [1,2]. A wide variety of painful conditions have a component of neuropathic pain, such as traumatic injury, nerve compression (e.g., radiculopathies, cancer metastases), metabolic disturbances (e.g., B12 deficiency, painful diabetic neuropathy), and infectious disease (e.g., post-herpetic neuralgia, HIV-associated neuropathy) [3].
Prior studies have suggested that dysregulation of neurotransmitters and over-excitation of ion channels responsible for signal transmission may contribute to the sensation of neuropathic pain [4,5]. Current first-line pharmacological treatments, antidepressants and anticonvulsants, target specific neurotransmitter receptors and ion channels to decrease neuropathic pain [2]. However, many patients continue to suffer from pain refractory to existing treatments. Therefore, better understanding of neuropathic pain mechanisms may offer alternative approaches to the management of neuropathic pain.
Recently, more studies have focused on the role of the immune system in neuropathic pain. In contrast to neuropathic pain, immune-mediated or inflammatory pain has classically been understood as pain secondary to inflammation from tissue damage [6]. Treatment approaches may differ depending on the type of pain identified. However, increasing evidence has demonstrated that inflammation at an affected nerve may play a role in mediating neuropathic pain [7,8]. Peripheral nerve damage activates glial cells, which release inflammatory mediators and stimulate production of pain signaling molecules (e.g., glutamate, substance P, calcitonin gene-related peptide); prolonged release of pro-inflammatory mediators can cause central nervous system changes that may result in neuropathic pain [9]. As various shared mechanisms are identified between the two types of pain, they warrant reconsideration of our understanding, diagnosis, and treatment of both neuropathic and inflammatory pain [10].
The signaling molecules of the immune system are cytokines, which can be broadly categorized as either pro-inflammatory or anti-inflammatory. Elevated pro-inflammatory cytokines have been associated with the presence of pain following nerve damage, whereas anti-inflammatory cytokines are associated with down-regulation of the immune system and neuropathic pain relief [7,8,11]. In this review, we will provide a broad overview of the role of cytokines in modulating neuropathic pain and assess their potential therapeutic value in the treatment of this challenging pain disorder.
2 Targeting pro-inflammatory cytokines
Immune system activation has been shown to facilitate and increase neuropathic pain [12]. A number of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-17, have been found to be elevated in animal models of neuropathic pain. The same cytokines have also been found to be increased in the cerebrospinal fluid (CSF) and blood of patients with chronic neuropathic pain conditions [13,14,15,16]. Therefore, pharmacologically lowering the levels of inflammatory cytokines may reduce pain, which has been demonstrated for various cytokines in both animal models and clinical studies (Table 1).
Comparison of cytokine targets in treating neuropathic pain in animal models and their clinical correlates.
| Cytokine | Location of action | Animal model | Clinical trials for neuropathic pain | Clinical drugs |
|---|---|---|---|---|
| Pro-inflammatory | ||||
| TNF-α | Periphery | CCI[a], DM[b], Disc herniation | Sciatica, spinal stenosis, lumbosacral radiculopathy | Infliximab, etanercept adalimumab, certolizumab pegol, golimumab |
| IL-1β | Periphery, brain, spine | Knock-out mice, peripheral nerve injury | – | |
| IL-6 | Periphery | CCI, peripheral nerve injury | Disc herniation, chronic | Tocilizumab |
| spine | knock-out mice | regional pain syndrome, Sciatica | ||
| IL-17 | Periphery | CCI, peripheral nerve injury, chemical injection, knock-out mice, arthritis | Secukinumab | |
| Anti-inflammatory | ||||
| IL-4 | Periphery | CCI, partial nerve injury | – | Glatiramer acetate |
| IL-10 | Periphery, brain | CCI, partial/complete nerve injury, neuritis | – | Calcineurin, uliastatin |
| TGF-β | Periphery, brain | CCI, partial nerve injury | – | Flexibilide |
2.1 TNF-α
Tumor necrosis factor-α (TNF-α) is a cytokine first discovered in the context of facilitating cancer cell death [17]. Its involvement in neuropathic pain modulation has also been explored over the years. Studies have demonstrated that elevated TNF-α and its receptor are found at the sites of nerve damage in the classic chronic constriction injury (CCI) animal model of neuropathic pain [18,19,20,21]. Administration of exogenous TNF-α can also induce allodynia in rodents [22,23,24,25,26], while the administration of TNF-α antagonists has been found to decrease behaviors suggestive of pain and hyperalgesia in rodents following CCI [27,28,29,30].
Interestingly, the efficacy of TNF-α inhibitors seems to depend on the type of neuropathic pain. Despite promising findings in the CCI model as noted above, which is often considered a model of radiculopathy, TNF-α inhibitors have been shown to be only minimally effective in a rat disc-herniation model [31]. In contrast, TNF-α antagonists attenuated allodynia in diabetic mice, suggesting a possible treatment for diabetic neuropathy [32].
TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, are currently FDA-approved for painful disorders such as inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis [33]. Clinical trials of TNF-α antagonists in patients with chronic neuropathic pain conditions have had mixed results. In pilot studies of patients diagnosed with severe sciatica, both intravenous and subcutaneous administration of a TNF-α inhibitor, either infliximab or etanercept, led to decreased pain scores and improved work status [34,35,36,37]. A placebo-controlled, dose-response study found that 14 out of 18 patients with subacute lumbosacral radiculopathy who received 2, 4, or 6 mg of etanercept via transforaminal epidural injection reported long-term leg pain relief in at 1 and 6 months following administration, compared to only one out of six patients in the saline control group [38]. However, limitations of the study included the small sample size, unknown therapeutic dose range of etanercept, and the fact that non-responders in both the etanercept and control groups were not followed past 1 month, per study protocol. Given the heterogeneity of the low back pain population, it is possible that initial non-responders in both treatment groups could have later developed improvements in pain, independent of the study intervention. Subsequent randomized, controlled trials (RCTs) have suggested no long-term benefit of TNF-α inhibitors compared to placebo [39,40,41]. Korhonen et al. reported similar efficacy of infliximab infusion compared to placebo for pain and functional status in 40 sciatica patients at 3 months and 1 year [36]. In a larger trial of 84 patients with lumbosacral radiculopathy, Cohen et al. found that epidural steroids resulted in a larger reduction in leg pain than etanercept 4 mg or saline at 1 month, and that these differences were not statistically significant [41]. By contrast, a different RCT of 80 patients with lumbar spinal stenosis found that epidural administration of etanercept 10 mg was safe and more effective than dexamethasone in reducing low back and leg pain, although functional status 4 weeks was similarly improved between the two groups [42]. However, blinding in this study was not clear, there was no placebo group, all patients were taking non-steroidal anti-inflammatory drugs (NSAIDs) concurrently with treatment, and follow-up was limited to only 4 weeks after treatment.
Despite promising early studies, the failure of RCTs to establish the clinical efficacy of TNF-α inhibitors in neuropathic pain may reflect insufficient data regarding the appropriate indication, dose, treatment duration, and route of administration to achieve meaningful clinical benefit. Furthermore, differences in duration of symptoms and mechanism of injury (e.g., traumatic vs. degenerative) could also affect the response to TNF-α antagonist treatment. Lastly, it is important to note that TNF-α inhibitors are generally safe and well-tolerated, even with long-term use [43]. A better understanding of the role of TNF-α in the mediation of neuropathic pain will help identify appropriate patients forTNF-α blockade and elucidate its potential value in the treatment of chronic pain.
2.2 IL-1β
Interleukin 1β (IL-1β) is another pro-inflammatory cytokine associated with immune activation. Elevated levels of IL-1β have been found in rats with chronic neuropathic pain, both peripherally and in areas of the brain, including the hippocampus, brainstem, and prefrontal cortex [44,45,46,47,48]. Moreover, administration of IL-1β provokes allodynia in rats [49,50]. Possible mechanisms include activation of the dorsal root ganglion neurons and increased spinal cord activity [51,52,53]. Knockout mice without IL-1β demonstrate no hyperalgesia following partial nerve injury, suggesting that IL-1β is essential in mediating neuropathic pain [54]. Likewise, exogenous IL-1β antibody also reduces allodynia in animal models of neuropathic pain [55,56,57]. Recent studies have shown that alternative approaches, such as administration of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) and electroacupuncture, can decrease IL-1β levels, suggesting a possible mechanism for their attenuation of pain [58,59]. While canakinumab, an IL-1β inhibitor, has been FDA-approved for other conditions such as juvenile idiopathic arthritis, there have been no published studies on its use in chronic pain patients.
2.3 IL-6
Interleukin 6 (IL-6) appears to be associated with neuropathic pain, but its precise role is not well-understood. Early animal studies have shown that there is a local increase in IL-6 mRNA and protein levels following peripheral nerve injury [60,61,62,63]. Further studies have suggested that the upregulation of IL-6 maybe through a prostaglandin E2-stimulated pathway [64,65]. However, in a rat nerve compression experiment, onset of allodynia immediately followed the compressing injury, whereas IL-6 elevation was delayed [66]. In addition to the temporal discrepancy, a spatial inconsistency has also been suggested. Following unilateral lumbar CCI in rats, elevated IL-6 was not only detected in the area of nerve injury, but also on the opposite side and in cervical regions, suggesting that IL-6 may be a non-specific marker of neuroinflammation, as opposed to a mediator of pain [67,68]. Nonetheless, reduction in IL-6 has been found to alleviate neuropathic pain in animals. IL-6 knockout mice had significantly less mechanical allodynia after nerve injury than control mice [69], and administration of anti-IL-6 antibody produces the same pain attenuation in rodents [70,71,72].
There have been several human studies of IL-6 in relation to neuropathic pain, with mixed results. Herniated vertebral disc samples obtained from patients showed elevated levels of numerous inflammatory markers, including IL-6 [73,74]. Two separate prospective cohort studies have suggested some benefit of tocilizumab, an anti-IL-6 antibody, in the treatment of sciatica and discogenic low back pain. Ohtori et al. reported that epidural administration of tocilizumab was safe and led to statistically significant improvements in low back and leg pain when compared to dexamethasone [75]. However, it is unclear whether this was a clinically significant benefit, particularly given that treatment blinding was not specified, there was no placebo group, all patients were on NSAIDs, and participants were only followed to 4 weeks after intervention. A more recent study from Sainoh et al. evaluated intradiscal tocilizumab bupivacaine versus bupivacaine only for discogenic back pain [76]. The authors reported statistically significant differences in pain relief and disability favoring tocilizumab at 2 and 4 weeks, but no difference at 6 weeks. However, these findings are difficult to interpret, since the study was neither blinded nor randomized, and there were significantly more males in the tocilizumab group. The investigators also noted that intradiscal pressure limited the dose administered, such that the actual dose of study drug varied by patient. However, the degree of dose variation was not reported. It is important to note that although no patients experienced complications in the epidural study, one patient who received intradiscal tocilizumab developed discitis [76]. Finally, in a six-year longitudinal study of patients with complex regional pain syndrome, authors found no association between IL-6 levels and symptoms [77].
