Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice

Abstract

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...

Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes

“…We elected to employ a knockin approach, as PGDS heterozygous knockout mice are viable with no obvious phenotype (Eguchi et al, 1999). A nuclear-targeted Cre recombinase gene was integrated into the PGDS coding region by replacing exon 1 of the murine Pdgs gene (Supplementary Figures S2 and S3).…”

Prostaglandin D2 DP1 receptor is beneficial in ischemic stroke and in acute exicitotoxicity in young and old mice

“…In peripheral tissues, PGD 2 executes a wide range of functions, including vasodilatation, inhibition of platelet aggregation, glycogenolysis, vasoconstriction, allergic reaction mediation, and intraocular pressure reduction (Whittle et al 1983;Narumiya and Toda 1985;Casteleijn et al 1988;Sturzebecher et al 1989;Darius et al 1994;Matsugi et al 1995;Matsuoka et al 2000;Angeli et al 2004). In the brain, PGD 2 has been shown to contribute to sleep induction, modulation of body temperature, olfactory function, hormone release, nociception, and neuromodulation (Eguchi et al 1999;Urade and Hayaishi 1999;Mizoguchi et al 2001;Hayaishi 2002;Hayaishi and Urade 2002;Gelir et al 2005).…”

Anti-tumor effects of prostaglandin D2 and its metabolites, 15-deoxy-Δ12, 14-PGJ2, by peroxisome proliferator-activated receptor (PPAR) γ-dependent and -independent pathways.

“…Prostaglandin D 2 and its metabolite, 15-deoxy-∆ 12, 14 -PGJ 2 Prostaglandins (PGs) are autacoids synthesized from 20 carbon-containing polyunsaturated fatty acids, principally arachidonic acid (AA) generated from membrane phospholipids by phospholipase A 2 (PLA 2 ). Prostaglandin H 2 (PGH 2 ) is a common precursor of each PG and produced from AA by the cyclooxygenase-1 and -2 (COX-1, COX-2), then converted to the major active prostanoids such as PGD 2 , PGE 2 , PGF 2α , PGI 2 , and thromboxane Α 2 (TXA 2 ), by PGD 2 synthase (PGDS), PGE 2 synthase (PGES), PGI 2 synthase (PGIS) and TXA 2 synthase (TXAS), respectively.…”

“…Two kinds of PGDS, such as lipocalin (L-) and hematopoietic (H-) PGDS, are known. L-PGDS is a brain enzyme and its product, PGD 2 , is the most potent somnogenic substance so far known and is involved in various physiological events, such as regulation of sleep and pain responses 1,2) . In contrast, H-PGDS is a splenetic enzyme and is expressed in antigen-presenting dendritic cells as well as in mast cells of various organs 3) .…”

“…Prostaglandin H 2 (PGH 2 ) is a common precursor of each PG and produced from AA by the cyclooxygenase-1 and -2 (COX-1, COX-2), then converted to the major active prostanoids such as PGD 2 , PGE 2 , PGF 2α , PGI 2 , and thromboxane Α 2 (TXA 2 ), by PGD 2 synthase (PGDS), PGE 2 synthase (PGES), PGI 2 synthase (PGIS) and TXA 2 synthase (TXAS), respectively. Two kinds of PGDS, such as lipocalin (L-) and hematopoietic (H-) PGDS, are known.…”