We identified a novel
neuropeptide and named it "
nocistatin." Its presence was expected by analysis of the precursor for the
neuropeptide nociceptin or
orphanin FQ (Noc/OFQ), previously identified as an endogenous
ligand for the orphan
opioid receptor-like receptor. The precursor
prepronociceptin/
orphanin FQ (ppNoc/OFQ) comprises at least two bioactive
peptides,
nocistatin and Noc/OFQ. Noc/OFQ is involved in a broad range of pharmacological actions in various tissues from the central nervous system to the periphery. In
pain transmission, Noc/OFQ is reported to have different effects including nociception, no effect, and
analgesia, depending on the animal species tested, doses, route of administration, and so on. We found that intrathecal administration of Noc/OFQ induced
pain responses including
allodynia and
hyperalgesia. Simultaneous administration of
nocistatin blocked the
allodynia and
hyperalgesia induced by Noc/OFQ, whereas anti-
nocistatin antibody decreased the threshold for the Noc/OFQ-induced
allodynia. The endogenous heptadecapeptide
nocistatin was isolated from bovine brains and recently identified in mouse, rat, and human brain and in human cerebrospinal fluid. Although human, rat and mouse ppNoc/OFQ produced larger respective counterparts with 30, 35, and 41
amino acid residues, all
peptides showed the antinociceptive activity. This activity was ascribed to the carboxyl-terminal hexapeptide of
nocistatin, Glu-Gln-Lys-Gln-Leu-Gln, which is conserved beyond species.
Nocistatin also attenuated the
allodynia and
hyperalgesia evoked by
prostaglandin E(2) and the inflammatory
hyperalgesia induced by
formalin or
carrageenan/
kaolin, and reversed the Noc/OFQ-induced inhibition of
morphine analgesia at picogram doses. Furthermore,
nocistatin counteracted the impairment of learning and memory induced by Noc/OFQ or
scopolamine.
Nocistatin is widely present in the spinal cord and brain. Although
nocistatin did not bind to the Noc/
OFQ receptor, it bound to the membrane of mouse brain and spinal cord with a high affinity.
Nocistatin is a novel bioactive
peptide produced from the same precursor as Noc/OFQ, and it plays important roles in the regulation of
pain transmission and learning and memory processes in the central nervous system.