Modulation of synaptic transmission by nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the nociceptin/orphanin FQ receptor

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides d erived from the same precursor protein that exhibit opposing effects on spi nal neurotransmission and nociception. Here, we have used whole-cell, patch -clamp recordings from visually identified neurons in spinal cord dorsal ho rn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma -aminobutyric acid (GAB A)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppre ssed excitatory transmission in a concentration-dependent manner but left i nhibitory synaptic transmission unaffected. In contrast, NST reduced only i nhibitory but not alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R rece ptor-deficient (N/OFQ-R-/-) mice and significantly reduced in heterozygous (N/OFQ-R+/-) mice, whereas the action of NST on inhibitory neurotransmissio n was completely retained. To test for the relevance of these results for s pinal nociception, we investigated the effects of intrathecally injected N/ OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmo l/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R-/- mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmissi on and its spinal antinociceptive action are mediated via the N/OFQ recepto r, whereas the action of NST is independent of this receptor.