Exogenous tumor necrosis factor‐α rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn

Abstract

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is involved in the generation of inflammatory and neuropathic pain. This study investigated if TNF-alpha has any effect on spinal synaptic and/or sensory transmission by using whole-cell recordings of substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of adult rats and by using behavioral tests. After intrathecal administration of TNF-alpha in adult rats, spontaneous hind paw withdrawal behavior and thermal hyperalgesia were rapidly induced (approximately 30 min), while mechanical allodynia slowly developed. Bath application of TNF-alpha (0.1-1 nM, 8 min) depressed peak amplitude of monosynaptic Adelta and C fiber-evoked excitatory postsynaptic currents (EPSCs) without changing in holding currents and input resistances, whereas this application generally potentiated polysynaptic Adelta fiber-evoked EPSCs. Moreover, the frequencies, but not the amplitudes, of spontaneous and miniature EPSCs and spontaneous inhibitory postsynaptic currents were significantly increased by bath-applied TNF-alpha in most of the SG neurons. The effects of TNF-alpha on Adelta/C fiber-evoked monosynaptic and polysynaptic or spontaneous EPSCs were significantly blocked by 5 microM TNF-alpha antagonist that inhibits TNF-alpha binding to its type 1 receptor (TNFR1). Because this study also found high protein expression of TNFR1 in the adult dorsal root ganglion and no change of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) induced whole-cell currents by TNF-alpha, we conclude that presynaptic TNFR1 at Adelta/C primary afferent terminals contributes to the rapid alteration of synaptic transmission in the spinal SG, and the development of abnormal pain hypersensitivity by exogenous TNF-alpha.

Perispinal etanercept: a new therapeutic paradigm in neurology

“…TNF causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal neurons [125]. Rapid synaptic effects of TNF, within minutes, were reported in 2008 in an experimental rat spinal cord model [114]. More recently, even more rapid synaptic effects of TNF have been reported [110,112].…”

“…• Inhibition of long-term potentiation [56,59,60,162] • Modulation of AMPA and GABA receptors [125] • Control of synaptic strength [123] • Modulation of synaptic scaling [124] • Modulation of synaptic transmission by gliotransmission [13][14][15] • Rapid alteration of synaptic transmission in the spinal cord dorsal horn [114] • Rapid modulation of enzymes (nSmase2) (within seconds) involved in NMDA trafficking [110] Review Perispinal etanercept: a new therapeutic paradigm in neurology and disability, even in patients presenting with years of severe, intractable pain [23,24]. In a 143-patient, open-label study, rapid improvement (within 20 min) and significant and sustained reductions in pain, sensory disturbance and weakness were documented in a patient population with an average pain duration of 9.8 years [44].…”

“…Of related interest is new data suggesting that an antidepressant, imipramine, may prevent cognitive decline and amyloid-b accumulation in a murine AD model, in part by inhibiting TNF [109]. Moreover, the rapidity of these effects, and other clinical effects that may occur within minutes of perispinal etanercept administration, such as improvements in cognition and attention, suggests the existence of novel TNF-mediated pathways that have not been fully characterized and are highly deserving of investigation [5,23,61,62,85,[110][111][112][113][114]. Investigational techniques that are capable of demonstrating rapid brain changes, such as functional MRI and evoked potentials, may be capable of documenting such effects.…”

Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

“…Spinal neuroinflammation in peripheral neuropathy is characterized by activation of microglia and astrocytes, as well as upregulation of the proinflammatory mediator, tumor necrosis factor-α (TNF-α) [8, 13, 14]. Microglia and astrocytes synthesize TNF-α [15], and TNF-α contributes to neuropathic pain [16, 17]. Additionally, inhibiting activation of microglia and astrocytes [18–20], as well as spinal TNF-α [21] have analgesic effects.…”

Modulation of synaptic transmission from primary afferents to spinal substantia gelatinosa neurons by group III mGluRs in GAD65-EGFP transgenic mice

“…A␦ fibers mediate first, sharp pain, and C fibers mediate second, burning pain (Torebjork and Hallin 1973). Several studies have found similar modulations on A␦ and C fiber-mediated synaptic transmission by various neuromodulators (Lao et al 2004;Youn et al 2008), whereas other studies have found different modulations (Ataka et al 2000;Ikoma et al 2007;Ito et al 2000).…”