2.4 IL-17
Rodent models of neuropathic pain induced by nerve ligation, CCI, and chemical injections, have all revealed an upregulation of interleukin 17 (IL-17), indicating its potential involvement in the development of allodynia [78,79,80]. The surge in IL-17 has been found to increase with time, suggesting that it may be part of the chronic pain phase, rather than the initial period of injury and acute pain [78,79]. Administration of exogenous IL-17 results in neuropathic pain, possibly secondary to an increase in the activity of transient receptor protein vanilloid 4 (TRPV4), an ion channel that has been found to mediate mechanical allodynia [81,82]. By contrast, IL-17 knockout mice showed less response to pain after induced nerve injury [83], and anti-IL-17 antibody injection has been demonstrated to decrease pain in a murine model of arthritis [84]. The IL-17 inhibiting monoclonal antibody, secukinumab, is FDA-approved for the treatment of plaque psoriasis, and it has been studied as a possible treatment in autoimmune diseases [85,86], but there are currently no human studies on the use of IL-17 antagonists in patients with neuropathic pain conditions.
3 Targeting anti-inflammatory cytokines
The immune system depends on the balance between pro-inflammatory and anti-inflammatory forces. Given that neuropathic pain is associated with a pro-inflammatory state, it is not surprising to find that high levels of anti-inflammatory cytokines are associated with a reduction in symptoms. Unfortunately, while anti-inflammatory cytokines offer an exciting new therapeutic opportunity for neuropathic pain, the current scientific evidence is limited to in vitro and animal studies.
Lower levels of anti-inflammatory cytokines have been demonstrated in patients with chronic neuropathic pain conditions, such as complex regional pain syndrome, atypical facial pain, lower back pain, and post-herpetic neuralgia [87,88]. Currently, there have been no published studies on whether treatments designed to increase anti-inflammatory cytokines can be used to reduce neuropathic pain in humans (Table 1).
3.1 IL-4
Interleukin 4 (IL-4) is an anti-inflammatory cytokine that has recently garnered attention as a mediator of neuropathic pain. IL-4 knockout mice demonstrate an increase in mechanical allodynia after CCI compared to controls [89]. Conversely, intrathecal injections of IL-4 in mice with CCI have been shown to reduce inflammation and levels of pro-inflammatory cytokines [90]. IL-4 treatment has also been found to reduce behavioral measures of mechanical allodynia after partial nerve ligation in mice [91].
Interestingly, glatiramer acetate, an immunomodulator used in the treatment of multiple sclerosis, has also been shown to decrease pain. Its use is correlated with an increase in IL-4 and IL-10, another anti-inflammatory cytokine [92]. These findings suggest that the anti-inflammatory pathway can be targeted to shift the immune environment and reduce neuropathic pain.
3.2 IL-10
Recent studies of interleukin 10 (IL-10) indicate an ambiguous relationship to neuropathic pain. Interestingly, IL-10 levels differ depending on type of nerve injury: decreased after CCI and partial nerve ligation, increased after complete nerve ligation, and no change after neuritis [93]. Elevated IL-10 levels have also been detected in the ventrolateral orbital cortex of the brain, signifying the involvement of the central nervous system in neuropathic pain [55]. Administration of exogenous IL-10 alleviates allodynia in animal models of CCI and paclitaxel-induced neuropathic pain [94,95]. Drugs such as calcineurin, uliastatin, plasmid DNA, and viral vector indirectly increase IL-10 concentrations [7,96,97], and may be promising therapeutic targets in the treatment of neuropathic pain.
3.3 TGF-β
Similar to IL-10, transforming growth factor beta (TGF-β) has been identified to affect neuropathic pain in different ways, depending on the anatomical location. Intrathecal administration of TGF-β reduces pain secondary to CCI and partial nerve ligation [98,99]. In contrast, injection of anti-TGF-p antibody into the red nucleus causes mechanical hypersensitivity in rats [100]. The underlying mechanism may be a tightening of the blood-spinal-cord-barrier (BSCB) against inflammatory molecules following nerve damage. In rats, it has been shown that TGF-β administration maintains elevated levels of tight junction proteins in the setting of nerve injury, thereby preserving the integrity of the BSCB [101]. Flexibilide, a substance derived from soft coral, has also been shown to alleviate neuropathic pain in rats via prevention of TGF-p decrease after CCI [102]. More recently, delivery of bone marrow stromal cell into the spinal cord of mice was used to induce TGF-β secretion, reducing CCI-induced neuropathic pain [103].
4 Alternative approaches to reduce neuroinflammmation
Rather than targeting specific cytokines, other methods have been developed to modulate the immune system as a whole in the treatment of neuropathic pain. These approaches aim to reduce the amount of neuroinflammation following nerve injury, thereby producing an analgesic effect. Glucocorticoids, which broadly and nonspecifically suppress the immune response, are commonly used in clinical practice to alleviate neuropathic pain in conditions such as lumbar radiculopathy and to prevent inflammation following nerve damage, such as spinal cord injury [104,105]. They have also been found to prevent development of neuropathic pain [106], possibly through a decrease in TNF-α concentrations in mast cells [107]. However, despite a number of clinical trials for various conditions, the true clinical effectiveness of glucocorticoids for neuropathic pain remains unclear [108]. Given the complexity of the issue, a detailed discussion of is beyond the scope of this review, but the ongoing debate explains the interest in alternative immunosuppressive therapies for neuropathic pain.
Novel immunomodulatory approaches being explored for neuropathic pain include ibudilast, hyperbaric oxygen, and botulinum toxin injection. Ibudilast is a phosphodiesterase inhibitor originally developed as an asthma medication. It crosses the blood-brain barrier, and has been found to decrease hindpaw hypersensitivity in both spinal cord injury (SCI) and CCI rats [109]. In other animal studies of neuropathic pain models, ibudilast has been found suppresses glial cell activation and reduce the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) [110]. A recently published RCT of found that an 8-week course of ibudilast was not effective for migraine, but there are no published studies of ibudilast for neuropathic pain conditions [111].
