Mid-axonal tumor necrosis factor-alpha induces ectopic activity in a subset of slowly conducting cutaneous and deep afferent neurons

Leem, Jeong Gill; Bove, Geoffrey M.

doi:10.1054/jpai.2002.27138

Cited by 37 publications

(21 citation statements)

References 29 publications

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“…Once a neuron had been identified by electrical stimulation, receptive fields were searched below the knee by squeezing the periphery, using either fingers or blunt forceps. The loose properties of the skin were exploited to carefully discriminate cutaneous vs. deep fields (Leem and Bove 2002). After a receptive field was located, the neuron was electrically “collided” to ensure that the electrical and mechanically evoked responses were from the same neuron.…”

Section: Methodsmentioning

confidence: 99%

“…The role of TNF-α in pain mechanisms has been investigated extensively. For example, the direct exposure of uninjured DRG neurons to TNF-α can lead to the development of ongoing activity (Leem and Bove 2002; Liu et al 2002; Sorkin et al 1997; Zhang et al 2002), although there is substantial controversy over the extent of this effect (Leem and Bove 2002). Following nerve injury, however, it is in agreement that TNF-α can further sensitize neurons and increase the rate of firing from those neurons that are already ongoing (Liu et al 2002; Schafers et al 2003).…”

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confidence: 99%

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CCL2 has similar excitatory effects to TNF-α in a subgroup of inflamed C-fiber axons

Richards

Batty

Dilley

2011

Journal of Neurophysiology

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Peripheral nerve inflammation can cause neuronal excitability changes that have been implicated in the pathogenesis of chronic pain. Although the neuroimmune interactions that lead to such physiological changes are unclear, in vitro studies suggest that the chemokine CCL2 may be involved. This in vivo study examines the effects of CCL2 on untreated and inflamed neurons and compares its effects with those of TNF-α. Extracellular recordings were performed in the anesthetized rat on isolated neurons with C-fiber axons. On untreated neurons, CCL2, as well as TNF-α, had negligible effects. Following neuritis, both cytokines transiently caused the firing of action potentials in 27–30% of neurons, which were either silent or had background (ongoing) activity. The neurons with ongoing activity, which responded to either cytokine, had significantly slower baseline firing rates {median = 3.0 spikes/min [interquartile range (IQR) 3.0]} compared with the nonresponders [median = 24.4 spikes/min (IQR 24.6); P < 0.001]. In an additional group, 26–27% of neurons, which were sensitized due to repeated noxious mechanical stimulation of the periphery, also responded to the effects of both cytokines. Neither cytokine caused axons to become mechanically sensitive. Immunohistochemistry confirmed that the cognate CCL2 receptor, CCR2, is mainly expressed on glia and is therefore not likely to be an axonal target for CCL2 following inflammation. In contrast, the cognate TNF-α receptor (TNFR), TNFR1, was present on untreated and inflamed neurons. In summary, CCL2 can excite inflamed C-fiber neurons with similar effects to TNF-α, although the underlying mechanisms may be different. The modulatory effects of both cytokines are limited to a subgroup of neurons, which may be subtly inflamed.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

CCL2 has similar excitatory effects to TNF-α in a subgroup of inflamed C-fiber axons

Richards

Batty

Dilley

2011

Journal of Neurophysiology

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“…However, the mechanisms by which TNF elicits pain behavior are still unclear. Previous studies suggest that TNF modulates neuronal activity in various classes of neurons (Sawada et al, 1990;Soliven and Albert, 1992;Furukawa and Mattson, 1998;Diem et al, 2001) and peripheral axons (Sorkin et al, 1997;Junger and Sorkin, 2000;Leem and Bove, 2002). The role of injured afferents appears probable, because disconnection of injured afferents from spinal cord before or after spinal nerve ligation (SNL) has been reported by several investigators to be effective in attenuating pain behavior (Sheen and Chung, 1993;Kinnman and Levine, 1995;Yoon et al, 1996;Na et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

