Figure 2.

Pain circuitry in the spinal dorsal horn. Four primary sub-circuits are represented: (1) post-synaptic inhibition of nociceptive projection neurons, (2) pre-synaptic inhibition of nociceptive projection neurons, (3) basally inhibited PKCγ excitatory interneurons, and (4) polysynaptically excited nociceptive projection neurons. (A) In a healthy case there is a balance between nociceptive and non-nociceptive afferent input and dorsal horn circuit strengths, resulting in minimal activation of nociceptive projection neurons. (B) In the case of chronic pain, peripheral nerve damage/inflammation elevates firing of nociceptive afferent fibers. Additionally, GABAergic and glycinergic drive from inhibitory interneurons are reduced, resulting in: (1) reduction in post-synaptic inhibition, (2) reduction in pre-synaptic inhibition, (3) disinhibition of PKCγ interneurons, enabling allodynia-producing circuits, and (4) sensitization of nociceptive projection neurons, characterized by increased excitability and decreased inhibition. (C) Neurostimulation is believed to cause elevated firing of Aα/β afferent fibers, counteracting many of the circuit-level effects of chronic pain. Specifically, high rates of Aα/β firing induce: (1) elevated post-synaptic inhibition, (2) elevated pre-synaptic inhibition (3) return of inhibition to the PKCγ cells, reducing allodynia, and (4) elevated inhibition and reduction of nociceptive drive to the nociceptive projection neurons.