Involvement of Spinal IL-6Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha

König, Christian; Morch, Eric; Eitner, Annett; Möller, Christian; Turnquist, Brian; Schaible, Hans‐Georg; Ebersberger, Andrea

doi:10.1523/jneurosci.4159-15.2016

Cited by 39 publications

(37 citation statements)

References 48 publications

(32 reference statements)

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“… 79 Spinal IL-6 can prompt a state of spinal hyperexcit-ability. 80 Inhibition of IL-6 receptor activation suppressed Fos expression and inhibited the upregulation of glutamate receptor subunits NR2B in dorsal horn neurons in rats with monosodium iodoacetate-induced osteoarthritis in dorsal horn neurons. 78 Similarly, we found that, in early-stage DNP in STZ-induced DNP rats, the increased expression of IL-6 and NR2B phosphorylation at tyrosine 1472 in the dorsal spinal cord can be significantly suppressed by MRS2211.…”

Section: Discussionmentioning

confidence: 99%

Activation of spinal dorsal horn P2Y13 receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Zhou

Liu

et al. 2018

JPR

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ObjectiveThe dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP).MethodsA rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr1336, and pTyr1472 NR2B in rat spinal dorsal horn.ResultsCompared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y13 receptor, Iba-1, IL-1β, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr1336 NR2B was significantly decreased, whereas pTyr1472 NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats.ConclusionIntrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y13 receptor downregulates levels of IL-1β and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y13 receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.

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Section: Discussionmentioning

confidence: 99%

Activation of spinal dorsal horn P2Y13 receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Zhou

Liu

et al. 2018

JPR

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“…However, although microglia activation is a prominent feature of neuropathic pain, it does not per se prove the presence of a neuropathic process because it occurs in inflammatory as well as in neuropathic conditions (Clark et al, 2007 ). An activation of microglia can even be observed functionally within 1–2 h after application of cytokines to the intact spinal cord (König et al, 2016 ), and in such a short period the generation of a neuropathic process is unlikely.…”

Section: Features Of Oa Pain and Neuronal Mechanisms Of Oa Painmentioning

confidence: 99%

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Eitner

Hofmann

Schaible

2017

Front. Mol. Neurosci.

168

155

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Pain due to osteoarthritis (OA) is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF) is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1β and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate OA pain, and in some cases genetic factors influencing OA pain were found. Considering the local factors in the joint, the neuronal processes and the comorbidities, a better definition of OA pain phenotypes may become possible. Studies are under way in order to improve OA and OA pain monitoring.

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“…Peripheral nerve fibres express gp130, and IL-6/sIL-6R complexes administered to rodents intra-articularly or intra-thecally sensitized non-myelinated Cfibres, caused spinal release of IL-6 from neurons and elicited central hyperexcitability (Vazquez et al 2012). Previous studies indicated that the IL-6 induced central hyperexcitability relied on an IL-6sR dependent mechanism (Vazquez et al 2012;König et al 2016), and demonstrated that IL-6sR is released by microglia (König et al 2016). Currently it is uncertain whether our analysis method reliably detects IL-6/IL-6sR complexes or only IL-6.…”

Section: The Role Of Chemokines In Oa Neuroimmune Signallingmentioning

confidence: 99%

Differences in neuroimmune signalling between male and female patients suffering from knee osteoarthritis

Kosek

Finn

Ultenius

et al. 2018

Journal of Neuroimmunology

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The primary aim was to identify cytokines involved in blood borne, neuroimmune joint-to-CNS signalling in knee osteoarthritis (OA) patients. Monocyte chemoattractant protein 1 (MCP1) and Interleukin-8 (IL-8) were elevated in the cerebrospinal fluid (CSF) in patients indicating neuroinflammation. Significant positive correlations were found for MCP1 across CSF, serum and synovial fluid (SF), in female, but not male patients. The results revealed sex differences in neuroimmune signalling and implicated MCP1 in blood borne joint-to-CNS signalling in female patients. Symptom severity correlated with IL-6 and IL-8 levels in SF, but was inversely associated with IL-6 and IL-8 levels in CSF, indicating that neuroinflammation in OA may be an adaptive, possibly neuroprotective mechanism promoting symptom reduction.

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Involvement of Spinal IL-6Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha

Cited by 39 publications

References 48 publications

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Differences in neuroimmune signalling between male and female patients suffering from knee osteoarthritis

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Involvement of Spinal IL-6Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha

Cited by 39 publications

References 48 publications

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1&beta; and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1&beta; and IL-6 in rats with diabetic neuropathic pain

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Differences in neuroimmune signalling between male and female patients suffering from knee osteoarthritis

Contact Info

Product

Resources

About

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain