Identification of the molecule required for transmission of IL-31–induced itch sensation in the spinal cord
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Abstract:
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous legions and intense itch. Itch can be induced by various chemical mediators. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator since the discovery of the pruritogenic action of IL-31 in mice. IL-31 is mainly produced by CD4+ T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the neuronal mechanism underlying IL-31–induced itch sensation is poorly understood. By analyzing a mouse model for atopic dermatitis, we found that the expression of Tac2, which encodes neurokinin B (NKB), markedly increased in the DRG neurons in response to IL-31. While NKB-deficient mice lost IL-31–induced itch response, scratching behaviors induced by other pruritogens such as histamine, chloroquine and protease-activated receptor 2 (PAR2) agonist were unaffected in the absence of NKB. NKB transmits the signal through neurokinin 3 receptor (NK3R), a G protein-coupled tachykinin receptor. When wild-type mice were pre-treated with NK3R antagonists, IL-31–induced scratching was significantly attenuated, without affecting itch responses induced by other pruritogens. These results indicate that NKB-NK3R axis could be a novel therapeutic target controlling IL-31–induced itch in AD patients.Keywords:
Neurokinin B
Scratching
Dorsal root ganglion
Neurokinin B
Tachykinin receptor
Tachykinin receptor 1
Neurokinin A
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Neurokinin B
Neurokinin A
Enteric Nervous System
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Neurokinin B
Tachykinin receptor
Eledoisin
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Neurokinin B
Neurokinin A
Tachykinin receptor
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Our experiments were conducted to determine whether substance P (SP) would elicit an itch sensation mediated by mast cells in mice. An intradermal injection of SP (10-135 microgram site-1) into the rostral back of the ICR mouse dose-dependently produced scratching of the injected site. The SP- (135 microgram site-1 = 100 nmol site-1) induced scratching was inhibited by capsaicin (repeated administration) and naloxone; features being similar to itch in humans. SP elicited scratching in mast cell-deficient (WBB6F1 W/Wv) mice as well as control (+/+) mice. Pretreatment with compound 48/80 produced similar degrees of inhibition of SP-induced scratching in mast cell-deficient mice as well as control +/+ and ICR mice. Intradermal injections of the NK1 receptor agonist GR73632 produced dose-dependent scratching, while the NK2 agonist GR64349 and the NK3 agonist senktide were without effects. SP-induced scratching was inhibited by the NK1 receptor antagonists spantide and L-668,169, but not by the NK2 antagonist L-659,877. The results suggest that scratching of the mouse induced by an i.d. injection of SP is itch-associated response. The SP action may be mediated at least partly by cutaneous NK1 receptors, and mast cells may not be key factors in SP-induced itching.
Scratching
NK1 receptor antagonist
Intradermal injection
Itching
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Substance P and selective neurokinin receptor agonists have been tested for their ability to induce shape change in rabbit platelets. Substance P and the NK1 receptor agonist Ac [Arg6,Sar9,Met(O2)11]-substance P (6-11) induced shape change (EC50 = 3 and 6 nM, respectively), whereas the selective NK2 agonist [Nle10]-Neurokinin A (4-10) and the selective NK3 agonist [MePhe7]-Neurokinin B did not show any effect. Moreover, the specific NK1 receptor antagonist CP-96,345 selectively and dose-dependently counteracted the effect of substance P or of the NK1 receptor agonist (IC50 = 2 and 0.8 nM, respectively), whereas the selective NK2 receptor antagonist, SR 48968, had no effect. Unlike for serotonin or low doses of ADP, epinephrine did not allow substance P or the NK1 receptor agonist to become a proaggregating substance. These data therefore show that the NK1 receptor is solely involved in the neurokinin-induced shape change of rabbit platelets.
Neurokinin B
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NK1 receptor antagonist
Tachykinin receptor
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Identification of the subtype of neurokinin receptor on the endothelium of the rabbit mesenteric artery was demonstrated by comparing the relative potencies of the naturally occurring tachykinins, substance P, neurokinin A and neurokinin B and the highly selective agonists [Glp 6 ,L‐Pro 9 ]SP 6–11 (L‐Pro), [Glp 6 ,D‐Pro 9 ]SP 6–11 (D‐Pro) and N‐succinyl‐[Asp 6 ,MePhe 8 ]SP 6–11 (senktide). Relaxations of the rabbit mesenteric artery to substance P, neurokinin A and neurokinin B were concentration‐dependent and were abolished by the removal of the endothelium. Substance P was more potent than neurokinin A or neurokinin B and L‐Pro was more potent than D‐Pro or senktide. Substance P, neurokinin A and neurokinin B all significantly reduced the nerve‐mediated contractile response in the presence of the endothelium at a concentration of 0.1 μ m , with a rank order of potency substance P > neurokinin A > neurokinin B. At a concentration of 0.1 μ m , L‐Pro also significantly reduced the nerve‐mediated contractile response, unlike D‐Pro and senktide. It is concluded that the relaxation of the rabbit mesenteric artery produced by substance P is mediated by neurokinin‐1 receptors (NK‐1) located on the endothelium. Furthermore, of the analogues, L‐Pro was particularly potent for these receptors.
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Neurokinin B
Tachykinin receptor
Tachykinin receptor 1
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Neurokinin B
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Tachykinin receptor
Eledoisin
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