Induction of interleukin-6 in axotomized sensory neurons

Murphy, PG; Grondin, Julie; Altares, M.; Richardson, P. M.

doi:10.1523/jneurosci.15-07-05130.1995

Cited by 255 publications

(177 citation statements)

References 70 publications

(54 reference statements)

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“…Furthermore, spinal cord IL-6 has been implicated in other exaggerated pain states, such as allodynia induced by peripheral nerve injury (Arruda et al, 2000;DeLeo et al, 1996), sciatic inflammatory neuropathy (Chacur et al, 2004;Milligan et al, 2003), and intrathecal fractalkine . IL-6 has been suggested to be involved in nociception at the level of the skin, nerve, dorsal root ganglia (DRG), and spinal cord, and its expression is induced in response to nerve injury in spinal cord, DRG sensory neurons (Arruda et al, 1998;Lee et al, 2004;Murphy et al, 1995), and in peripheral nerves (Ma and Quirion, 2005;Okamoto et al, 2001).…”

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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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%

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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“…In contrast, the neurotrophin BDNF is a viable candidate by our criteria. BDNF increases at the injury site soon after axonal injury (Murphy et al, 1995;Omura et al, 2005) and in large DRG (IA) cell bodies of crushed primary axons (Cho et al, 1998;Michael et al, 1999); it is transported centrally when bound to its TrkB receptor, although the exact transport mechanism remains uncertain (Ginty and Segal, 2002). Also, BDNF trafficking can be influenced by neuronal activity (Nagappan and Lu, 2005), and if it were somehow impeded by stimulating axons electrically, then BDNF would meet all of our criteria.…”

Section: Signals Initiating Synaptic Enhancementmentioning

confidence: 96%

Enhanced Transmission at a Spinal Synapse TriggeredIn Vivoby an Injury Signal Independent of Altered Synaptic Activity

Bichler¹,

Nakanishi²,

Wang³

et al. 2007

J. Neurosci.

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Peripheral nerve crush initiates a robust increase in transmission strength at spinal synapses made by axotomized group IA primary sensory neurons. To study the injury signal that initiates synaptic enhancement in vivo, we designed experiments to manipulate the enlargement of EPSPs produced in spinal motoneurons (MNs) by IA afferents 3 d after nerve crush in anesthetized adult rats. If nerve crush initiates IA EPSP enlargement as proposed by reducing impulse-evoked transmission in crushed IA afferents, then restoring synaptic activity should eliminate enlargement. Daily electrical stimulation of the nerve proximal to the crush site did, in fact, eliminate enlargement but was, surprisingly, just as effective when the action potentials evoked in crushed afferents were prevented from propagating into the spinal cord. Consistent with its independence from altered synaptic activity, we found that IA EPSP enlargement was also eliminated by colchicine blockade of axon transport in the crushed nerve. Together with the observation that colchicine treatment of intact nerves had no short-term effect on IA EPSPs, we conclude that enhancement of IA-MN transmission is initiated by some yet to be identified positive injury signal generated independent of altered synaptic activity. The results establish a new set of criteria that constrain candidate signaling molecules in vivo to ones that develop quickly at the peripheral injury site, move centrally by axon transport, and initiate enhanced transmission at the central synapses of crushed primary sensory afferents through a mechanism that can be modulated by action potential activity restricted to the axons of crushed afferents.

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“…Precise pathophysiological mechanisms implicated in the development of neuropathic pain states are still unclear, but numerous data have recently suggested a major role for activated glial cells via the production of cytokines (Watkins et al, 2001). Indeed, proinflammatory cytokines [such as and IL-1␤] have been reported to be upregulated in ipsilateral ganglia (Murphy et al, 1995;Lee et al, 2004) and spinal cord (Arruda et al, 1998;Raghavendra et al, 2002Raghavendra et al, , 2003Lee et al, 2004) after nerve injury. Moreover, both the overexpression of these cytokines and the associated pain behavior could be prevented in injured animals by minocycline, a semisynthetic second-generation tetracycline described as an inhibitor of microglial activation in animal models of neuropathic pain (Raghavendra et al, 2003;Ledeboer et al, 2005;Piao et al, 2006;Scholz and Woolf, 2007), further accrediting the idea that this cell type plays a key role in neuropathic pain induction.…”

Section: Introductionmentioning

confidence: 99%

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

et al. 2008

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Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1␤, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

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Induction of interleukin-6 in axotomized sensory neurons

Cited by 255 publications

References 70 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

Enhanced Transmission at a Spinal Synapse TriggeredIn Vivoby an Injury Signal Independent of Altered Synaptic Activity

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

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