Interleukin-6-Mediated Hyperalgesia/Allodynia and Increased Spinal IL-6 Expression in a Rat Mononeuropathy Model

DeLeo, Joyce A.; Colburn, Raymond W.; Nichols, Michelle; Malhotra, Amit D.

doi:10.1089/jir.1996.16.695

Cited by 349 publications

(231 citation statements)

References 29 publications

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“…It has been reported that IL-6 also interferes with pain sensation in rats; for instance, intracerebro-ventricular injection of IL-6 induces thermal hyperalgesia [15]. In line with this finding is the observation that intrathecal IL-6 production results in allodynia and thermal hyperalgesia following peripheral nerve injury [6]. The possible effects of IL-6 on nerve root are still unknown.…”

Section: Fibronectinmentioning

confidence: 84%

Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine

et al. 2002

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IntroductionThe pathogenetic mechanism of low back pain and nerve root damage in lumbar disc herniation is the subject of ongoing debate. In particular, given that the mechanicalischaemic hypothesis alone cannot explain the cause-effect relationship between disc degeneration and neurological impairment, a biochemical mechanism is likely to be involved. It has recently been demonstrated that the autologous nucleus pulposus can induce histological and functional changes in spinal nerve roots when applied epidurally [17]. Cells of the nucleus pulposus can produce prostaglandin E2, interleukin-1 and interleukin-6 (IL-6) [31], phospholipase A2 [26], and growth factors like fibroblast-like growth factor (FGF) [32] and insulin-like growth factor-1 (IGF-1) [18]. These factors are known to control cell metabolism and to promote inflammatory processes. Moreover, recent studies suggest a critical role for IL-6 and its receptor in the modulation of pain [8]. The mechanisms of action underlying the possible effect of these factors on spinal nerve root structure and function are, however, still unknown. In addition, the fact that nerve roots differ from peripheral nerves in their anatomical, biomechanical, and physiological properties prevents extrapolation from the extensive literature and the numerous experimental models of peripheral nerve compression to the pathophysiology of root injury [5,23,25]. The working hypothesis of the present study is that transforming growth factor-β1 (TGF-β1), IGF-1, IL-6 and IL-6-receptor (IL-6R) can be produced at the site of herniation. This hypothesis was immunohistochemically explored by analysing normal and protruded intervertebral disc tissue for these factors.Abstract Nerve root irritation induced by factors produced by the intervertebral disc may play a crucial role in the pathophysiology of sciatic pain production. In this study we used immunohistochemistry to investigate the presence of transforming growth factor-β1 (TGF-β1), insulinlike growth factor-1 (IGF-1), interleukin-6 (IL-6), IL-6-receptor (IL-6R) and fibronectin in lumbar disc bioptic specimens from 30 patients with disc herniation (protrusion type). Chondrocytes of herniated discs stained positive for TGF-β1, IGF-1, IL-6 and fibronectin. We demonstrated for the first time the presence of IL-6-R in the chondrocytes of herniated tissue. Specimens from autoptic healthy tissue were used as controls. In these sections no immunoreaction for TGF-β1, IL-6, or IL-6R was found, while they expressed IGF-1 and fibronectin, but in lower quantities than herniated discs. These results demonstrated the production of factors such as TGF-β1, IGF-1, IL-6, IL-6R and fibronectin at the site of lumbar disc herniation.

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Section: Fibronectinmentioning

confidence: 84%

Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine

et al. 2002

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“…The concentrations of neurofilament and nociceptin were increased in the experimental spinal nerve root injury group; however, there were no intergroup differences in glial fibrillary acidic protein, neuron-specific enolase, S-100, IL-8, or substance P endopeptidase activity. DeLeo et al [4] demonstrated that IL-6 was produced both locally and centrally in response to nerve damage. The elevated IL-6 levels in the patients with lumbar radiculopathy were ascribed to nerve damage rather than nucleus pulposus.…”

Section: Discussionmentioning

confidence: 99%

“…The highest possible JOA score-L is 29 points. The mean JOA score-L was 12.4 points (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. To evaluate the relationships between neurological deficits and the concentrations of the cytokines, the sum of motor disturbance and the sensory disturbance of JOA score-L (neurological deficits score) was calculated.…”

Section: Methodsmentioning

confidence: 99%

Tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the cerebrospinal fluid of patients with cervical myelopathy and lumbar radiculopathy

et al. 2009

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There have been few reports describing cytokines in the cerebrospinal fluid (CSF) of patients with spinal degenerative disorders. This study investigated whether interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a) could be detected in CSF of patients with cervical myelopathy or lumbar radiculopathy and whether the concentrations of those cytokines correlated with the severity of disease conditions. CSF samples were obtained from 21 patients with cervical myelopathy (Group M) and 19 patients with lumbar radiculopathy (Group R), and six volunteers (control). The concentration of IL-6 was significantly higher in Groups M and R than in the control, possibly demonstrating spinal cord and nerve root damage, respectively. However, TNF-a was lower than the detection limit. IL-1b was detected in only five samples from three patients in Group M and two volunteers in the control. The concentrations of IL-6 did not show any correlation with symptom duration, the scoring system by the Japanese Orthopaedic Association, or the duration of nerve root block. There is a possibility that the concentration of inflammatory cytokines in CSF can indicate certain pathological aspects of cervical myelopathy or lumbar radiculopathy.

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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%

“…While IL-6 can act as a proinflammatory cytokine, under other circumstances it can act as an anti-inflammatory cytokine instead (Jordan et al, 1995;Tilg et al, 1997;Tilg et al, 1994). Given that IL-6 can exert diametrically opposing actions under different conditions, it is perhaps not surprising that both pain facilitatory and pain inhibitory effects of IL-6 have been reported (DeLeo et al, 1996;Flatters et al, 2003). We have recently documented that i.t.…”

Section: Introductionmentioning

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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Interleukin-6-Mediated Hyperalgesia/Allodynia and Increased Spinal IL-6 Expression in a Rat Mononeuropathy Model

Cited by 349 publications

References 29 publications

Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine

Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine

Tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the cerebrospinal fluid of patients with cervical myelopathy and lumbar radiculopathy

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

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