• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • The mitogen activated protein kinase MAPK


    The mitogen-activated protein kinase (MAPK) family, which consists of extracellular signal-regulated protein kinase 1/2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK), is involved in the development of NP (Hung et al., 2012, Ji et al., 2009). Recently, Zhuang et al. (2005) demonstrated that the activation of ERK1/2 displayed a temporal pattern in neurons, microglia and astrocytes in the ipsilateral dorsal horn following spinal nerve ligation. Inhibition of ERK1/2 rosmarinic acid of by intrathecal administration of a MEK1 (a component of MAPK/ERK) inhibitor, PD98059, at various time-points (i.e., 2, 10 or 21days after SNL) improved nerve injury-induced mechanical allodynia. Moreover, the activation of astrocytes and microglia appeared to provoke a long-lasting effect on the maintenance of the development of allodynic behavior associated with partial SNL-NP (Coyle, 1998). These studies implied that the activation of ERK1/2 in the glial cells, especially astrocytes, might contribute to the long-lasting effect on the development of chronic NP. Therefore, an understanding of the mechanism that underlies the delayed response of astrocytes may be a promising direction for the management of persistent NP. We have also investigated another signaling molecule, Akt(s), which is from the phosphatidylinositol-3-kinase (PI3K)/Akt(s)/mammalian target of rapamycin (mTOR) pathway. It stimulates cell-cycle progression and proliferation that the regulation of this pathway has important physiological and pathological effects on the CNS (Wu et al., 2010). It has been demonstrated that the activation of Akt(s) contributes substantially to central sensitization in the development of NP (Guedes et al., 2008, Xu et al., 2007) and the activation of PI3K-mediated Akt(s) is stimulated by ET-1 (Bagnato and Rosano, 2008). These results further support an important modulatory role of ET-1 in the pathophysiology of NP. Together with the MAPK pathway, ERK and Akt are major intracellular signaling modules that have been associated with nociceptive transmission and the development of NP (Calvo et al., 2011, Sun et al., 2006). In this study, we aimed to investigate whether Akt(s) and ERK1/2 were involved in astrocytic ET-1-mediated anti-allodynic and anti-hyperalgesic responses in SNL-NP via the differential activation of ET receptors.
    Discussion This study aimed to investigate the functions of the over-expression of central (astrocytic) ET-1 in SNL-NP processing. Although the role of ET-1-mediated nociceptive response has been demonstrated in various animal models of pathological pain by direct injection of active ET-1 peptide either with or without selective ET-1 receptor antagonists (Hasue et al., 2004, Jarvis et al., 2000, Joseph et al., 2011, Khodorova et al., 2003, Klass et al., 2005, Piovezan et al., 2000, Yamamoto et al., 1994), little is known about the endogenous effects of central ET-1 in NP. Moreover, the long-term effects of cell type- or tissue-specific ET-1 on pain is difficult to determine due to the limited half-life of the drugs studied. Therefore, the current study used a transgenic approach to address the role of cell-specific central ET-1 synthesis on SNL-NP in mice that over-express ET-1 specifically in astrocytes (GET-1). In a previous study on GET-1 mice, microscopic examination of their brain sections showed no deformities in glial fibrillary acidic protein-stained cells, which implied that over-expression of astrocytic ET-1 did not cause gliosis in GET-1 mice. This was also demonstrated by immunohistochemistry and in-situ hybridization in the same study, in which GET-1 mice did not present any gross structural or morphological abnormalities in the brain (Lo et al., 2005). Behavior-wise, GET-1 mice did not show a significant difference in the baseline threshold to mechanical and heat stimuli compared with NTg mice, suggesting that specific ET-1 over-expression in astrocytes does not normally interfere with pain transmission (Hung et al., 2012). By using GET-1 mice in which ET-1 is over-expressed continuously in the astrocytes, the long-term effect of central ET-1 could be assessed repeatedly at various time-points following SNL injury.