Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0

Abstract

Microglia are increasingly recognized as critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. The core signalling pathway is through P2X4 purinergic receptors on the microglia which, via the release of brain-derived neurotrophic factor, cause disinhibition of nociceptive dorsal horn neurons by raising intracellular chloride levels. This disinhibition works in synergy with enhanced excitatory synaptic transmission in the dorsal horn to transform the output of the nociceptive network. There is increased discharge output, unmasking of responses to innocuous peripheral inputs and spontaneous activity in neurons that otherwise only signal nociception. Together the changes caused by microglia-neuron signalling may account for the main symptoms of neuropathic pain in humans.

Figure 1. Microglia-neuronal signalling 1.0

Conceptual model developed in 2005 illustrating the changes seen in the P2X4R – BDNF-KCC2–Cl− pathway. The normal situation is shown in the top panel. Microglia maintain a surveillance mode and do not express P2X4 receptors. Dorsal horn neurons, shown enlarged on the right, express KCC2 and have normal chloride extrusion capacity, thus maintaining low intracellular chloride concentration. Consequently, GABA activation produces a net inward flux of chloride and therefore inhibition. Following peripheral nerve injury, microglia in the spinal dorsal horn adopt a P2X4R+ phenotype. Activation of these receptors causes release of BDNF which subsequently downregulates neuronal KCC2. Unable to extrude chloride, intracellular concentrations rise, impairing the inhibitory ability of the neuron.

Figure 2. Microglia-neuronal signalling 2.0

The current hypothesis, combining new evidence that builds on the original model. Several factors have now been demonstrated to upregulate microglial P2X4 following peripheral nerve injury. These include the extracellular matrix molecule fibronectin, the cytokine IFNγ and the chemokine CCL2 (MCP-1). Activation of P2X4Rs increases both BDNF synthesis and release that is p38MAPK-dependent. BDNF-dependent downregulation of KCC2 changes the membrane properties of dorsal horn lamina I neurons which can then affect neuronal excitability via NMDAR potentiation. These changes are sufficient to cause a transformation in the firing properties of identified lamin I projection neurons in vivo such that normally nociceptive-specific neurons change phenotype to wide dynamic range, providing a substrate for the behavioural aspects of pain hypersensitivity: hyperalgesia, allodynia and spontaneous pain behaviours.