Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain
Figure 5
Chloride-opathies and allodynia. Symbolic representation of the concepts and results of Coull et al. [3]. (a) A normal nociceptive neuronal circuit in the mammalian dorsal horn. A myelinated fiber synapses directly onto a lamina I projection neuron (PN), which projects to the thalamus. The fiber also synapses onto a GABAergic inhibitory interneuron, which suppresses PN activity via feedforward inhibition [25]. (b) Electrodynamics of chloride-dependent synapses. After neuronal or vascular injury, microglia in the dorsal horn release BDNF, resulting in a downregulation of KCC2 (Figure 2). This causes an increase in intracellular chloride (Figure 3), and a shift in the normal chloride Nernst potential to a more positive value, . A shift in resting membrane potential may also occur, to a new resting level, . When synaptic conversion occurs in the chloride-dependent synapse, resulting in the generation of excitatory postsynaptic potentials (EPSPs), instead of inhibitory postsynaptic potentials (IPSPs). (c) A symbolic representation of tactile allodynia. When the PN develops high intracellular chloride (yellow), its chloride-dependent synapses undergo synaptic conversion. Activation of the GABAergic interneuron results in the aberrant excitation of the PN, resulting in tactile allodynia. Synaptic conversion has produced a pathology in the logic of the nociceptive circuit. Because of the chloride-opathy in the PN, the nociceptive circuit with feedforward inhibition (a) has been converted into a nociceptive circuit that manifests aberrant feedforward facilitation.
