Exogenous interleukin-6 increases cold allodynia in rats with a mononeuropathy

Vissers, Kris; Jongh, Raf F De; Hoffmann, Vincent; Meert, Theo

doi:10.1016/j.cyto.2005.01.008

Cited by 23 publications

(23 citation statements)

References 32 publications

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“…Generally there has been a trend of endogenous IL-6 having pro-nociceptive effects on exaggerated pain states as revealed by use of anti-IL-6 neutralizing antibodies (Arruda et al, 2000;Chacur et al, 2004;DeLeo et al, 1996;Milligan et al, 2003); present study) and exogenous IL-6 having anti-nociceptive effects as revealed by administration of IL-6 protein (Choi et al, 2003;Flatters et al, 2003). However, three studies using exogenous IL-6 did report pro-nociceptive effects (DeLeo et al, 1996;Oka et al, 1995;Vissers et al, 2005). Comparison of the dosages between these studies does not indicate that these differences in effects are seen because of low vs. high drug doses, as these studies used several different drug doses.…”

Section: Discussionmentioning

confidence: 39%

“…Also, IL-6 in combination with its soluble receptor can sensitize skin nociceptors to heat (Obreja et al, 2002;Opree and Kress, 2000). Thus, both endogenous IL-6 (Arruda et al, 2000;Chacur et al, 2004;Milligan et al, 2003), as in the present study, and exogenous IL-6 (DeLeo et al, 1996;Vissers et al, 2005) have been reported to have pronociceptive effects. Moreover, in IL-6 knockout mice, mechanical allodynia that is induced in wild-type mice following chronic constriction injury or spinal nerve injury is absent or delayed compared to wild-type mice, further indicating that endogenous IL-6 may mediate hypersensitivity responses associated with neuropathic pain (Murphy et al, 1999;Ramer et al, 1998).…”

Section: Discussionmentioning

confidence: 63%

“…In terms of its pro-nociceptive effects beyond the present study, intracerebroventricular injection of IL-6 induced thermal hyperalgesia in naïve rats (Oka et al, 1995), intrathecal injection of IL-6 induced touch-evoked allodynia in naïve rats (DeLeo et al, 1996), thermal hyperalgesia in rats with a sciatic nerve lesion (DeLeo et al, 1996), and increased cold allodynia in neuropathic rats (Vissers et al, 2005). In addition, an anti-IL-6 antibody blocked or attenuated the mechanical allodynia induced by peripheral nerve trauma (Arruda et al, 2000) or peripheral nerve inflammation (Chacur et al, 2004;Milligan et al, 2003), and CCI-induced cold allodynia (Vissers et al, 2005). Also, IL-6 in combination with its soluble receptor can sensitize skin nociceptors to heat (Obreja et al, 2002;Opree and Kress, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120

Schoeniger-Skinner

Ledeboer

Frank

et al. 2007

Brain, Behavior, and Immunity

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Spinal cord glia (microglia and astrocytes) contribute to enhanced pain states. One model that has been used to study this phenomenon is intrathecal (i.t.) administration of gp120, an envelope glycoprotein of HIV-1 known to activate spinal cord glia and thereby induce low-threshold mechanical allodynia, a pain symptom where normally innocuous (non-painful) stimuli are perceived as painful. Previous studies have shown that i.t. gp120-induced allodynia is mediated via the release of the glial pro-inflammatory cytokines, tumor necrosis factor-α (TNF), and interleukin-1β (IL-1). As we have recently reported that i.t. gp120 induces the release of interleukin-6 (IL-6), in addition to IL-1 and TNF, the present study tested whether this IL-6 release in spinal cord contributes to gp120-induced mechanical allodynia and/or to gp120-induced increases in TNF and IL-1. An i.t. anti-rat IL-6 neutralizing antibody was used to block IL-6 actions upon its release by i.t. gp120. This IL-6 blockade abolished gp120-induced mechanical allodynia. While the literature predominantly documents the cascade of pro-inflammatory cytokines as beginning with TNF, followed by the stimulation of IL-1, and finally TNF plus IL-1 stimulating the release of IL-6, the present findings indicate that a blockade of IL-6 inhibits the gp120-induced elevations of TNF, IL-1, and IL-6 mRNA in dorsal spinal cord, elevation of IL-1 protein in lumbar dorsal spinal cord, and TNF and IL-1 protein release into the surrounding lumbosacral cerebrospinal fluid. These results would suggest that IL-6 induces pain facilitation, and may do so in part by stimulating the production and release of other proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 39%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120

Schoeniger-Skinner

Ledeboer

Frank

et al. 2007

Brain, Behavior, and Immunity

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“…All these studies support IL-6 being the downstream effector of the calpain-2-triggered pain pathway following motor nerve injury. Although IL-6 is critically involved in the cascade of events after nerve injury leading to the development and maintenance of pain behaviors (DeLeo et al, 1996;Dubovy et al, 2013;Vissers et al, 2005;Wei et al, 2013a), the peripheral mechanism by which IL-6 elicits nociception is still largely unknown. Our previous work has shown that TNF-a through triggering the abnormal Na + channels expression increases the excitability of primary afferents after L5-VRT (Chen et al, 2011), which contributes to neuropathic pain by sequentially leading to the central sensitization.…”

Section: Calpain-2 Triggers Il-6 Up-regulation In Drg Neuronsmentioning

confidence: 99%

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

Zang

Chen

Liao

et al. 2015

Brain, Behavior, and Immunity

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“…It has been shown that exogenous administration of IL-6 is sufficient to stimulate nociceptors and cause pain [11,52,53]. It has been reported, however, that an increase in plasma IL-6 did not induce a hyperalgesic effect that would indicate IL-6 effects in the nervous structures, e.g., in DRG or the spinal cord [53,54].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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BackgroundIL-6 is a typical injury-induced mediator. Together with its receptors, IL-6 contributes to both induction and maintenance of neuropathic pain deriving from changes in activity of primary sensory neurons in dorsal root ganglia (DRG). We used in situ hybridization to provide evidence of IL-6 and IL-6 receptors (IL-6R and gp130) synthesis in DRG along the neuraxis after unilateral chronic constriction injury (CCI) of the sciatic nerve as an experimental model of neuropathic pain.ResultsAll rats operated upon to create unilateral CCI displayed mechanical allodynia and thermal hyperalgesia in ipsilateral hind paws. Contralateral hind paws and forepaws of both sides exhibited only temporal and nonsignificant changes of sensitivity. Very low levels of IL-6 and IL-6R mRNAs were detected in naïve DRG. IL-6 mRNA was bilaterally increased not only in DRG neurons but also in satellite glial cells (SGC) activated by unilateral CCI. In addition to IL-6 mRNA, substantial increase of IL-6R mRNA expression occurred in DRG neurons and SGC following CCI, while the level of gp130 mRNA remained similar to that of DRG from naïve rats.ConclusionsHere we evidence for the first time increased synthesis of IL-6 and IL-6R in remote cervical DRG nonassociated with the nerve injury. Our results suggest that unilateral CCI of the sciatic nerve induced not only bilateral elevation of IL-6 and IL-6R mRNAs in L4–L5 DRG but also their propagation along the neuraxis to remote cervical DRG as a general neuroinflammatory reaction of the nervous system to local nerve injury without correlation with signs of neuropathic pain. Possible functional involvement of IL-6 signaling is discussed.

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Exogenous interleukin-6 increases cold allodynia in rats with a mononeuropathy

Cited by 23 publications

References 32 publications

Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120

Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

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

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