Cytokine Modulation is Necessary for Efficacious Treatment of Experimental Neuropathic Pain

Sacerdote, Paola; Franchi, Silvia; Moretti, Sarah; Castelli, Mara; Procacci, Patrizia; Magnaghi, Valerio; Panerai, Alberto E.

doi:10.1007/s11481-012-9428-2

Cited by 107 publications

(79 citation statements)

References 65 publications

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“…Once a nerve is injured, Schwann cells and local macrophages initiate an immune response, releasing pro-inflammatory cytokines and algesic mediators in the spinal cord, such as TNF-α, IL-1β, and IL-6, and thus propagating the inflammatory response over time, which further aggravates central sensitization, hyperalgesia, and allodynia [29][30][31]. TNF-α appears early in the cytokine cascade; it is an early-stage prototype pro-inflammatory factor that has been well verified in peripheral and central sensitization of neuropathic pain and is sufficient to trigger pro-inflammatory events that lead to the development of pain [32,33]. The sciatic nerve and DRG activation of TNF coincides well with that of pain behaviors, such as hyperalgesia and allodynia [33].…”

Section: Discussionmentioning

confidence: 99%

“…TNF has been reported to be excessively released at 1 day after injury and to remain at a high level until 3 days later. However, in fact, TNF overexpression is delayed and lasts longer [34][35][36], and the presence of activation has been shown to start from the periphery and then move toward the center [32]. IL-1β, a major pro-inflammatory cytokine, has been found to be upregulated in the injured sciatic nerve, DRG, and spinal cord in various models of neuropathic pain [37][38][39][40][41].…”

Section: Discussionmentioning

confidence: 99%

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H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

Chen

Xie

et al. 2015

Inflammation

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Neuropathic pain (NP) is characterized by persistent pain, tactile allodynia, or hyperalgesia. Peripheral nerve injury contributes to rapid progress of inflammatory response and simultaneously generates neuropathic pain. Hydrogen (H2) has anti-inflammation, anti-apoptosis, and anti-oxidative stress effects. Therefore, we hypothesized that H2 treatment could alleviate allodynic and hyperalgesic behaviors and the release of inflammatory factors in rats with neuropathic pain. Peripheral neuropathic pain was established by chronic constriction injury of sciatic nerve in rats. H2 was given twice through intraperitoneal injection at a daily dose of 10 mL/kg during days 1-7 after the operation. Hyperalgesia and allodynia were tested, pro-inflammatory factors of dorsal root ganglia (DRG) and the spinal cord were measured by enzyme-linked immunosorbent assay (ELISA) during days 1-14 after the operation, and heme oxygenase (HO)-1 messenger RNA (mRNA) and protein expression and activities were measured at day 14 after sciatic nerve injury in rats. After Sn (IV) protoporphyrin IX dihydrochloride (SnPP)-IX, hemin, and carbon monoxide-releasing molecule (CORM)-2 had been given for chronic constriction injury (CCI) in rats, the above indicators were assessed. We found that H2 clearly inhibited hyperalgesia and allodynia in neuropathic pain and also attenuated the pro-inflammatory cytokines TNF-α, IL-1β, and high-mobility group box (HMGB) 1. H2 improved HO-1 mRNA and protein expression and activities in the process of pain. SnPP-IX reversed the inhibitory effect of H2 on hyperalgesia and allodynia and on pro-inflammatory cytokines in DRG and the spinal cord. The antinociceptive and anti-inflammatory effects of H2 were involved in the activation of HO-1/CO signaling during neuropathic pain in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

Chen

Xie

et al. 2015

Inflammation

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“…Activation of a variety of glial signaling cascades will lead to the release of a variety of cytokines including activation of NF-B and results in the production of proinflammatory mediators such as TNF, IL-6, and IL-1β that activate pro-algesic cascades [377]. Conversely, these cascades can lead to the release of so-called anti-inflammatory products that may bind the soluble product (IL-1ra) and cytokines such as, IL-4, IL-6, IL-10, IL-11, IL-13, TGF-β, and various soluble cytokine receptors [378], which can regulate the inflammatory cascade [379].…”

Section: Anti-inflammatory Cytokines (Il-10)mentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…However, the pathophysiological mechanisms underlying neuropathic pain are poorly understood and the available treatments are unsatisfactory [4] . Animal models of neuropathic pain are available that help to clarify the underlying mechanisms [5] . Especially, compression-related nerve injury is the main model for neuropathic pain, and it includes chronic construction injury (CCI), partial sciatic nerve ligation, and spinal nerve ligation [6] .…”

Section: Introductionmentioning

confidence: 99%

Periferik Sinirde Kronik Konstrüksiyon Hasarı Tedavisi Üzerine Dekompresyonun Etkisi

Özatik¹,

Koçman²,

Dag³

et al. 2016

Kafkas Univ Vet Fak Derg

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Chronic constriction injury (CCI) is a common clinical entity and characterized by allodynia or spontaneous neuropathic pain. Treatment of neuropathic pain is difficult, because a lack of knowledge about the underlying mechanisms and limited effectiveness of the existing drugs. Surgical decompression enables a more radical treatment by releasing the compressed nerve. Beside the pain behaviour morphological changes occur in CCI. Ultrastructural morphological changes at the injury site of the sciatic nerve and in the dorsal root ganglia (DRG) are believed to play role in the pathogenesis of CCI and in the development of neuropathic pain behaviour in individuals. However, the effects of surgical decompression on the ultrastructure of constricted nerve site as well as in the dorsal root ganglia have not been studied in details. We investigated the effect of nerve decompression on ultrastructure of rat sciatic nerve and DRG by light and transmission electron microscopic methods. For this aim, CCI was established on the rat sciatic nerve with four loose ligatures. Surgical decompression was held at 1 st , 3 rd and 5 th the weeks after CCI by removing the ligatures. Our results suggest that the efficacy of decompression was superior when applied one week after compression. The results of the study verify the need for early surgical decompression to prevent irreversible damage of the peripheral nerve and DRG. Keywords: Decompression, Sciatic nerve, Chronic constriction injury, TEM Periferik Sinirde Kronik Konstrüksiyon Hasarı Tedavisi Üzerine Dekompresyonun Etkisi ÖzetKronik konstrüksiyon hasarı (CCI), yaygın klinik bir oluşumdur ve allodini ya da spontan nöropatik ağrı ile karakterize edilir. Nöropatik ağrının tedavisi, altta yatan mekanizmaların yeterince bilinmemesi ve mevcut ilaçların sınırlı etkisinden dolayı oldukça zordur. Cerrahi dekompresyon uygulaması, sıkışmış sinirin serbestleştirilmesi suretiyle oldukça radikal bir tedavi imkanı sağlar. CCI'da ağrının yanısıra morfolojik değişimler de olur. Siyatik sinirin yaralı bölgesi ve dorsal kök gangliyonundaki (DRG) ultrayapısal morfolojik değişimlerin, CCI patojenezinde ve bireylerdeki nöropatik ağrı davranışı gelişiminde rol oynadığına inanılır. Ancak, sıkışmış sinir bölgesinde ve dorsal kök gangliyonlarındaki ultrayapı üzerine cerrahi dekompresyonun etkileri henüz detaylı olarak çalışılmamıştır. Çalışmamızda rat siyatik siniri ve DRG'nun ultrayapısı üzerine sinir dekompresyonunun etkisini ışık ve geçirimli elektron mikroskobik metodlarla inceledik. Bu amaçla CCI rat siyatik siniri üzerine yapılan dört gevşek bağ ile oluşturulmuştur. Cerrahi dekompresyon, CCI sonrası 1. 3. ve 5. haftalarda bağların uzaklaştırılmasıyla sağlanmıştır. Verilerimiz dekompresyon etkisinin sinir sıkıştırılmasından bir hafta sonra uygulandığında çok daha iyi sonuç verdiğini desteklemektedir. Erken cerrahi dekompresyonun, periferik sinir ve dorsal kök ganglionunun geri dönüşümsüz hasarını önlemeye etkileri üzerine ilave çalışmalara ihtiyaç bulunmaktadır.

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Cytokine Modulation is Necessary for Efficacious Treatment of Experimental Neuropathic Pain

Cited by 107 publications

References 65 publications

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

Current and Future Issues in the development of spinal agents for the management of pain

Periferik Sinirde Kronik Konstrüksiyon Hasarı Tedavisi Üzerine Dekompresyonun Etkisi

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