Endogenous interleukin‐6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice

Murphy, PG; Ramer, Matt S.; Borthwick, Lee A.; Gauldie, Jack; Richardson, P. M.; Bisby, Mark A.

doi:10.1046/j.1460-9568.1999.00641.x

Cited by 193 publications

(109 citation statements)

References 68 publications

(135 reference statements)

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“…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). In terms of its anti-nociceptive effects, intrathecal IL-6 elicited anti-nociceptive effects in neuropathic rats (Flatters et al, 2003), and intracisternally injected IL-6 had anti-nociceptive effects in an acute orofacial pain model (Choi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Also, IL-6 is known to have pleiotropic actions on both glial cells and neurons, and may induce the synthesis or release of both painenhancing or pain-inhibitory, neuroprotective or neuromodulatory factors. For example, IL-6 knockout mice exhibit decreased allodynia following CCI, but they also show decreased expression of substance P, involved in pain transmission, in sensory neurons (Murphy et al, 1999). In addition, differences in IL-6 receptors and/or signaling may account for differential effects of IL-6.…”

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: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Recently, several lines of evidence indicate that the cytokines leukemia inhibitory factor (LIF) and IL-6 regulate galanin gene expression in the DRG after peripheral nerve damage. (a) Injection of LIF or IL-6 into the sciatic nerve significantly increases galanin expression in the DRG (37,38). (b) Conversely, axotomy-induced up-regulation of galanin is markedly attenuated in IL-6 (37) and LIF knockout mice (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

Holmes

Mahoney²,

King³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

191

170

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The neuropeptide galanin is expressed developmentally in the dorsal root ganglion (DRG) and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. Here we report that adult mice carrying a loss-of-function mutation in the galanin gene have a 13% reduction in the number of cells in the DRG associated with a 24% decrease in the percentage of neurons that express substance P. These deficits are associated with a 2.8-and 2.6-fold increase in the number of apoptotic cells in the DRG at postnatal days 3 and 4, respectively. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons. D amage to a peripheral nerve causes changes within the cell body that promote neuronal survival, axonal regeneration, and functional recovery. Under favorable conditions, for instance after a crush injury, most nerve fibers successfully regenerate. However, in many clinically relevant circumstances, traumatic or disease-induced nerve injury has a poor outcome with only limited return of function and often with considerable delay. The molecular and cellular interactions that control the degree and rate of peripheral nerve regeneration are poorly understood and remain important clinical and scientific issues.In an attempt to define the mechanisms that regulate neuronal survival and regeneration, we and others have used the approach of studying factors whose expression patterns are known to change in response to injury. One of the most potent changes in the dorsal root ganglion (DRG) after peripheral nerve injury is the 120-fold increase in the levels of the 29-aa neuropeptide galanin (1). Studies have demonstrated that galanin is expressed at high levels in most cells of the developing DRG from day 16 of gestation until shortly after birth (2). In the adult, galanin is expressed at low levels in only 2-3% of DRG cells, which are predominantly small fiber neurons (1). After axotomy, mRNA and peptide are abundantly expressed in 40-50% of all DRG neurons (3) and remain elevated while the nerve is regenerating (1). Similarly, axotomy also up-regulates galanin expression in motor (4) and sympathetic (5) neurons. The rise in expression in the dorsal horn after axotomy is modest compared with the marked elevation in the DRG (6), reflecting an increase in anterograde transport of galanin from the cell body to the site of injury (7), analogous to that described in axotomized sympathetic neurons (8). Despite these findings, there is no direct evidence that galanin plays a role in axonal regeneration after injury.We previously have generated mice carrying a loss-of-function mutation in the galanin gene (9) and most recently have demonstrated that the chronic absence of galanin throughout prenatal and postnatal development causes an atte...

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“…Se injetada nos ventrículos laterais de ratos, a IL-6 induz hiperalgesia térmica 51 . Apesar de estudos controversos, em ratos que não produzem IL-6 há um retardo no desenvolvimento de alodinia mecânica após lesão de nervo periférico 52 . O TNF-α, após agir em receptores específicos, ativa fatores transcricionais (p38 MAPK e NFκβ) e libera fatores dependentes de COX-2.…”

Section: Citocinasunclassified

“…In mice, the injection of IL-6 in the lateral ventricles produces thermal hyperalgesia 51 . Des-pite controversial studies, in mice that do not produce IL-6 the development of mechanical allodynia after peripheral nerve lesion is delayed 52 . After acting on specific receptors, TNFα activates transcriptional factors (p36 MAPK and NFκβ) and releases COX-2-dependent factors.…”

Section: Cytokinesmentioning

confidence: 99%

Dor neuropática: aspectos neuroquímicos

Kraychete¹,

Gozzani²,

Kraychete³

2008

Rev. Bras. Anestesiol.

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Rev Bras AnestesiolARTIGO DE REVISÃO 2008; 58: 5: 492-505 REVIEW ARTICLE RESUMO Kraychete DC, Gozzani JL, Kraychete AC -Dor Neuropática -Aspectos Neuroquímicos. JUSTIFICATIVA E OBJETIVOS:A dor neuropática é causada por lesão ou inflamação do sistema nervoso. É síndrome complexa, com mecanismos biológicos pouco esclarecidos, envolvendo teorias inflamatórias e imunes. O objetivo desta revisão foi descrever os principais fatores biológicos relacionados com a dor neuropática, associando de forma lógica as hipóteses sugeridas pela literatura. CONTEÚDO:Foram descritos os principais neuromediadores, canais iônicos e células, incluindo as do sistema imune envolvidos na excitabilidade neuronal, assim como enfatizada possível seqüência de ativação ou interação desses agentes na alteração neuroplástica decorrente da agressão ao nervo.CONCLUSÕES: Do estudo, foi possível concluir que os avanços no conhecimento da fisiopatologia da dor neuropática podem determinar novos alvos para abordagem farmacológica dessa síndrome.Unitermos: DOR: neuropática; FISIOLOGIA: neurotransmissores. SUMMARYKraychete DC, Gozzani JL, Kraychete AC -Neuropathic PainNeurochemical Aspects. BACKGROUND AND OBJECTIVES:Neuropathic pain is caused by damage or inflammation of the nervous system. It is a complex syndrome and its biological mechanisms, involving inflammatory and immunologic theories, are not clear. The objective of this review was to describe the main biologic factors associated with neuropathic pain, making a logical association between hypotheses suggested in the literature. CONTENTS:The main neuromediators, ion channels, and cells, including cells in the nervous system involved in neuronal excitation are described, and the possible activation sequence or interaction among those agents in the neoplastic change secondary to nerve damage are emphasized. CONCLUSIONS:It was possible to conclude that the advances on the knowledge of the pathophysiology of neuropathic pain can determine new pharmacologic approaches for this syndrome.

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Endogenous interleukin‐6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice

Cited by 193 publications

References 68 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

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

Dor neuropática: aspectos neuroquímicos

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