Furthermore, intrathecal administration of microglia activated by ATP into na?ve animals produces mechanical allodynia, which can be alleviated by blockade of the BDNF receptor TrkB [95]

Furthermore, intrathecal administration of microglia activated by ATP into na?ve animals produces mechanical allodynia, which can be alleviated by blockade of the BDNF receptor TrkB [95]. and in disease says. TNFis known to play a role in synaptic plasticity, which has been studied mainly in hippocampal slices. Glial TNFhas been shown to enhance synaptic efficacy by increasing the surface expression of GluR1-possessing AMPA receptors via TNFR1-mediated PI3?K activation [56, 57]. Glial TNFalso causes endocytosis of GABAA receptors resulting in a decrease in inhibitory synaptic currents [57]. Homeostatic synaptic scaling of excitatory synapses increases their strength in response to network activity reduction or decreases their strength in response to increased network activity. In response TAS-102 to decreases in network activity, glial TNFwas shown to increase AMPA-mediated currents by increasing the number of calcium permeable AMPA receptors at the cell surface [58]. However, its role may be more permissive rather than instructive in this change [59]. The effects of TNFhave also been studied in the dorsal horn of the spinal cord (see Physique 3). Intrathecal TAS-102 injection of TNFcauses the development of thermal and mechanical hyperalgesia [51]. To investigate the synaptic mechanisms of TNFspinal cord slice preparation. Incubation with TNFincreases the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II excitatory interneurons [60]. This could be indicative of a change in presynaptic glutamate release. TNFincreases sEPSC frequency via activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) in presynaptic terminals, possibly through activation of adenylyl cyclase, protein kinase (PKA), or extracellular signal-related kinase (ERK) [60]. Activation of TRPV1 results in increased presynaptic calcium influx and, therefore, increased vesicular glutamate release [60]. Open in a separate window Physique 3 Schematic of TNFinduced potentiation of spinal cord synaptic transmission. Microglial release of TNFincreases excitatory neurotransmission in the dorsal horn via both presynaptic and postsynaptic mechanisms. At presynaptic sites, TNFincreases glutamate release via TRPV1 activation and there will be a subsequent increase in intracellular Ca2+. At postsynaptic sites, TNFincreases the activity of AMPA and NMDA receptors via activation of PI3? K and ERK on glutamatergic neurons to increase excitatory drive. TNFalso acts around the postsynaptic neurons in the spinal cord. In a carrageenan model of inflammation, TNFrecruited Ca2+ permeable AMPA receptors to dorsal horn neurons resulting in increased sEPSC amplitude [61]. NMDA currents in lamina II neurons are also enhanced by application of TNF[51], and TNFincreases NMDA receptor (NMDAR) activity through phosphorylation of ERK in dorsal horn, neurons [62]. Thus via pre- TAS-102 and post synaptic mechanisms TNFincreases excitatory neurotransmission in the dorsal horn. In spinal cord slices, TNFnot only enhances sEPSCs but also suppresses the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) [63]. This was found to be mediated by a decrease in spontaneous action potentials in GABAergic neurons via activation of TNF receptor 1 (TNFR1) and activation of p38 MAPK [63]. Neurons in the dorsal horn possess both TNFR1 and 2 (TNFR2), however, TNFR1 seems to make a greater contribution to enhancing nociceptive signaling in the dorsal horn [64]. In spinal cord slices from TNFR1 KO mice, TNFwas unable to elicit increases in sEPSCs or increases in NMDA currents [64]. However in TNFR2 KO mice, TNFwas still able to produce a small increase in sEPCS, and it elicited a normal increase in NMDA currents [64]. Both TNFR1 and TNFR2 knockout (KO) Spry2 animals show decreased pain behavior in response to complete Freund’s adjuvant and formalin induced inflammatory pain as well as intrathecal injection of TNF[64]. Thus, microglial release of TNFin the dorsal horn both enhances excitatory neuronal/synaptic activity and suppresses inhibitory neuronal/synaptic activity to enhance central sensitization primarily through the activation of TNFR1 on nociceptive dorsal horn neurons. Long-term potentiation (LTP) in the spinal cord is usually implicated in pathological pain [65]. LTP in the spinal cord can be brought on by stimulation of the primary afferent fibers with the typical high-frequency titanic stimulation [66] and also by low-frequency stimulation (a more physiological firing pattern of nociceptors) [67] as well as by formalin or capsaicin administration to the paw or by nerve injury [16, 17,.