مدولاسیون کانال سدیمی ولتاژی با فعالیت گیرنده ۱ و ۲ فاکتور نکروز تومور در نورون های DRG کوچک موش ها

ABSTRACT Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats

Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine that is expressed by a variety of cell types, such as immune or neuronal cells. TNF is involved in the development and maintenance of inflammatory and neuropathic pain [1, 2]. However, the mechanisms by which TNF elicits neuropathic pain are not fully understood. The effects of TNF are mediated by two distinct receptor subtypes, TNFR-1 and TNFR-2, which colocalize in nucleated cells [3, 4]. Both TNF and its receptors are expressed in rat dorsal root ganglion (DRG) neurons and are upregulated after nerve injury [5, 6]. In vivo application of TNF to DRG neurons induces pain-related behavior in rats [6], which is accompanied by mechanical and thermal hyperalgesia. These pain-inducing effects are prevented by preemptively using TNF-neutralizing agents [7, 8] or by inhibiting the TNF-signaling pathway [6]. In addition, TNF influences neuronal excitability by increasing voltage-gated sodium channel (VGSC) currents ( I_Na(V) ), which promotes action potential generation and may maintain neuropathic pain [9]. Local application of TNF to nociceptive neurons evokes action potentials and increases discharge rates of nerve fibers [10]. Tetrodotoxin- (TTX-) resistant NaV1.8 channel currents (I_NaV(1.8)), which are essential in the pathogenesis of neuropathic pain, are increased by a TNF-mediated MAP kinase-dependent pathway in DRG neurons [11, 12]. Furthermore, the lack of TNFR-1 in TNFR-1^−/− mice led to reduced mechanical hypersensitivity, which is induced by exogenous TNF or inflammation [13]. Neutralizing antibodies against TNFR-1 also reduced thermal or mechanical hypersensitivity induced by nerve injury, while antibodies against TNFR-2 were ineffective [14]. These results suggest a crucial role for TNFR-1, but not TNFR-2, in the sensitization of VGSCs [12].

In the present study, we examined the influence of TNFR-1 and TNFR-2 on the modulation of I_Na(V) and I_NaV(1.8)  in rat DRG neurons by using selective TNFR agonists.