Hyperbaric oxygen therapy (HBOT) has been studied as a potential treatment for neuropathic pain. In rats following CCI, HBOT led to a decrease in allodynia. The treatment was associated with lower levels of TNF-α, suggesting a potential anti-inflammatory effect, but it did not affect levels of IL-1β. The investigators proposed that HBOT increases the total oxygen content within the circulation, thereby supplying the increased need for oxygen in the damaged areas, which would reduce ischemic and reperfusion damage (and inflammation) that may result in pain [112].
Botulinum toxin (BoNT), the paralytic neurotoxin produced by the bacterium Clostridium botulinum, is currently prescribed for a variety of medical conditions, including muscle spasm, cervical dystonia, migraines, and hyperhidrosis, in addition to its well-known cosmetic uses. BoNT has been shown to attenuate pain via modification of neuroinflammatory activity induced by nerve damage [113]. In a rat model of neuropathic pain, botulinum toxin administration reduced pain-related behaviors, with corresponding downregulation of pro-inflammatory cytokines (IL-1β and IL-18) and upregulation of anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) [114]. The largest trial of BoNT for neuropathic pain is an unpublished study from Allergan (manufacturer of Botox ), which found a lack of efficacy of Botox for the treatment of postherpetic neuralgia [115]. However, two recent clinical trials suggest that BoNT may prove to be beneficial in providing neuropathic pain relief. Han et al. studied 40 patients with SCI-associated neuropathic pain and found that a one-time dose of subcutaneous BoNT provided at least 20% pain relief to 45% of patients at 8 weeks, compared to only 10% of patients in the placebo group [116]. Attal et al. found that two administrations of BoNT 12 weeks apart significantly reduced pain intensity over 24 weeks compared with placebo [117]. Patients with the best response to BoNT treatment were those who had increased brush allodynia and increased intra-epidermal nerve fiber density. The investigators suggested that BoNT may therefore more effective for pain related to nociceptor sensitization, ectopic firing, and central sensitization (i.e., “irritable nociceptors”), which hints at a possible mechanism for BoNT-mediated analgesia in neuropathic pain conditions.
5 Conclusion
Neuropathic pain is a complex phenomenon caused by interactions between multiple physiologic systems, including the immune system. Based on the current evidence, both pro- and antiinflammatory cytokines appear to play an important role in the development of neuropathic pain. Although there have been several intriguing preclinical studies suggesting specific cytokines as promising treatment targets for neuropathic pain, there have been very few clinical trials of immune modulators for neuropathic pain. Results from those studies have been mixed, and limited by small sample size and patient heterogeneity. Other approaches may include using a single agent to target multiple aspects of the immune pathway to treat neuropathic pain. As we improve our understanding of the various mechanistic underpinnings of neuropathic pain and the role of cytokines in its development, we may find even more opportunities to treat this difficult pain condition.
Highlights
Elevated pro-inflammatory cytokines are associated with neuropathic pain.
Therapies to alter cytokines levels have shown promise as potential therapies.
Indirect therapeutic options have been shown to modulate the immune landscape.
Additional studies are needed to determine efficacy in neuropathic pain patients.
-
Ethical issues: None.
-
Conflict of interest: The authors declare that there is no conflict of interest.
-
Disclosures
Alice Hung: None.
Michael Lim, MD: Research support: Arbor, Aegenus, Altor, BMS, Immunocellular, Celldex, Accuray. Consultant: Aegenus, BMS, Regeneron, Oncorus, and Boston Biomedical. Non-research: Consultant of Stryker.
Tina Doshi, MD: None.
References
[1] Callin S, Bennett MI. Assessment of neuropathic pain. Contin Educ Anaesth Crit Care Pain 2008;8:210–3.Search in Google Scholar
[2] Gilron I, Watson CPN, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ 2006;175:265–75.Search in Google Scholar
[3] Dieleman JP, Kerklaan J, Huygen FJPM, Bouma PAD, Sturkenboom MCJM. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008;137:681–8.Search in Google Scholar
[4] Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353:1959–64.Search in Google Scholar
[5] Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;429:23–37.Search in Google Scholar
[6] Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanism-based classification of pain? Pain 1998;77:227–9.Search in Google Scholar
[7] Thacker MA, Clark AK, Marchand F, McMahon SB. Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg 2007;105:838–47.Search in Google Scholar
[8] Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010;229:26–50.Search in Google Scholar
[9] Mika J, Zychowska M, Popiolek-Barczyk K, Rojewska E, Przewlocka B. Importance of glial activation in neuropathic pain. Eur J Pharmacol 2013;716:106–19.Search in Google Scholar
[10] Bennett GJ. Can we distinguish between inflammatory and neuropathic pain? Pain Res Manag 2006;11:11A-5A.Search in Google Scholar
[11] Clark AK, Old EA, Malcangio M. Neuropathic pain and cytokines: current perspectives. J Pain Res 2013;6:803–14.Search in Google Scholar
