Liu X, Wang Y, Tao T, Zeng L, Wang D, Wen Y, Li Y, Zhao Z, Tao A (2021) GRPR/Extracellular Signal-Regulated Kinase and NPRA/Extracellular Signal-Regulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch. J Invest Dermatol 141(4):863-873. doi: 10.1016/j.jid.2020.09.008
Summary: This study investigates whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. Bombesin-SAP completely abolished ERK (extracellular signal-regulated kinase) activation. ERK was the most highly activated by their agonists BNP (Nppb, brain-derived natriuretic peptide) and octreotide. Nppb-SAP only partially reduced pERK in cervical spinal cord.
Liu X, Wang D, Wen Y, Zeng L, Li Y, Tao T, Zhao Z, Tao A. Spinal GRPR and NPRA Contribute to Chronic Itch in a Murine Model of Allergic Contact Dermatitis. (2020) J Invest Dermatol 140(9):1856-1866.e7. doi: 10.1016/j.jid.2020.01.016
Meng J, Chen W, & Wang J. Intervening B-Type Natriuretic Peptide Signaling for Controlling Chronic Itch. (2020) Brit J Pharmacol, 177(5):1025-1040. doi: 10.1111/bph.14952
Objective: Review of recent findings used to examine the role of B-type natriuretic peptide (BNP) in itch transduction and the modulation of other pururitic proteims.
Summary: Mice treated with Nppb-saporin, a toxin ablated 70% BNP receptor positive neurons in the spinal cord (Mishra & Hoon, 2013; Pitake, Ralph, DeBrecht & Mishra, 2018).
Tseng PY, Hoon MA (2020) Molecular Genetics of Kappa Opioids in Pain and Itch Sensations. Handb Exp Pharmacol. doi: 10.1007/164_2020_397
Summary: The authors review the functions of the kappa opioid receptor (KOR) and its endogenous agonists dynorphins in modulating itch and pain. Nppb-SAP ablation of neurons expressing the Natriuretic olypeptide B receptor greatly reduced itch responses evoked by histamine or by intrathecal administration of Nppb, suggesting that these neurons transmit itch signals from Nppb primary afferents. Also see: Mishra SK, Hoon MA (2013) The cells and circuitry for itch responses in mice. Science 340(6135):968-971. doi: 10.1126/science.1233765
Fatima M, Ren X, Pan H, Slade HFE, Asmar AJ, Xiong CM, Shi A, Xiong AE, Wang L, & Duan B. Spinal somatostatin-positive interneurons transmit chemical itch. (2019) PAIN, 160 (5):1166-1174. doi: 10.1097/j.pain.0000000000001499
Objective: To further study the cellular identity of spinal interneurons that contribute to itch processing.
Summary: Findings reveal a novel spinal mechanism for sensory encoding of itch perception.
Dose: Npra receptor–expressing spinal cord interneurons were ablated through intrathecal injection of Nppb-SAP (5 μg/10 μL) or control Blank-SAP in lumbar segment 3 to 4. Behavioral analyses were performed 1 week after the toxin injection.
Pan H, Fatima M, Li A, Lee H, Cai W, Horwitz L, Hor CC, Zaher N, Cin M, Slade H, Huang T, Xu XZS, Duan B. Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch. (2019) Neuron 103(6):1135-1149.e6. doi: 10.1016/j.neuron.2019.06.016
IT-40: Bombesin-SAP; IT-69: Nppb-SAP; IT-21: Blank-SAP
Objective: To identify a spinal circuit for mechanical and persistent spontaneous itch.
Summary: Findings indicate excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a valid cellular target for future therapeutic interventions against chronic itch, without affecting normal touch.
Dose: To ablate spinal GRPR+ neurons, mice were given a single intrathecal injection of either Bombesin-SAP or Blank-SAP (400 ng in 10 mL sterile saline). To ablate spinal Npra+ neurons, mice were given a single intrathecal injection of either Nppb-SAP or Blank-SAP (5 mg in 10 mL sterile saline).
