title: Spinal Functions of B-Type Natriuretic Peptide, Gastrin-Releasing Peptide, and Their Cognate Receptors for Regulating Itch in Mice.
abstract: B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. Our results showed that intrathecal administration of BNP (0.3-3 nmol) dose dependently elicited scratching responses, which could be blocked by the NPRA antagonist (Arg6,β-cyclohexyl-Ala8,D-Tic16,Arg17,Cys18)-atrial natriuretic factor(6-18) amide (A71915). However, A71915 had no effect on intrathecal GRP-induced scratching. In contrast, pretreatment with a GRPR antagonist (D-Tpi6,Leu13ψ(CH2-NH)-Leu14)bombesin(6-14) (RC-3095) inhibited BNP-induced scratching. Immunostaining revealed that NPRA proteins colocalize with GRP, but not GRPR, in the superficial area of dorsal horn, whereas BNP proteins do not colocalize with either GRP or GRPR in the dorsal horn. Intradermal administration of ligands including endothelin-1, U-46619, bovine adrenal medulla 8-22, and Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL) increased scratching bouts at different levels of magnitude. Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that: 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord, and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch.
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Norikazu
authors.initials: N
authors.lastname: Kiguchi
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Devki D
authors.initials: DD
authors.lastname: Sukhtankar
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Huiping
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.).
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Peters
authors.affiliation: Department of Physiology and Pharmacology (N.K., D.D.S., H.D., M.-C.K.) and Department of Anesthesiology (C.M.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology and Pharmacology, Saitama Prefectural University, Saitama, Japan (K.T.); Department of Pharmacology, Wakayama Medical University, Wakayama, Japan (S.K.) mko@wakehealth.edu.
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology / Q000627:therapeutic use; D001839:Bombesin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D020097:Natriuretic Peptide, Brain / Q000037:antagonists & inhibitors / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011537:Pruritus / Q000188:drug therapy / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010446:Peptide Fragments; D018004:Receptors, Bombesin; D044005:Tetrahydroisoquinolines; C058930:brain natriuretic peptide receptor; D020097:Natriuretic Peptide, Brain; C078792:A 71915; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; D001839:Bombesin