Cellular mechanisms for antinociception produced by hypothalamus–derived neuropeptides in the rat spinal superficial dorsal horn —oxytocin and orexins actions

Abstract

There is much evidence showing that a group of neuropeptides produced in the hypo thalamus, oxytocin and orexins, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to reveal cellular mechanisms underlying this antinociception, we examined how oxytocin, orexins A and B affect spontaneous synaptic transmission in rat spinal lamina II (substantia gelatinosa; SG) neurons, which play a pivotal role in regulating nociceptive transmission. The experiments were performed by applying the blind whole–cell patch–clamp technique to SG neurons in adult rat spinal cord slices. Bath–applied oxytocin unaffected glutamatergic spontaneous excitatory transmission while producing an inward current at − 70 mV (membrane depolarization) and enhancing both GABAergic and glycinergic spontaneous inhibitory transmissions in > 70 % of the neurons tested. The depolarization, and increased GABAergic and glycinergic spontaneous inhibitory postsynaptic current (sIPSC) frequencies were concentration–dependent with half–maximal effective concentration (EC 50 ) values of 0 . 022 , 0 . 024 and 0 . 038 µM, respectively. On the other hand, orexins A and B produced an inward current at − 70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current (sEPSC) without changing its amplitude in some 70 % of the neurons examined. EC 50 values for orexin A in their effects were 0 . 0045 and 0 . 030 µM, respectively; those for orexin B were 0 . 020 and 0 . 039 µM, respectively. EC 50 value for orexin B in producing inward current was similar to that of oxytocin nist (SB 334867 ) but not an orexin– 2 receptor antagonist (JNJ 10397049 ) while orexin B activities were inhibited by JNJ 10397049 but not SB 334867 , indicating that orexins A and B activities are mediated by orexin– 1 and – 2 receptors, respectively. It is concluded that oxytocin, orexins A and B increase neuronal activity through membrane depolari zation and/or increased L –glutamate release from nerve terminals, by activating their specific receptors, which in turn results in GABAergic and/or glycinergic spontaneous inhibitory transmission enhancements, a possible mechanism for antinociception.