Figure 7

Proposed mechanism of Ca _v α ₂ δ ₁ -mediated spinal hypersensitivity. A model of enhanced spinal glutamate release illustrates the possible mechanism of Ca_vα₂δ₁-mediated spinal hypersensitivity. A. Under normal conditions, the Ca_vα₂δ₁ expression level and quantum release of excitatory neurotransmitter glutamate from pre-synaptic A-fiber terminals is low so that post-synaptic deep dorsal horn neurons maintain a normal excitation threshold. As a consequence, glutamate release in response to stimuli results in a physiological activation of deep dorsal horn neurons mainly by activating AMPA/kainate receptors. The Ca_vα₂δ₁ expression level at C-fiber terminals is relatively high (causing a ceiling effect for C-fiber activation), but there is little C-fiber input onto deep dorsal horn neurons at a resting state. B. Under a pathological condition with an elevated Ca_vα₂δ₁-level at the A-fiber pre-synaptic terminals, such as post peripheral nerve injuries, the quantum release of glutamate from these terminals at a resting membrane potential is dramatically enhanced. This glutamate "leaking" causes a partial depolarization of post-synaptic deep dorsal horn neurons by activating AMPA/kainate receptors. As a consequence, these primed deep dorsal horn neurons have lowered excitation thresholds to subsequently evoked glutamate release, and also hyperexcitability due to lowered thresholds to NMDA receptor activation. Neither the partial depolarization of deep dorsal horn neurons nor the increased Ca_vα₂δ₁ expression in C-fiber terminals has any detectable effect to high intensity C-fiber stimulations. C. Proposed potential mechanisms mediating the Ca_vα₂δ₁-enhancement of spinal glutamate release.