Review p 38 MAPK , microglial signaling , and neuropathic pain

Accumulating evidence over last several years indicates an important role of microglial cells in the pathogenesis of neuropathic pain. Signal transduction in microglia under chronic pain states has begun to be revealed. We will review the evidence that p38 MAPK is activated in spinal microglia after nerve injury and contributes importantly to neuropathic pain development and maintenance. We will discuss the upstream mechanisms causing p38 activation in spinal microglia after nerve injury. We will also discuss the downstream mechanisms by which p38 produces inflammatory mediators. Taken together, current data suggest that p38 plays a critical role in microglial signaling under neuropathic pain conditions and represents a valuable therapeutic target for neuropathic pain management. Background Injuries of the nervous system, including peripheral nervous system (PNS, e.g. peripheral nerves, dorsal root ganglia, and dorsal roots) and central nervous system (CNS, e.g. spinal cord and thalamus), often result in neuropathic pain. These injuries may result from diabetic neuropathy, viral infection, major surgeries (e.g. amputation, thoracotomy), spinal cord injury, and stroke [1-3]. Spontaneous pain, described as shooting, lancinating or burning pain, and mechanical allodynia (painful responses to normally innocuous tactile stimuli) are distinct symptoms of neuropathic pain, although neuropathic pain is also characterized by heat hyperalgesia, mechanical hyperalgesia, and cold allodynia. Neuropathic pain is a consequence of neural plasticity, developed both in the PNS (peripheral sensitization) and CNS (central sensitization). After nerve injury, neuropathic pain can arise from injury discharge at the site of axonal injury and ectopic/spontaneous activity in dorsal root ganglion (DRG) neurons [4-6]. Inflammatory mediators (e.g. cytokines) play a critical role in the generation of spontaneous activity and neuropathic pain. Peripheral nerve injury also induces marked phenotypic changes in DRG neurons [1,2]. While spontaneous activity from primary afferents drives central sensitization, central sensitization is responsible for persistent neuropathic pain. Central sensitization may also directly drive neuropathic pain in central neuropathic pain conditions caused by spinal cord injury or stroke. Central sensitization is induced by enhanced synaptic strength in the spinal cord and brain regions, due to an increase in excitatory synaptic transmission (e.g. AMPA and NMDA currents) or/and a reduction in inhibitory synaptic transmission (e.g. GABA currents) [7-9]. In addition to increased primary afferent input, enhanced descending facilitation also contributes Published: 1 November 2007 Molecular Pain 2007, 3:33 doi:10.1186/1744-8069-3-33 Received: 24 August 2007 Accepted: 1 November 2007 This article is available from: http://www.molecularpain.com/content/3/1/33 © 2007 Ji and Suter; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.