Selective suppression of inhibitory synaptic transmission by nocistatin inthe rat spinal cord dorsal horn

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identi fied neuropeptides with opposing effects on several CNS functions, includin g spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters L-glutam ate, glycine, and GABA in the superficial layers of the rat spinal cord hor n, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter releas e from inhibitory interneurons via a presynaptic Bordetella pertussis toxin -sensitive mechanism but left excitatory glutamatergic transmission unaffec ted. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinoci ceptive activity, NST induced profound hyperalgesia after intrathecal appli cation. Similar to glycine and GABAA receptor antagonists, NST had no signi ficant effects in the rat tail-flick test, a model of acute thermal pain. O ur results provide a cellular basis for the antagonism of N/OFQ and NST and suggest the existence of a so far unidentified membrane receptor for NST. In addition, they support a role of NST as an endogenous inhibitor of glyci nergic and GABAergic neurotransmission in the sensory part of the spinal co rd and as a mediator of spinal hyperalgesia.