Opposite regulation of medullary pain-related projection neuron excitability in acute and chronic pain.

Pain hypersensitivity is associated with increased activity of peripheral and central neurons along the pain neuroaxis. We show that at the peak of acute inflammatory pain, superficial medullary dorsal horn projection neurons (PNs) that relay nociceptive information to the parabrachial nucleus reduce their intrinsic excitability and, consequently, action potential firing. When pain resolves, the excitability of these neurons returns to baseline. Using electrophysiological and computational approaches, we found that an increase in potassium A-current (I(A)) underlies the decrease in the excitability of medullary dorsal horn PNs in acute pain conditions. In chronic pain conditions, no changes of I(A) were observed, and medullary dorsal horn PNs exhibit increased intrinsic excitability and firing. Our results reveal a differential modulation of the excitability of medullary dorsal horn projection neurons in acute and chronic pain conditions, suggesting a regulatory mechanism that, in acute pain conditions, tunes the output of the dorsal horn and, if lacking, could facilitate pain chronification.