[12] Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010;16:1267–76.Search in Google Scholar
[13] Allison DJ, Thomas A, Beaudry K, Ditor DS. Targeting inflammation asatreatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial. J Neuroinflamm 2016;13:152.Search in Google Scholar
[14] Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ. Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 2005;116:213–9.Search in Google Scholar
[15] Wang K, Bao J-P, Yang S, Hong X, Liu L, Xie X-H, Wu X-T. A cohort study comparing the serum levels of pro- or anti-inflammatory cytokines in patients with lumbar radicular pain and healthy subjects. Eur Spine J 2016;25:1428–34.Search in Google Scholar
[16] Brisby H, Olmarker K, Larsson K, Nutu M, Rydevik B. Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica. EurSpineJ 2002;11:62–6.Search in Google Scholar
[17] Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975;72:3666–70.Search in Google Scholar
[18] Shubayev VI, Myers RR. Upregulation and interaction of TNF alphaandgelatinases A and B in painful peripheral nerve injury. Brain Res 2000;855:83–9.Search in Google Scholar
[19] George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 1999;160:124–32.Search in Google Scholar
[20] Shubayev VI, Myers RR. Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol 2001;114:48–56.Search in Google Scholar
[21] Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine 2004;29:1082–8.Search in Google Scholar
[22] Li Y-Y, Wei X-H, Lu Z-H, Chen J-S, Huang Q-D, Gong Q-J. Src/p38 MAPK pathway in spinal microglia is involved in mechanical allodynia induced by peri-sciatic administration of recombinant rat TNF-a. Brain Res Bull 2013;96:54–61.Search in Google Scholar
[23] Wei X-H, Zang Y, Wu C-Y, Xu J-T, Xin W-J, Liu X-G. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodyniaviaupregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 2007;205:471–84.Search in Google Scholar
[24] Liu Y-L, Zhou L-J, Hu N-W, Xu J-T, Wu C-Y, Zhang T, Li Y-Y, Liu X-G. Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 2007;52:708–15.Search in Google Scholar
[25] Sorkin LS, Doom CM. Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J Peripher Nerv Syst 2000;5:96–100.Search in Google Scholar
[26] Wagne R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 1996;7:2897–901.Search in Google Scholar
[27] Sommer C, Schafers M, Marziniak M, Toyka KV. Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 2001;6: 67-72.Search in Google Scholar
[28] Lindenlaub T, Teuteberg P, Hartung T, Sommer C. Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res 2000;866:15–22.Search in Google Scholar
[29] Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV. Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res 2001;913:86–9.Search in Google Scholar
[30] Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L, McKay WF. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine 2008;33:227–34.Search in Google Scholar
[31] Norimoto M, Ohtori S, Yamashita M, Inoue G, Yamauchi K, Koshi T, Suzuki M, Orita S, Eguchi Y, Sugiura A, Ochiai N, Takaso M, Takahashi K. Direct application of the TNF-alpha inhibitor, etanercept, does not affect CGRP expression and phenotypic change of DRG neurons following applicationofnucleus pulposus onto injured sciatic nerves in rats. Spine 2008;33:2403–8.Search in Google Scholar
[32] Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O. Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta Diabetol 2011;48:135–42.Search in Google Scholar
[33] C.for D. E. and Research Drug Safety and Availability - Information on Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi).Search in Google Scholar
[34] Karppinen J, Korhonen T, Malmivaara A, Paimela L, Kyllonen E, Lindgren K-A, Rantanen P, Tervonen O, Niinimaki J, Seitsalo S, Hurri H. Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica. Spine 2003;28:750–834.Search in Google Scholar
[35] Genevay S, Stingelin S, Gabay C. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Ann Rheum Dis 2004;63:1120–3.Search in Google Scholar
[36] Korhonen T, Karppinen J, Malmivaara A, Autio R, Niinimaki J, Paimela L, Kyllonen E, Lindgren K-A, Tervonen O, Seitsalo S, Hurri H. Efficacyofinfliximab for disc herniation-induced sciatica: one-year follow-up. Spine 2004;29:2115–9.Search in Google Scholar
[37] Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin 2004;20:1075–85.Search in Google Scholar
[38] Cohen SP, Bogduk N, Dragovich A, Buckenmaier CC, Griffith S, Kurihara C, Raymond J, Richter PJ, Williams N, Yaksh TL. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology 2009;110:1116–26.Search in Google Scholar
[39] Cohen SP, White R, Kurihara C, Larkin TM, Chang A, Griffith SR, Gilligan C, Larkin R, Morland B, Pasquina PF, Yaksh TL, Nguyen C. Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann Intern Med 2012;156:551.Search in Google Scholar
[40] Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren K-A, Bowman C, Hammond A, Kirkham B, Jarvinen S, Niinimaki J, Veeger N, Haapea M, Torkki M, Tervonen O, Seitsalo S, Hurri H. The treatment of disc-herniation-induced sciaticawith infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine 2006;36:2759–66.Search in Google Scholar
[41] Cohen SP, Wenzell D, Hurley RW, Kurihara C, Buckenmaier CC, Griffith S, Larkin TM, Dahl E, Morlando BJ. A double-blind, placebo-controlled, dose-response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy. Anesthesiology 2007;107:99–105.Search in Google Scholar
