Neuronal and microglial mechanisms of neuropathic pain

Abstract

Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. Effective treatment for neuropathic pain is still lacking, due in part to poor understanding of pathological mechanisms at the molecular level. Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury. Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions. In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain.

Figure 1

Signaling pathways for NMDA receptor-dependent LTP in the ACC. Neural activity releases glutamate in the ACC synapses. Subsequent to activation of glutamate NMDA receptors, Ca²⁺ binds to CaM and leads to activation of calcium-stimulated ACs, including AC1 and AC8 and Ca²⁺/CaM dependent protein kinases (PKC, CaMKII and CaMKIV). Activation of CaMKIV, a kinase predominantly expressed in the nuclei, will trigger CaMKIV-dependent CREB. In addition, activation of AC1 and AC8 lead to activation of PKA, and subsequently CREB. CREB and other immediate early genes (e.g., Egr1) in turn activate targets that are thought to lead to more permanent structural changes. Inset box: the simplified neuronal network for sensory synaptic transmission, plasticity and regulation in the central nervous system. DRG: dorsal root ganglion.

Figure 2

Simultaneous confocal imaging and patch clamp recordings in microglia in situ. ATP-containing pipette induced both outward current and chemotaxis in brain microglia. Outward current appears after pipette approaches, while disappears after the pipette moves away from the recording microglia (middle). DIC image showed the recording pipette and ATP-containing pipette. Fluorescent images showed that the chemotactic effect during the insertion of the ATP pipette (upper). When the pipette was removed out of the slice, the moving terminals rapidly disappeared (lower, right). Scale bar, 15 μm. Modified from [53].

Figure 3

Spinal but not cortical microgliosis after peripheral nerve injury. Left column, sham-operated; right column, peripheral nerve injury. Nerve injury evoked an ipsilateral increase of microglial cells in L4 spinal dorsal horns. Asterisks indicate contralateral side of nerve injury. The structures in the cortex are indicated by arrow or enclosed by dashed lines. 1, ACC (Anterior cingulate cortex). Bar = 350 μm. Modified from [66].