Schäfers¹,

et al. 2003

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Tumor necrosis factor-␣ (TNF) is upregulated after nerve injury, causes pain on injection, and its blockade reduces pain behavior resulting from nerve injury; thus it is strongly implicated in neuropathic pain. We investigated responses of intact and nerve-injured dorsal root ganglia (DRG) neurons to locally applied TNF using parallel in vivo and in vitro paradigms. In vivo, TNF (0.1-10 pg/ml) or vehicle was injected into L5 DRG in naive rats and in rats that had received L5 and L6 spinal nerve ligation (SNL) immediately before injection. In naive rats, TNF, but not vehicle, elicited long-lasting allodynia. In SNL rats, subthreshold doses of TNF synergized with nerve injury to elicit faster onset of allodynia and spontaneous pain behavior. Tactile allodynia was present in both injured and adjacent uninjured (L4) dermatomes. Preemptive treatment with the TNF antagonist etanercept reduced SNL-induced allodynia by almost 50%. In vitro, the electrophysiological responses of naive, SNL-injured, or adjacent uninjured DRG to TNF (0.1-1000 pg/ml) were assessed by single-fiber recordings of teased dorsal root microfilaments. In vitro perfusion of TNF (100 -1000 pg/ml) to naive DRG evoked shortlasting neuronal discharges. In injured DRG, TNF, at much lower concentrations, elicited earlier onset, markedly higher, and longerlasting discharges. TNF concentrations that were subthreshold in naive DRG also elicited high-frequency discharges when applied to uninjured, adjacent DRG. We conclude that injured and adjacent uninjured DRG neurons are sensitized to TNF after SNL. Sensitization to endogenous TNF may be essential for the development and maintenance of neuropathic pain.

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“…CGRP=calcitonin gene related peptide, IL-1β=interleukin 1 beta, IL-1RA= interleukin 1 receptor antagonist; IL-4=interleukin 4, IL-6=interleukin 6, IL10=interleukin 10, NGF=nerve growth factor, NK1=neurokinin receptor 1, µ-OR=mu-opioid receptor, SP=Substance P, TRPV1=transient receptor potential vanilloid 1, TNF=tumour necrosis factor-alpha, TNFR=tumour necrosis factor receptor, VIP=vasointestinal peptide. cation of TNF to the peripheral terminals of neurons activates a greater proportion of fibres, than application to the DRG, indicating differential receptor distribution [54]. These data suggest a rapid action of the cytokines, which indicate a possible direct effect on sensory neurones.…”

Section: Cytokinesmentioning

confidence: 78%

What We have Learned about Pain from Rodent Models of Arthritis?

Inglis¹,

Schutze²,

McNamee

2010

CRR

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Rheumatoid arthritis (RA) and Osteoarthritis (OA) are both common diseases of the joints. RA is distinguished by inflammation and synovitis leading to joint destruction, whereas OA is typified by degenerative and mostly noninflammatory disease. Although differing in their pathology, both forms can elicit chronic disabling pain in patients. Relief from this pain is an unmet need for many patients, and this has lead to a drive to understand the pain mechanisms occurring in each disease in order to develop new analgesics. This necessitates the use of pre-clinical models. Here we discuss the methods and limitations of animal pain assessment, rodent models of RA and OA, and how these models have been used to investigate the genesis of pain. Specifically, we focus on processes studied in both RA and OA models, and how the mediators involved in the development of pain may differ between these two arthritic states and during acute and chronic pain. From this we have learnt that the key mediators of RA pain include inflammatory cells, inflammatory cytokines, astrocytes, substance P, and CGRP. Endogenous analgesic mediators in RA include β-endorphin, µ-opioid receptor, and various anti-inflammatory cytokines. Less is known of the mediators of OA pain, but important factors include CGRP, TRPV1, NGF, VIP and the µ-opioid receptor. Interestingly, several factors have been found not to play a role in OA pain, including glial cells, neutrophils and TNF. It must be noted that the vast majority of candidate drugs from animal research never reach the human clinic, in part due to false positives from animal models. This may be due to flaws in the models themselves, the methods used to assess pain, the physical properties of the candidate drug, or an inherent difference between animal and human pain pathways. By developing more clinically relevant models, novel diseasespecific analgesics are being developed with the hope of improving the quality of life for sufferers of arthritis pain.

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Mid-axonal tumor necrosis factor-alpha induces ectopic activity in a subset of slowly conducting cutaneous and deep afferent neurons

Cited by 37 publications

References 29 publications

CCL2 has similar excitatory effects to TNF-α in a subgroup of inflamed C-fiber axons

CCL2 has similar excitatory effects to TNF-α in a subgroup of inflamed C-fiber axons

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

What We have Learned about Pain from Rodent Models of Arthritis?

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