Orexin B Modulates Spontaneous Excitatory and Inhibitory Transmission in Lamina II Neurons of Adult Rat Spinal Cord

Cellular mechanisms underlying the antinociceptive properties of orexins, a group of neuropeptides produced by the hypothalamus, in the spinal dorsal horn have not been thoroughly investigated. We examined how orexin B affects spontaneous synaptic transmission in lamina II neurons, which play a pivotal role in regulating nociceptive transmission, by applying a whole-cell patch-clamp technique to lamina II neurons in adult rat spinal cord slices. In 66% of neurons tested, bath-applied orexin B concentration dependently produced an inward current at −70 mV and/or increased the frequency of glutamatergic spontaneous excitatory postsynaptic current (sEPSC) without changing its amplitude, in a manner resistant to the voltage-gated Na+-channel blocker tetrodotoxin (TTX). Glycinergic spontaneous inhibitory transmission was enhanced by orexin B in a TTX-sensitive manner in 71% of neurons examined, whereas GABAergic transmission was unaffected in the majority of these neurons. These activities were inhibited by an orexin-2 receptor antagonist (JNJ10397049) but not an orexin-1 receptor antagonist (SB334867). While the effects of orexin B in orexin B-sensitive neurons were mimicked by orexin A, another hypothalamic neuropeptide, oxytocin, produced an inward current but no increase in sEPSC frequency. These results indicate that orexin B produces membrane depolarization and/or increased spontaneous l-glutamate release in lamina II neurons by activating orexin-2 receptors, leading to increased excitability of these neurons. Such increases potentially produce an action potential, resulting in enhancement of glycinergic transmission in lamina II neurons. This activity of orexin B, and possibly orexin A, may contribute to its antinociceptive effects, which are partly shared by oxytocin.