Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury

Abstract

Recent work regarding chronic central neuropathic pain (CNP) following spinal cord injury (SCI) suggests that activation of key signaling molecules such as members of the mitogen activated protein kinase (MAPK) family play a role in the expression of at-level mechanical allodynia. Previously, we have shown that the development of at-level CNP following moderate spinal cord injury is correlated with increased expression of the activated (and thus phosphorylated) forms of the MAPKs extracellular signal related kinase and p38 MAPK. The current study extends this work by directly examining the role of p38 MAPK in the maintenance of at-level CNP following spinal cord injury. Using a combination of behavioral, immunocytochemical, and electrophysiological measures we demonstrate that increased activation of p38 MAPK occurs in the spinal cord just rostral to the site of injury in rats that develop at-level mechanical allodynia after moderate SCI. Immunocytochemical analyses indicate that the increases in p38 MAPK activation occurred in astrocytes, microglia, and dorsal horn neurons in the spinal cord rostral to the site of injury. Inhibiting the enzymatic activity of p38 MAPK dose dependently reverses the behavioral expression of at-level mechanical allodynia and also decreases the hyperexcitability seen in thoracic dorsal horn neurons after moderate SCI. Taken together, these novel data are the first to demonstrate causality that increased activation of p38 MAPK in multiple cell types play an important role in the maintenance of at-level CNP following spinal cord injury.

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

“…46 Importantly, p38 MAPK modulates neuronal apoptosis following SCI, 47 and elevated levels of spinal p38 have been strongly implicated in the generation and maintenance of neuropathic pain in models of nerve and spinal cord injury. [48][49][50][51] Evidence suggests that these neurotoxic and hyperalgesic effects may result from p38-mediated glial activation and inflammation. 52 Treatment with p38 inhibitors prevents glial proliferation in the spinal cord and decreases the expression of neuropathic pain symptoms after injury.…”

“…52 Treatment with p38 inhibitors prevents glial proliferation in the spinal cord and decreases the expression of neuropathic pain symptoms after injury. 39,48,49,51 NorBNI may decrease KOR-mediated p38 signaling, preventing aberrant glial activation. As morphine administration also results in increased expression of many pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6, 2,53-56 using norBNI as an adjuvant may also reduce the development of paradoxical pain observed with prolonged morphine administration.…”

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

“…p38 MAPK influences the production of proinflammatory cytokines, excitatory molecules, and mediators of oxidative stress (Saklatvala, 2004;Peifer et al, 2006). Previous studies have shown that p38 MAPK is expressed after SCI in microglia/macrophages, neurons and astrocytes, and is implicated in mediating chronic pain (Jin et al, 2003;Crown et al, 2008;Kobayashi et al, 2008). However, p38 MAPK also mediates a variety of cellular functions involved in development, cell survival and proliferation (Roux and Blenis, 2004;Krens et al, 2006).…”

Neuronal Hyperexcitability Mediates Below-Level Central Neuropathic Pain after Spinal Cord Injury in Rats

“…예를 들면 below-level pain에는 척수 손상 에 의한 내재성 억제 신경로의 손상이 관여하는 것으로 알려지고 있다 (Gwak et al, 2006). 하지만, 각 부위 척수 후각 신경세포의 과흥분성(hyperexcitability of spinal dorsal horn neurons)은 이들 세 부위에서 유발되는 신경 병증성 통증의 기전에 공통적으로 관여하는 것으로 알려 지고 있다 (Drew et al, 2001;Hains et al, 2003;Crown et al, 2008;Gwak et al, 2008;Carlton et al, 2009). (Hains et al, 2003;Gwak and Hulsebosch, 2005;McAdoo et al, 2005;Waxman, 2006, Liu et al, 2008).…”

“…세포내 작용기전 으로서는 cAMP, mitogen-associated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA), cAMP response element binding protein (CREB), calcium/calmodulin-dependent protein kinase (CaMKinase) 등의 활성화에 따른 전사와 번역과정의 활성화로 인한 해 당 단백질의 과발현 및 인산화 등 일련의 분자생물학적 인 반응들이 신경병증성 통증의 유발 및 유지에 관여하 는 것으로 보고되었다 (Crown et al, 2006;Labombarda et al, 2008;Lin et al, 2008 (Hains et al, 2003;Gwak et al, 2003;. 전기생리학적인 연구결과에 의하면, 척수손상 후 척수후각 신경세포들이 비유해성 자극이나 유해성 자극에 의해 과도하게 증가되 고 지속적인 반응을 보이는 것으로 알려지고 있는데 이 러한 상태를 척수후각 신경세포의 과흥분성 또는 중추성 감작이라고 한다 (Hains et al, 2003;Gwak et al, 2006;Crown et al, 2008) (Figure 1 (Chung et al, 1986;Dougherty et al, 199l;Gwak et al, 2008) (Hains et al, 2003;. 만일 WDR 신경세포가 그들의 자극 분별에 관여하는 코드화를 소실한다면 WDR 신경세포의 분포가 감소할 것이나 전기생리학적인 결과로서는 WDR 신경세 포가 증가하였기 때문이다 (Hains et al, 2003;.…”