Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF-Induced Pain-Related Behavior

Received Jan 20, 2017; Revised Jun 11, 2017; Accepted Jun 21, 2017

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1. Introduction

Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine that is expressed by a variety of cell types, including immune and neuronal cells. TNF is expressed by microglial cells and astrocytes in the central nervous system and by Schwann cells in the peripheral nervous system, especially after nerve injury [1]. In the development and maintenance of inflammatory and neuropathic pain, TNF effects are mediated by two distinct receptors, TNF receptor-1 (TNFR1) and TNF receptor-2 (TNFR2) [2]. Both TNF and its receptors are expressed in dorsal root ganglion (DRG) neurons and are upregulated after nerve injury [3, 4]. While numerous studies have shown a critical role of TNF in neuropathic pain, the exact mechanisms by which TNF elicits neuropathic pain are not fully understood. Intraganglional application of TNF induces pain-related behavior in rats, which is accompanied by mechanical and thermal hyperalgesia [5] and can be prevented by the preemptive use of TNF-neutralizing agents or by the inhibition of the TNF signaling pathway [6–8]. In addition to its influence on different ion channels such as voltage-gated sodium channels (VGSC) [9–11], TNF has been shown to sensitize the transient receptor potential vanilloid 1 (TRPV1), suggesting its crucial role for thermal hyperalgesia [9–11].

TRPV1 is a nonselective cation channel that is predominantly expressed in sensory neurons, but can also be detected in other tissues such as human epidermal keratinocytes, the submandibular gland, and human hair follicles [12, 13]. Its activation can be triggered by various stimuli, such as heat >43°C, by protons, or by capsaicin and resiniferatoxin (RTX) [14, 15]. RTX is a chemical compound isolated from Euphorbia resinifera and Euphorbia poissonii which are cactus-like plants. RTX irreversibly binds TRPV1 and induces a sustained calcium influx [14, 16]. Additionally, RTX ablates TRPV1-expressing C-fibers,...