Norepinephrine Restores Inhibitory Tone of Spinal Lamina X Circuitry, thus Contributing to Analgesia Against Inflammatory Pain

Norepinephrine (NE) acts directly on the inhibitory interneurons of spinal lamina X and may act on spinal lamina X neurons for inhibiting nociceptive synaptic transmission against pain. We investigated this mechanism within inflammatory pain model rats. Using immunohistochemical staining and in vivo extracellular recording, the increased number of phosphorylated extracellular signal-regulated kinase profiles in lamina X (n = 6/group) and increased frequency of spontaneous neuronal firing on putative lamina X (n = 14) under the inflammatory pain were significantly suppressed by the direct application of NE (P < 0.01). Following in vivo observation of enhanced spontaneous neuronal firing, we tested the impact of NE on this discharge using an in vitro spinal slice preparation. Using in vitro patch-clamps recording, the baseline level of miniature inhibitory postsynaptic currents (mIPSCs) frequency on spinal lamina X neurons cord is decreased under inflammatory pain. Direct application of NE to spinal lamina X neurons in inflammatory pain model rats facilitates mIPSCs frequency and induces an outward current (n = 8; P < 0.05), and these responses are inhibited by α1A- and α2-receptor antagonists (n = 8; P > 0.05). Considering these results and those of our previous study (Ohashi et al., 2019), NE might act on inhibitory interneurons of spinal lamina X to facilitate inhibitory transmission and induces neurons located in or around lamina X membrane hyperpolarization. These NE-mediated responses acted through α1A- and α2-receptors. These mechanisms of NE on spinal lamina X might contribute to analgesia against inflammatory pain.