[42] Ohtori S, Miyagi M, Eguchi Y, Inoue G, Orita S, Ochiai N, Kishida S, Kuniyoshi K, Nakamura J, Aoki Y, Ishikawa T, Arai G, Kamoda H, Suzuki M, Takaso M, Furuya T, Toyone T, Takahashi K. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine 2012;37:439–44.Search in Google Scholar
[43] Elalouf O, Elkayam O. Long-term safety and efficacy of infliximab for the treatment of ankylosing spondylitis. Ther Clin Risk Manag 2015;11:1719–26.Search in Google Scholar
[44] Apkarian AV, Lavarello S, Randolf A, Berra HH, Chialvo DR, Besedovsky HO, del Rey A. Expression of IL-1beta in supraspinal brain regions in rats with neuropathic pain. Neurosci Lett 2006;407:176–81.Search in Google Scholar
[45] del Rey A, Yau H-J, Randolf A, Centeno MV, Wildmann J, Martina M, Besedovsky HO, Apkarian AV. Chronic neuropathic pain-like behavior correlates with IL-1 p expression and disrupts cytokine interactions in the hippocampus. Pain 2011;152:2827–35.Search in Google Scholar
[46] Eliav E, Benoliel R, Herzberg U, Kalladka M, Tal M. The role of IL-6 and IL-1beta in painful perineural inflammatory neuritis. Brain Behav Immun 2009;23:474–84.Search in Google Scholar
[47] O’eyler N, Tscharke A, Sommer C. Early cytokine expression in mouse sciatic nerve afterchronic constriction nerve injurydepends on calpain. Brain Behav Immun 2007;21:553–60.Search in Google Scholar
[48] Ruohonen S, Khademi M, Jagodic M, Taskinen H-S, Olsson T, Roytta M. Cytokine responses during chronic denervation. J Neuroinflamm 2005;2:26.Search in Google Scholar
[49] Zelenka M, Schafers M, Sommer C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 2005;116:257–63.Search in Google Scholar
[50] Wei X-H, Yang T, Wu Q, Xin W-J, Wu J-L, Wang YQ, Zang Y, Wang J, Li Y-Y, Liu X-G. Peri-sciatic administration of recombinant rat IL-1 p induces mechanical allodynia by activation of src-family kinases in spinal microglia in rats. Exp Neurol 2012;234:389–97.Search in Google Scholar
[51] Stemkowski PL, Smith PA. Long-term IL-1 p exposure causes subpopulation-dependent alterations in rat dorsal root ganglion neuron excitability. J Neurophysiol 2012;107:1586–97.Search in Google Scholar
[52] Stemkowski PL, Noh M-C, Chen Y, Smith PA. Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1p exposure is K (+) channel dependent and reversible. J Physiol 2015;593:3739–55.Search in Google Scholar
[53] Sung C-S, Wen Z-H, Chang W-K, Ho S-T, Tsai S-K, Chang Y-C, Wong C-S. Intrathecal interleukin-1bet administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res 2004;1015:145–53.Search in Google Scholar
[54] Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CBA, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 2005;114:386–96.Search in Google Scholar
[55] Shao Q, Li Y, Wang Q, Zhao J. IL-10 and IL-1 p mediate neuropathic-pain like behavior in the ventrolateral orbital cortex. Neurochem Res 2015;40:733–9.Search in Google Scholar
[56] Wang Z, Wang J, Li X, Yuan Y, Fan G. Interleukin-1 betaofRed nucleus involved in the development of allodynia in spared nerve injury rats. Exp Brain Res 2008;188:379–84.Search in Google Scholar
[57] Schafers M, Brinkhoff J, Neukirchen S, Marziniak M, Sommer C. Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice. Neurosci Lett 2001;310:113–6.Search in Google Scholar
[58] Chen C, Chen F, Yao C, Shu S, Feng J, Hu X, Hai Q, Yao S, Chen X. Intrathecal injection of human umbilical cord-derived mesenchymal stem cells ameliorates neuropathic pain in rats. Neurochem Res 2016;12:3250–60.Search in Google Scholar
[59] Tu W, Wang W, Xi H, He R, Gao L, Jiang S. Regulation of neurotrophin-3 and interleukin-1p and inhibition of spinal glial activation contribute to the analgesic effect of electroacupuncture in chronic neuropathic pain states of rats. Evid Based Complement Alternat Med 2015;2015:642081.Search in Google Scholar
[60] Arruda JL, Colburn RW, Rickman AJ, Rutkowski MD, DeLeo JA. Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain. Brain Res Mol Brain Res 1998;62:228–35.Search in Google Scholar
[61] Lee H-L, Lee K-M, Son S-J, Hwang S-H, Cho H-J. Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model. Neuroreport 2004;15:2807–11.Search in Google Scholar
[62] Rothman SM, Huang Z, Lee KE, Weisshaar CL, Winkelstein BA. Cytokine mRNA expression in painful radiculopathy. J Pain 2009;10:90–9.Search in Google Scholar
[63] Burke JG, Watson RWG, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM. Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Jt Surg Br 2002;84:196–201.Search in Google Scholar
[64] Ma W, Quirion R. Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. J Neurochem 2005;93:664–73.Search in Google Scholar
[65] St-Jacques B, Ma W. Role of prostaglandin E2 in the synthesis of the proinflammatory cytokin interleukin-6 in primary sensory neurons: an in vivo and in vitro study. J Neurochem 2011;118:841–54.Search in Google Scholar
[66] Rothman SM, Ma LH, Whiteside GT, Winkelstein BA. Inflammatory cytokine and chemokine expression is differentially modulated acutely in the dorsal root ganglion in response to different nerve root compressions. Spine 2011;36:197–202.Search in Google Scholar
[67] Dubovy P, Brazda V, Klusakova I, Hradilova-Svizenska I. Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J Neuroinflamm 2013;10:55.Search in Google Scholar
