Nocistatin, a peptide that blocks nociceptin action in pain transmission

Abstract

Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). The neuropeptide nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid-like receptor which induces both hyperalgesia and allodynia when administered by injection through the theca of the spinal cord into the subarachnoid space (that is, intrathecally). Here we show that the nociceptin precursor contains another biologically active peptide which we call nocistatin. Nocistatin blocks nociceptin-induced allodynia and hyperalgesia, and attenuates pain evoked by prostaglandin E2. It is the carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln), which is conserved in bovine, human and murine species, that possesses allodynia-blocking activity. We have also isolated endogenous nocistatin from bovine brain. Furthermore, intrathecal pretreatment with anti-nocistatin antibody decreases the threshold for nociceptin-induced allodynia. Although nocistatin does not bind to the nociceptin receptor, it binds to the membrane of mouse brain and of spinal cord with high affinity. Our results show that nocistatin is a new biologically active peptide produced from the same precursor as nociceptin and indicate that these two peptides may play opposite roles in pain transmission.

Central injections of nocistatin or its C‐terminal hexapeptide exert anxiogenic‐like effect on behaviour of mice in the plus‐maze test

“…NST for reversal of the antagonism of morphine-induced analgesia by N/OFQ in the rat is also bell-shaped (Zhao et al, 1999), as is that for the allodynic e ect of i.t. N/OFQ in mice (Okuda-Ashitaka et al, 1998). Bell-shaped curves have also been reported for anxiolytic-like e ects of i.c.v.…”

“…The distribution of NOP receptor mRNA or receptor-like binding sites in the brain appears to be somewhat more widespread than that of ppN/OFQ mRNA or of N/OFQ, but also encompasses the septum, hippocampus and amygdala (Neal et al, 1999b). On the other hand, there are as yet no reports on the relative distribution of NST binding sites throughout the brain, although selective binding of bovine NST has been demonstrated to occur in membranes obtained from mouse brain and spinal cord (Okuda-Ashitaka et al 1998).…”

“…To the best of our knowledge, the binding sites/receptors underlying the actions of the heptadecapeptide nociceptin II have not yet been identi®ed. NST, on the other hand, has been shown to associate with speci®c binding sites in membranes from mouse brain and spinal chord which are clearly distinct from the NOP receptors (Okuda-Ashitaka et al, 1998). The length of NST varies considerably among species (comprising 17, 30, 35 and 41 amino-acid residues in oxen, humans, rats and mice, respectively), but the last six residues of the C-terminal are fully conserved in all variants .…”

“…The length of NST varies considerably among species (comprising 17, 30, 35 and 41 amino-acid residues in oxen, humans, rats and mice, respectively), but the last six residues of the C-terminal are fully conserved in all variants . Importantly in this regard, synthetic NST C-terminal hexapeptide (NST-C6) has been shown to retain the biological agonistic activity of full-length bovine NST (Okuda-Ashitaka et al, 1998).…”

“…Interestingly, although the other ppN/OFQ-derived peptide, NST, does not bind to the NOP receptor, it seems to act as a functional antagonist of N/OFQ. Indeed, several biological e ects of N/OFQ are antagonized by NST, such as nociception in various experimental conditions (Martin et al, 1998;Okuda-Ashitaka et al, 1998;Yamamoto & Sakashita, 1999;Nakano et al, 2000), morphine analgesia (Zhao et al, 1999), N/OFQ impairing e ects on learning/memory (Hiramatsu & Inoue, 1999), food intake (Olszewski et al, 2000) and glutamate release (Nicol et al, 1998). Jenck et al (1997) have described anxiolytic-like e ects of i.c.v.…”