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

Abstract

To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

Do glial cells control pain?

“…Specific antibodies against activated (phosphorylated) forms of MAPKs and specific inhibitors available for all three MAPK pathways have allowed us to study both the activation of MAPKs in the spinal cord and behavioral consequences of the activation. Inhibition of all three MAPK pathways at the spinal level have been shown to alleviate inflammatory pain and neuropathic pain (reviewed in ; also see Daulhac et al, 2006;Obata et al, 2004;Schafers et al, 2003;Zhao et al, 2007a). Interestingly, some glial inhibitors such as minocycline can inhibit the activation of MAPKs (Nikodemova et al, 2006).…”

“…3e). Intrathecal MEK inhibitors were also shown to alleviate neuroapthic pain after spinal nerve ligation at time points when ERK is activated in spinal microglia (Obata et al, 2004;Zhuang et al, 2005). Thus, both ERK and p38 activation in spinal microglia are important for the pathogenesis of neuropathic pain.…”

Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

“…Recently MC4R was found in dorsal root ganglia (DRG) where nerve injury can affect its expression 3 , but the underlying mechanisms are still unclear. P38MAPK was improved to play an important role in the development and maintenance of nerve injury, inflammation and incision pain [4][5][6][7][8][9] . Intrathecal inhibitor of p38 has been shown to attenuate neuropathic pain in different ABSTRACT: Background: neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli.…”

Anisomycin protects cortical neurons from prolonged hypoxia with differential regulation of p38 and ERK

“…Three distinct but interlinked MAP kinases have been identified in mammalian cells, including neurons (Sweatt, 2001;Obata et al, 2004), i.e, the extracellular-signal regulated kinase (ERK), the c-Jun -terminal kinase (JNK) and p38. Several lines of evidence have suggested that ERK cascades mediate cell development, growth and survival (Skaper and Walsch, 1998;Seger and Krebs, 1995), while p38 and JNK respond to inflammatory cytokines and cellular stress and promote inflammation and cell death (Schaeffer and Weber, 1999).…”