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.

Prostaglandin (PG) D 2 is the most abundant prostanoid produced in the central nervous system of mammals and has been implicated in the modulation of neural functions such as sleep induction, nociception, regulation of body temperature, and odor responses. We generated geneknockout mice for lipocalin-type PGD 2 synthase (L-PGDS) and found that the intrathecal administration of PGE 2 , an endogenous pain-producing substance, failed to elicit allodynia (touch-evoked pain), which is one typical phenomenon of neuropathic pain, whereas it evoked thermal hyperalgesia, in L-PGDS؊͞؊ mice. We also found that the allodynic response induced by the ␥-aminobutyric acid (GABA) A receptor antagonist bicuculline was selectively abolished in the L-PGDS؊͞؊ mice, among excitatory and inhibitory agents that induced allodynia in wild-type mice. Interestingly, simultaneous injection of a femtogram amount of PGD 2 with PGE 2 or bicuculline induced allodynia in L-PGDS؊͞؊ mice to the same extent as in wild-type mice. The PGE 2 -or bicucullineevoked allodynia in wild-type and in PGD 2 -supplemented L-PGDS؊͞؊ mice was blocked by a PGD 2 receptor antagonist given in a femtogram amount. These results reveal that endogenous PGD 2 is essential for both PGE 2 -and bicucullineinduced allodynia.Prostaglandin (PG) D 2 is the major prostanoid produced in the central nervous system (CNS) of mammals (1, 2) and has been shown to be involved in a variety of central actions, e.g., it induces sleep, decreases body temperature, and modulates odor and pain responses (3-5). Among the three enzymes catalyzing the conversion of PGH 2 to PGD 2 (6, 7), lipocalintype PGD synthase (L-PGDS) is considered to be responsible for the biosynthesis of PGD 2 in the CNS. L-PGDS is present mainly in the leptomeninges, choroid plexus, and oligodendrocytes of the CNS (8, 9), and is secreted into the cerebrospinal fluid to become ␤-trace (10, 11), a major protein component of the cerebrospinal fluid (12-14). The receptor for PGD 2 , the D type of PG (DP) receptor (15, 16), also is localized in the leptomeninges of the brain (17, 18). Therefore, PGD 2 is assumed to be produced in the membranous tissues and oligodendrocytes of the CNS; to circulate through the cerebrospinal fluid in the ventricular system, subarachnoidal space, and extracellular space in the CNS; to interact with DP receptors in the meninges; and to act as a neurohormone or an informational substance for global regulation of various CNS functions (5).Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). In relation to clinically relevant hyperalgesic states, such as inflammation and neuropathic pain, there is considerable interest in the neurochemical mechanisms of hyperalgesia and allodynia (19-21). Since Vane (22) reported that aspirin-like drugs prevented the development of inflammation by blocking the synthesis of PGs, it has been widely accepted that PGs are involved in inflammation an...

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