Tumor necrosis factor α sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine

Abstract

Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor α (TNFα), is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord has been shown to play an important role in neuropathic and inflammatory pain conditions. Transient receptor potential vanilloid 1 (TRPV1) receptors are known as molecular integrators of nociceptive stimuli in the periphery, but their role on the spinal endings of nociceptive DRG neurons is unclear. The endogenous TRPV1 receptor agonist N-oleoyldopamine (OLDA) was shown previously to activate spinal TRPV1 receptors. In our experiments the possible influence of TNFα on presynaptic spinal cord TRPV1 receptor function was investigated. Using the patch-clamp technique, miniature excitatory postsynaptic currents (mEPSCs) were recorded in superficial dorsal horn neurons in acute slices after incubation with 60 nM TNFα. A population of dorsal horn neurons with capsaicin sensitive primary afferent input recorded after the TNFα pretreatment had a basal mEPSC frequency of 1.35 ± 0.20 Hz (n = 13), which was significantly higher when compared to a similar population of neurons in control slices (0.76 ± 0.08 Hz; n = 53; P < 0.01). In control slices application of a low concentration of OLDA (0.2 uM) did not evoke any change in mEPSC frequency. After incubation with TNFα, OLDA (0.2 uM) application to slices induced a significant increase in mEPSC frequency (155.5 ± 17.5%; P < 0.001; n = 10). Our results indicate that TNFα may have a significant impact on nociceptive signaling at the spinal cord level that could be mediated by increased responsiveness of presynaptic TRPV1 receptors to endogenous agonists. This could be of major importance, especially during pathological conditions, when increased levels of TNFα and TNFR are present in the spinal cord.

Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats

“…It is also known that TNF-α can directly activate TNF-α receptors on peripheral nerve terminals, amplify hyperalgesic responses (Cunha et al, 1992;Junger and Sorkin, 2000), and release enzymes to enhance inflammation. It has been shown that TNF-α mediated increase in TRPV1 promotes painful inflammatory processes locally, impacting subsequent responses in the immune system (Spicarova and Palecek, 2010). Kochukov et al also demonstrated up-regulation of TRP channel in human synovial cells after preincubation with TNFα (Kochukov et al, 2009).…”

Changes in Spinal Cord Following Inflammatory and Neuropathic Pain and the Effectiveness of Resiniferatoxin

“…We have observed that there is a significant increase in the levels of pro-inflammatory mediators IL-1β, IL-6 and TNF-α. These mediators can interact with TRPV1 expressing cells and alter TRPV1 expression and function [41,42]. Peripheral inflammation (intraplantar CFA-treatment) and peripheral nerve injury (CCI) have been shown to increase the levels of phosphorylated p38 and ERK in spinal cord tissue [43 -49].…”

TRPV1 Antagonists as Analgesic Agents

“…In addition, TRPV1 is receptive to pro-inflammatory agents such as prostaglandins, bradykinin, adenosine triphosphate (ATP), 5-hydroxytryptamine, protease activate receptors (PAR) 1, 2 and 4, nerve growth factor (NGF) and tumor necrosis factor alpha (TNF-alpha) [50] that cause allosteric modification of the channel protein, either directly or indirectly, such that the probability of channel opening by heat, protons and capsaicin is enhanced [9,40,43,[51][52][53][54] Fig. (1).…”