[68] Brazda V, Klusakova I, Hradilova Svizenska I, Dubovy P. Dynamic response to peripheral nerve injury detected by in situ hybridization of IL-6 and its receptor mRNAs in the dorsal root ganglia is not strictly correlated with signs of neuropathic pain. Mol Pain 2013;9:42.Search in Google Scholar
[69] Ramer MS, Murphy PG, Richardson PM, Bisby MA. Spinal nerve lesion-induced mechanoallodynia and adrenergic sprouting in sensory ganglia are attenuated in interleukin-6 knockout mice. Pain 1998;78:115–21.Search in Google Scholar
[70] Arruda JL, Sweitzer S, Rutkowski MD, DeLeo JA. Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain. Brain Res 2000;879:216–25.Search in Google Scholar
[71] Murakami T, Kanchiku T, Suzuki H, Imajo Y, Yoshida Y, Nomura H, Cui D, Ishikawa T, Ikeda E, Taguchi T. Anti-interleukin-6 receptor antibody reduces neuropathic pain following spinal cord injury in mice. Exp Ther Med 2013;6:1194–8.Search in Google Scholar
[72] Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A, Nesic O. Inhibition of IL-6 signaling: a novel therapeutic approach totreating spinal cord injury pain. Pain 2013;154:1115–28.Search in Google Scholar
[73] Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF, Evans CH. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 1996;21:271–7.Search in Google Scholar
[74] Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Evans CH. Herniated cervical intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 1995;20:373–8.Search in Google Scholar
[75] Ohtori S, Miyagi M, Eguchi Y, Inoue G, Orita S, Ochiai N, Kishida S, Kuniyoshi K, Nakamura J, Aoki Y, Ishikawa T, Arai G, Kamoda H, Suzuki M, Takaso M, Furuya T, Kubota G, Sakuma Y, Oikawa Y, Toyone T, Takahashi K. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve fortreatment of sciatica. EurSpineJ 2012;21:2079–84.Search in Google Scholar
[76] Sainoh T, Orita S, Miyagi M, Inoue G, Yamauchi K, Suzuki M, Sakuma Y, Kubota G, Oikawa Y, Inage K, Sato J, Nakata Y, Aoki Y, Takahashi K, Ohtori S. Single intradiscal injection of the interleukin-6 receptor antibody tocilizumab provides short-term relief of discogenic low back pain; prospective comparative cohort study. J Orthop Sci 2016;21:2–6.Search in Google Scholar
[77] Wesseldijk F, Huygen FJPM, Heijmans-Antonissen C, Niehof SP, Zijlstra FJ. Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1. Mediators Inflamm 2008;2008:469439.Search in Google Scholar
[78] Noma N, Khan J, Chen I-F, Markman S, Benoliel R, Hadlaq E, Imamura Y, Eliav E. Interleukin-17 levels in rat models of nerve damage and neuropathic pain. Neurosci Lett 2011;493:86–91.Search in Google Scholar
[79] Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol 2006;200: 480-5.Search in Google Scholar
[80] Meng X, Zhang Y, Lao L, Saito R, Li A, Backman CM, Berman BM, Ren K, Wei P-K, Zhang R-X. Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model. Pain 2013;154:294–305.Search in Google Scholar
[81] Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain 2011;12:370–83.Search in Google Scholar
[82] Segond von Banchet G, Boettger MK, Konig C, Iwakura Y, Brauer R, Schaible H-G. Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci 2013;52:152–60.Search in Google Scholar
[83] Day Y-J, Liou J-T, Lee C-M, Lin Y-C, Mao C-C, Chou A-H, Liao C-C, Lee H-C. Lack of interleukin-17 leads to a modulated micro-environment and amelioration of mechanical hypersensitivity after peripheral nerve injury in mice. Pain 2014;155:1293–302.Search in Google Scholar
[84] Richter F, Natura G, Ebbinghaus M, von Banchet GS, Hensellek S, Konig C, Brauer R, Schaible H-G. Interleukin-17 sensitizes joint nociceptorstome chanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents. Arthritis Rheum 2012;64:4125–34.Search in Google Scholar
[85] Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CEM, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai T-F, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C. Secukinumab in plaque psoriasis - results of two phase 3 trials. N EnglJ Med 2014;371:326–38.Search in Google Scholar
[86] Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17 A block a dewith secukinumab in autoimmune diseases. Ann Rheum Dis 2013;72:iii116-23.Search in Google Scholar
[87] Ufeyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum 2006;54:2656–64.Search in Google Scholar
[88] Ufeyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain 2007;132:195–205.Search in Google Scholar
[89] Ofeyler N, Topuzoglu T, Schiesser P, Hahnenkamp S, Sommer C. IL-4 deficiency is associated with mechanical hypersensitivity in mice. PLoS ONE 2011;6:e28205.Search in Google Scholar
[90] Sun S, Chen D, Lin F, Chen M, Yu H, Hou L, Li C. Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Mol Immunol 2016;77:184–92.Search in Google Scholar
[91] Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain 2015;156:684–93.Search in Google Scholar
[92] Leger T, Grist J, D’Acquisto F, Clark AK, Malcangio M. Glatirameracetate attenuates neuropathic allodynia through modulation of adaptive immune cells. J Neuroimmunol 2011;234:19–26.Search in Google Scholar
[93] Khan J, Ramadan K, Korczeniewska O, Anwer MM, Benoliel R, Eliav E. Interleukin-10 levels in rat models of nerve damage and neuropathic pain. Neurosci Lett 2015;592:99–106.Search in Google Scholar
[94] Wagner R, Janjigian M, Myers RR. Anti-inflammatory interleukin-10 therapy in CCI neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alpha expression. Pain 1998;74:35–42.Search in Google Scholar
