Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury

Abstract

BackgroundIntense nociceptive signaling arising from ongoing injury activates primary afferent nociceptive systems to generate peripheral sensitization. ERK1/2 phosphorylation in dorsal root ganglion can be used to visualize intracellular signal activity immediately after noxious stimulation. The aim of this study was to investigate spatiotemporal characteristics of ERK1/2 phosphorylation against tissue injury in the primary afferent neurons.MethodsPlantar incisions were made in the hind paws of Sprague-Dawley rats (n =150). Levobupivacaine was injected into the plantar aspect of the paws and ankles, Mitogen-activated protein kinase kinase (MEK) inhibitor was injected into the paw, and carbenoxolone, dual inhibitor of the gap junction and pannexin channel, was intraperitoneally injected. Pain hypersensitivity was investigated by a behavioral study, while phosphorylated ERK1/2 was detected in dorsal root ganglion and hind paw using immunohistochemistry and Western blot.ResultsPhosphorylated ERK1/2 was induced in dorsal root ganglion (26.8 ± 2.9% at baseline, 65.6 ± 3.6% at 2 min, and 26.3 ± 3.4% at 2 h) after the incision. NF-200 positive A-fiber neurons and satellite glial cells were positive for phosphorylated ERK1/2. Injury-induced pain hypersensitivity was abolished by MEK inhibitor. Levobupivacaine treatment inhibited phosphorylated ERK1/2 induction, carbenoxolone treatment inhibited glial phosphorylated ERK1/2 at 2 min after the injury, and carbenoxolone inhibited pain hypersensitivity and neuronal phosphorylated ERK1/2 at 1 h after the injury.ConclusionERK1/2 phosphorylation in A-fiber neurons and satellite glial cells immediately after injury contributes to the generation of pain hypersensitivity. Signal communication between neurons and satellite glial cells expands the duration of neuronal ERK1/2 phosphorylation and pain hypersensitivity at 1 h after tissue injury.

Emerging importance of satellite glia in nervous system function and dysfunction

“…In a PSP model based on paw incision, pERK1/2 expression was found to be increased 2-fold in A-fibre neurons and SGCs in the DRG. This increase was observed as early as 2 min after the incision, and returned to baseline at 2 h 99 . This effect is extremely fast, especially considering that SGCs are not influenced directly by the injury and must receive signals from the neurons.…”

“…The local anaesthetic levobupivacaine inhibited pERK1/2 induction. CBX, which blocks both gap junctions and Panx1 channels, inhibited the early glial pERK1/2 increase and also inhibited pain hypersensitivity 99 . This study indicates that early events induced in SGCs by nerve injury participate in the generation of hypersensitivity in PSP.…”

“…For example, skin and muscle incision and retraction in rats without visible nerve injury induced chronic PSP that persisted for more than 3 weeks 95 , suggesting that mechanisms other than nerve injury are involved in chronic PSP. It is assumed that chronic PSP is associated with central sensitization 96 , but peripheral mechanisms are also important 97 – 99 , as peripheral activity drives the central sensitization in PSP 100 and in other pain states 101 .…”

Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain

“…Plantar incision produced a rapid activation (within one hour) of ERK not only in large-size DRG neurons but also in surrounding SGCs. Blocking the coupling of neuron-SGC with the gap junction blocker carbenoxolone inhibited neuronal ERK activation and postsurgical pain 71 , supporting an essential role of neuron-SGC interactions in the initiation of postsurgical pain. It remains to be investigated if MMP-9 and IL-1β are involved in ERK activation in SGCs after plantar incision.…”

Purinergic Signaling in Endometriosis-Associated Pain

“…ATP release in neurons, astrocytes, and microglia also occurs through membrane channels, such as pannexin hemichannels, connexins, and the P2X7 receptor itself. In recent years, a wealth of evidence has pointed to pannexin-1 [ 124 , 159 , 160 ] and connexin-43 (reviewed in [ 161 , 162 , 163 ]) as crucial elements in the induction and maintenance of chronic pain. These ATP-permeable channels are, therefore, pain relief targets for further investigation.…”