Modulation of spinal cord synaptic activity by tumor necrosis factor α in a model of peripheral neuropathy

Abstract

BackgroundThe cytokine tumor necrosis factor α (TNFα) is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH) is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNFα incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy.MethodsSpontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs) were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls.ResultsIn slices after axotomy the sEPSC frequency was 2.8 ± 0.8 Hz, while neurons recorded from slices after TNFα incubation had significantly higher sEPSC frequency (7.9 ± 2.2 Hz). The effect of TNFα treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 ± 0.2 Hz in slices without and 2.0 ± 0.5 Hz with TNFα incubation. Tetrodotoxin (TTX) application in slices from axotomized animals and after TNFα incubation decreased the mEPSC frequency to only 37.4 ± 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNFα treatment (64.4 ± 6.4%). TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNFα untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 μM) in slices after axotomy induced a significant increase in mEPSC frequency (175.9 ± 17.3%), similar to the group with TNFα pretreatment (158.1 ± 19.5%).ConclusionsOur results indicate that TNFα may enhance spontaneous transmitter release from primary afferent fibres in the spinal cord DH by modulation of TTX-sensitive sodium channels following sciatic nerve transection. This nerve injury also leads to enhanced sensitivity of presynaptic TRPV1 receptors to endogenous agonist. Modulation of presynaptic receptor activity on primary sensory terminals by TNFα may play an important role in neuropathic pain development.

Curcumin Attenuates Diabetic Neuropathic Pain by Downregulating TNF-α in a Rat Model

“…TNF-α concentration in spinal cord dorsal horn are elevated in several neuropathological disorders associated with hyperalgesia 15, 16. In our study, rats with streptocotozin-induced diabetes had significantly elevated blood glucose levels, decreased body weights, and reduced pain threshold compared with control rats.…”

Peripheral inflammation affects modulation of nociceptive synaptic transmission in the spinal cord induced by N‐arachidonoylphosphatidylethanolamine

“…Consistent with this high level of expression of TRPV1 channels, regulation (activation, desensitization and inhibition) of TRPV1 channels has a marked effect on glutamate release from these afferents (Spicarova et al, ). It has been suggested that modulation of TRPV1 channels in the dorsal horn could underlie several pathological pain states (Kanai et al, ; Spicarova et al, ; Spicarova et al, ).…”

“…Painful peripheral pathologies including tissue inflammation alter the expression and/or activity of both TRPV1 channels and CB 1 receptors (Richardson et al, ; Amaya et al, , ; Luo et al, ; Kanai et al, ; Spicarova and Palecek, ; Spicarova et al, ; Kwon et al, ). Inflammation also induces changes in anandamide levels in the spinal cord (Buczynski et al, ; Costa et al, ) and the expression of enzymes synthesizing and hydrolysing anandamide, in DRG neurons (Lever et al, ; Sousa‐Valente et al, ).…”

TRPV1 Receptors Contribute to Paclitaxel-Induced c-Fos Expression in Spinal Cord Dorsal Horn Neurons

“…66 were made to minimize animal suffering and to reduce the number of animals used. Acute spinal cord slices were prepared altogether from 15 juvenile male Wistar rats ∼ P21, as previously described (Spicarova et al 2011, Spicarova et al 2014a. The rats were deeply anesthetized (Forane ®, Abb Vie Czech Republic), lumbar spinal cords were removed and immersed in oxygenated ice-cold dissection solution containing (in mM): 95 NaCl, 1.8 KCl, 7 MgSO 4 , 0.5 CaCl 2 , 1.2 KH 2 PO 4 , 26 NaHCO 3 , 25 D-glucose, 50 sucrose.…”