Figure 7.
Microglial-neuronal interactions disrupt GABAergic inhibitory control: Peripheral nerve injury activates spinal cord microglia, which in turn release numerous molecules that enhance the excitability of spinal corn neurons. Some studies indicate that chemokine ligand 2 (CCL2), which is upregulated in and released from injured primary sensory neurons, binds to the microglial chemokine receptor 2 (CCR2) to induce microglial activation. Nerve-injury-induced release of ATP, via an action on microglial P2X4 receptors, also activates the microglia. The latter release brain-derived neurotrophic factor (BDNF), which via an action on neuronal TrkB receptors, downregulates the neuronal potassium-chloride co-transporter KCC2. The net result is a reduced chloride gradient that alters the magnitude of any GABAergic inhibitory input to the neuron. In this setting there may be ongoing pain, mechanical allodynia and thermal hyperalgesia.