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

Abstract

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.

Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors

“…The cumulative effects of inflammations 1 and 2 on intact L4 C-fiber nociceptors appear to be responsible for the relatively high spontaneous firing rate in these neurons, which is accompanied by, and probably causes, SFL/spontaneous pain. rat as previously described and justified (Bennett and Xie, 1988;Mao et al, 1992;Choi et al, 1994;Han et al, 2000;Schafers et al, 2003;Lee et al, 2003). For further justification of SFL as a behavioral sign of spontaneous pain in the present study, see Results.…”

“…After CCI, SA in DRG neurons is markedly increased by inflammatory mediators (Song et al, 2003). In another neuropathic pain model, TNF␣ (tumor necrosis factor ␣), a proinflammatory cytokine, causes increased dorsal root SA in C-fibers and increased SFL when applied to the DRG (Schafers et al, 2003). Nerve growth factor (NGF) plays a key role in the response of sensory neurons to inflammation; inflamed peripheral tissues upregulate NGF (Woolf et al 1994), which leads to NGF-dependent SA in C-fiber DRG neurons , probably because NGF influences neuronal expression of ion channels or receptors that contribute to SA generation (Lawson, 2005).…”

IL-4, JAK-STAT signaling, and pain

“…24,30 Therefore, we will point out only a few exemplary studies here. TNF-α can directly sensitize nociceptive fibers as shown in electrophysiological studies 31,32 and enhances prostaglandin synthesis 24 (see Fig. 1A).…”

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

“…TNF␣ applied directly to dorsal root ganglion (DRG) neurons induces mechanical allodynia (Homma et al, 2002;Schafers et al, 2003c), and subcutaneous TNF␣ increases mechanical sensitivity of C-fibers (Junger and Sorkin, 2000). Furthermore, in vitro perfusion of TNF␣ to intact or injured DRG elicits neuronal discharges in A-and C-fibers Zhang et al, 2002;Schafers et al, 2003b), and application of TNF␣ to isolated skin enhances heatevoked CGRP release from nociceptor terminals (Opree and Kress, 2000).…”