Sakata D, Uruno T, Matsubara K, Andoh T, Yamamura K, Magoshi Y, Kunimura K, Kamikaseda Y, Furue M, & Fukui Y. Selective role of neurokinin B in IL-31–induced itch response in mice. (2019) J Allergy Clin Immunol, 144 (4):1130-1133. doi: 10.1016/j.jaci.2019.06.031
Objective: To examine the physiological significance of neurokinin B in IL-31–induced itch sensation.
Summary: IL-31–induced scratching was unaffected by intrathecal injection of Nppb-SAP. In contrast, treatment with Bombesin-SAP reduced IL-31–induced scratching. Neurokinin B acts upstream of GRP to transmit IL-31–induced itch sensation.
Dose: Intrathecal injection.
Huang J, Polgár E, Solinski HJ, Mishra SK, Tseng PY, Iwagaki N, Boyle KA, Dickie AC, Kriegbaum MC, Wildner H, Zeilhofer HU, Watanabe M, Riddell JS, Todd AJ, Hoon MA. (2018) Circuit dissection of the role of somatostatin in itch and pain Nat Neurosci 21(5):707-716. doi: 10.1038/s41593-018-0119-z
Objective: To determine the role of somatostatin in itch and pain.
Summary: Results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.
Dose: Ablation of Npr1- and GRPR-expressing spinal cord interneurons was accomplished by intrathecal (segment L3/4) injection of Nppb-SAP (4 μg/10 μL) and Bombesin-SAP (2.5 μg) respectively.
Meng QT, Liu XY, Liu XT, Barry DM, Jin H, Yang Q, Sun Y, Wan L, Jin JH, Munanairi A, Kim R, Yin J, Tao A, Chen ZF. (2018) Cross-Talk between Distinct Receptors Shapes Itch Behavior in the Spinal Cord. Neuron. doi: 10.2139/ssrn.3249822
Summary: Consistently, Nppb-SAP ablated spinal Npr1 and Npr3 neurons and impaired histamine-, but not CQ-evoked, itch. Thus, the findings identify the role of BNP-NPRC signaling in modulation of histamine-evoked itch via NPRC-NMBR cross-talk independent of GRP-GRPR signaling. Our studies reveal distinct modes of action for bombesin-related peptides and NP in itch transmission.
Pitake S, Ralph PC, DeBrecht J, & Mishra SK. Atopic Dermatitis Linked Cytokine Interleukin-31 Induced Itch Mediated via a Neuropeptide Natriuretic Polypeptide B. (2018). Acta Derm Venereol, 98 (8):795-796. 2018/05/26.
Objective: To determine if NPPB is involved as a neuropeptide in IL-31-mediated itch in atopic dermatitis (AD) via natriuretic polypeptide receptor A (NPRA) in the spinal cord.
Summary: This study reveals an important role of neuropeptide NPPB in AD that could provide a therapeutic target for alleviating chronic itch associated with AD.
Dose: To further demonstrate the IL-31-mediated itch response by NPRA receptors expressed in the spinal cord, Nppb-SAP (5 μg) was used to eliminate neurons expressing NPRA receptors in the spinal cord.
Mishra SK, Hoon MA. ( 2013 ) The cells and circuitry for itch responses in mice. Science 340(6135):968-971 . doi: 10.1126/science.1233765
Although previous work implicated neurons expressing the GRP (gastrin-releasing peptide) receptor were in the pruritic, or itch pathway, transgenic mice lacking natriuretic polypeptide b (Nppb) were almost completely insensitive to itch. Using the custom conjugate Nppb-SAP (Cat. #IT-69), the authors eliminated itch in response to a wide range of pruritic substances in normal mice through the administration of 5 μg of conjugate into the intrathecal space. Even after this lesion, the scratching response to intrathecal GRP was not changed, indicating that the role of GRP is at a later stage than previously hypothesized.