Differential Activation of Extracellular Signal-Regulated Protein Kinase in Primary Afferent Neurons Regulates Brain-Derived Neurotrophic Factor Expression after Peripheral Inflammation and Nerve Injury

Abstract

To investigate the intracellular signal transduction pathways involved in regulating the gene expression of brain-derived neurotrophic factor (BDNF) in primary afferent neurons, we examined the activation of extracellular signal-regulated protein kinase (ERK) in dorsal root ganglion (DRG) neurons after peripheral inflammation and sciatic nerve transection. Peripheral inflammation induced an increase in the phosphorylation of ERK, mainly in tyrosine kinase A-containing small-to-medium-diameter DRG neurons. The treatment of the mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor U0126 reversed the pain hypersensitivity and the increase in phosphorylated-ERK (p-ERK) and BDNF in DRG neurons induced by complete Freund's adjuvant. On the other hand, axotomy induced the activation of ERK mainly in medium-and large-sized DRG neurons and in satellite glial cells. U0126 suppressed the axotomy-induced autotomy behavior and reversed the increase in p-ERK and BDNF. The intrathecal application of nerve growth factor (NGF) induced an increase in the number of p-ERK-and BDNF-labeled cells, mainly small neurons, and the application of anti-NGF induced an increase in p-ERK and BDNF in some medium-to-large-diameter DRG neurons. The activation of MAPK in the primary afferents may occur in different populations of DRG neurons after peripheral inflammation and axotomy, respectively, through alterations in the target-derived NGF. These changes, including the changes in BDNF expression, might be involved in the pathophysiological changes in primary afferent neurons.

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

“…In the ipsilateral L5 DRG, the L5 SNL induced an increase in the phosphorylation of ERK, mainly in large DRG neurons and in satellite glial cells (Fig. 2 A, B), consistent with a previous study (Obata et al, 2003b). Seven days after L5 SNL surgery, 46 of 313 p-ERK-IR neurons counted (14.7%) were small, 76 (24.3%) were medium, and 191 (61.0%) were large in size (mean Ϯ SD of the cross-sectional area, 1414 Ϯ 673 m 2 ) (Fig.…”

“…The intrathecal delivery of MAPK inhibitors or anti-NGF was performed basically as described previously Obata et al, 2003b). A laminectomy of the L5 vertebra was performed under adequate anesthesia with sodium pentobarbital.…”

“…The MAPK family includes extracellular signal-regulated protein kinases (ERKs), p38 MAPK, and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). Activation of ERK in DRG neurons contributes to pain hypersensitivity by increasing gene transcription Obata et al, 2003b). p38 MAPK activation in DRG neurons has also been implicated in exaggerated pain states (Ji et al, 2002;Jin et al, 2003;Schafers et al, 2003b).…”

Roles of the hippocampal formation in pain information processing

“…The ERK (extracellular signal-regulated kinase) members of the MAPK family are originally identified as the primary effectors of growth factor receptor signaling [200] and supposed to regulate a wide array of cellular functions, including cell growth, differentiation, survival, as well as neuronal plasticity [201][202][203] . Nowadays, a growing number of reports also indicate that activated forms of ERKs would act both in the peripheral nociceptor terminal and the dorsal horn to produce pain hypersensitivity and hence contribute to the pathology of inflammatory and neuropathic pain [204][205][206][207][208] .…”

Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization

“…Indeed, a number of putative inflammatory mediators, including cytokines and NGF, can activate the Ras/MEK/ERK signaling pathway in sensory neurons (Hensellek et al 2007;Nicol and Vasko 2007;Zhuang et al 2004), and the consequences of long-term activation of this pathway are the subject of much study. Several investigations have shown that phosphorylation and activation of ERK are involved in peripheral sensitization (Dai et al 2002;Ji et al 1999;Obata et al 2003;Zhuang et al 2004). Furthermore, there is evidence that activation of the Ras/Raf/MEK/ERK pathway mediates neurotrophin-induced increases in expression of transient receptor potential cation channel subfamily V member 1 (TRPV1) (Bron et al 2003).…”