[95] Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, Martin D, Maier SF, Johnson KW, Leinwand LA, Chavez RA, Watkins LR. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 2007;21:686–98.Search in Google Scholar
[96] Ouyang H, Nie B, Wang P, Li Q, Huang W, Xin W, Zeng W, Liu X. Ulinastatinattenuates neuropathic pain induced by L5-VRT viathe calcineurin/IL-10 pathway. Mol Pain 2016;12, 1744806916646785.Search in Google Scholar
[97] Dengler EC, Alberti LA, Bowman BN, Kerwin AA, Wilkerson JL, Moezzi DR, Limanovich E, Wallace JA, Milligan ED. Improvement of spinal non-viral IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain. J Neuroinflamm 2014;11:92.Search in Google Scholar
[98] Chen N-F, Huang S-Y, Chen W-F, Che C-H, Lu C-H, Chen C-L, Yang S-N, Wang H-M, Wen Z-H. TGF-p1 attenuates spinal neuroinflammation and the excitatory amino acid system in rats with neuropathic pain. J Pain 2013;14:1671–85.Search in Google Scholar
[99] Echeverry S, Shi XQ, Haw A, Liu H, Zhang Z, Zhang J. Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain 2009;5:16.Search in Google Scholar
[100] Wang J, Yu J, Ding C-P, Han S-P, Zeng X-Y, Wang J-Y. Transforming growth factor-beta in the red nucleus plays antinociceptive effect underphysiological and pathological painconditions. Neuroscience 2015;291:37–45.Search in Google Scholar
[101] Echeverry S, Shi XQ, Rivest S, Zhang J. Peripheral nerv injury alters blood-spinal cord barrier functional an molecular integrity through a selective inflammatory pathway. J Neurosci 2011;31:10819–28.Search in Google Scholar
[102] Chen N-F, Huang S-Y, Lu C-H, Chen C-L, Feng C-W, Chen C-H, Hung H-C, Lin Y-Y, Sung P-J, Sung C-S, Yang S-N, Wang H-MD, Chang Y-C, Sheu J-H, Chen W-F, Wen Z-H. Flexibilide obtained from cultured soft coral has anti-neuroinflammatory and analgesic effects through the upregulation of spinal transforming growth factor-p1 in neuropathic rats. Mar Drugs 2014;12:3792–817.Search in Google Scholar
[103] Chen G, Park C-K, Xie R-G, Ji R-R. Intrathecalbone marrowstromalcellsinhibit neuropathic painvia TGF-p secretion. J Clin Invest 2015;125:3226–40.Search in Google Scholar
[104] Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev 2008:CD001824.Search in Google Scholar
[105] Hall ED, Braughler JM. Glucocorticoid mechanisms inacutespinalcord injury: a review and therapeutic rationale. Surg Neurol 1982;18:320–7.Search in Google Scholar
[106] Li H, Xie W, Strong JA, Zhang J-M. Systemic antiinflammatory corticosteroid reduces mechanical pain behavior, sympathetic sprouting, and elevation of proinflammatory cytokines in a rat model of neuropathic pain. Anesthesiology 2007;107:469–77.Search in Google Scholar
[107] Hayashi R, Xiao W, Kawamoto M, Yuge O, Bennett GJ. Systemic glucocorticoid therapy reduces pain and the number of endoneurial tumor necrosis factor-alpha (TNFalpha)-positive mast cells in rats with a painful peripheral neuropathy. J Pharmacol Sci 2008;106:559–65.Search in Google Scholar
[108] Rijsdijk M, vanWijck AJM, Kalkman CJ, Yaksh TL. The effects of glucocorticoids on neuropathic pain. AnesthAnalg 2014;118:1097–112.Search in Google Scholar
[109] Hama AT, Broadhead A, Lorrain DS, Sagen J. The antinociceptive effect of the asthma drug ibudilast in rat models of peripheral and central neuropathic pain. J Neurotrauma 2012;29:600–10.Search in Google Scholar
[110] Ledeboer A, Liu T, Shumilla JA, Mahoney JH, Vijay S, Gross MI, Vargas JA, Sultzbaugh L, Claypool MD, Sanftner LM, Watkins LR, Johnson KW. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol 2006;2:279.Search in Google Scholar
[111] Kwok YH, Swift JE, Gazerani P, Rolan P. Adouble-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine. J Pain Res 2016;9:899–907.Search in Google Scholar
[112] Li F, Fang L, Huang S, Yang Z, Nandi J, Thomas S, Chen C, Camporesi E. Hyperbaric oxygenation therapy alleviates chronic constrictive injury-induced neuropathic pain and reduces tumor necrosis factor-alpha production. Anesth Analg 2011;113:626–33.Search in Google Scholar
[113] Mika J, Rojewska E, Makuch W, Korostynski M, Luvisetto S, Marinelli S, Pavone F, Przewlocka B. The effect of botulinum neurotoxinAon sciatic nerve injuryinduced neuroimmunological changes in rat dorsal root ganglia and spinal cord. Neuroscience 2011;175:358–66.Search in Google Scholar
[114] Zychowska M, Rojewska E, Makuch W, Luvisetto S, Pavone F, Marinelli S, Przewlocka B, Mika J. Participation of pro- and anti-nociceptive interleukins in botulinum toxin A-induced analgesia in a rat model of neuropathic pain. EurJ Pharmacol 2016;791:377–88.Search in Google Scholar
[115] Allergan A. Multicenter. Double-Blind, Randomized, Placebo-Controlled, Parallel Study of the Safety and Efficacy of BOTOX (Botulinum Toxin Type A) Purified Neurotoxin Complex in Subjects with Postherpetic Neuralgia (PHN); 2005.Search in Google Scholar
[116] Han Z-A, Song DH, Oh H-M, Chung ME. Botulinum toxintype A for neuropathic pain in patients with spinal cord injury. Ann Neurol 2016;79:569–78.Search in Google Scholar
[117] Attal N, de Andrade DC, Adam F, Ranoux D, Teixeira MJ, Galhardoni R, Raicher I, of eyler N, Sommer C, Bouhassira D. Safety and efficacy of repeated injections of botulinum toxinA in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2016;15:555–65.Search in Google Scholar
© 2017 Scandinavian Association for the Study of Pain
