Krotov V. Changes in the functioning of neuronal circuitry of superficial dorsal horn laminae induced by chronic pain of various genesis

Theses are focused on the investigation of changes in the functioning of neuronal circuitry of the dorsal horn of the spinal cord induced by chronic pain of inflammatory and traumatic genesis. We have found cell-type specificity of changes in synaptic activity of superficial dorsal horn neurons. Detailed analysis of amplitudes and frequencies of spontaneous excitatory and inhibitory postsynaptic currents demonstrated that both peripheral inflammation and spinal cord injury led to the shift in the balance of network excitation-inhibition balance towards excitation of adapting-firing neurons (predominantly excitatory cells) and towards inhibition of tonic-firing neurons (presumably inhibitory cells). We also investigated possible mechanisms that mediated the aforementioned changes. Kinetics analysis of miniature AMPA-receptor-mediated events revealed that substantial increase of excitation in adapting-firing neurons is due to additional incorporation of calcium-impermeable AMPA-receptors in the synapses between the superficial dorsal horn interneurons. In the meantime, intrathecal administration of inhibitors of calcium-permeable AMPA-receptors and their modulatory enzyme protein kinase C significantly alleviated pain syndrome induced by peripheral inflammation. This fact indicates that hyperexcitation of neuronal circuitries of superficial dorsal horn laminae may be also attributed to incorporation of calcium-permeable AMPA-receptors that takes place in the synapses between primary afferent and dorsal horn interneurons. Thus, this work demonstrates both cell- and synapse-specificity of changes in the functioning of superficial dorsal horn circuitry, induced by chronic pain.