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.
Wang Z, Jiang C, Yao H, Chen O, Rahman S, Gu Y, Zhao J, Huh Y, Ji RR (2021) Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain 144(2):665-681. doi: 10.1093/brain/awaa430
Summary: Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal administration. Notably, morphine-elicited itch was suppressed by intrathecal administration of NPY and abolished by spinal ablation of GRPR+ neurons with intrathecal injection of Bombesin-SAP.
Dose: For ablation of GRPR+ neurons, mice were given an intrathecal injection of 400 ng Bombesin-SAP or Blank-SAP (control) 10 days before behavioral testing.
Barry DM, Liu XT, Liu B, Liu XY, Gao F, Zeng X, Liu J, Yang Q, Wilhelm S, Yin J, Tao A, Chen ZF. Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors. (2020) Nat Commun 11(1):1397. doi: 10.1038/s41467-020-15230-y
Objective: To determine the role of GRP in sensory neurons.
Summary: GRP is a neuropeptide in sensory neurons for nonhistaminergic itch, and GRP sensory neurons are dedicated to itch transmission.
Dose: Bombesin-SAP (200 ng/5 μL, i.t.) was injected 2 weeks prior to optical stimulation.
Kiguchi N, Uta D, Ding H, Uchida H, Saika F, Matsuzaki S, Fukazawa Y, Abe M, Sakimura K, Ko MC, Kishioka S. GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn. (2020) Neuropharmacology 170:108025. doi: 10.1016/j.neuropharm.2020.108025
Objective: To investigate the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH).
Summary: These findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP–GRPR and the glutamate–AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.
Dose: Bombesin-SAP and Control Blank-SAP were administered i.t. (5 μg/5 μl).
Liu X, Miao XH, Liu T. More than Scratching the Surface: Recent Progress in Brain Mechanisms Underlying Itch and Scratch. (2020) Neurosci Bull 36(1):85-88. doi: 10.1007/s12264-019-00352-1 (Review)
Acton D, Ren X, DiCostanzo S, Dalet A, Bourane S, Bertocchi I, Eva C, Goulding M. Spinal Neuropeptide Y1 Receptor-Expressing Neurons Form an Essential Excitatory Pathway for Mechanical Itch. (2019) Cell Reports, 28 (3):625-639.e6 . doi: 10.1016/j.celrep.2019.06.033
Objective: To determine the central pathway for mechanical itch.
Summary: NPY-Y1 signaling regulates the transmission of innocuous tactile information by establishing biologically relevant thresholds for touch discrimination and mechanical itch reflexes. neither the evoked nor spontaneous scratching seen following activation of Y1Cre neurons was affected by ablation of the GRPR+ neurons. NK1R+ neuron ablation failed to modulate mechanically evoked itch.
Dose: P28 mice were given a single intrathecal (i.t.) injection of either Bombesin-SAP (400 ng in 5 mL 0.9% sterile saline) to ablate GRPR+ cells or SSP-SAP to ablate NK1r+ neurons (100 ng in 5 mL 0.9% sterile saline). Littermate controls received Blank-SAP (equal mass in 5 mL 0.9% sterile saline).
Gao ZR, Chen WZ, Liu MZ, Chen XJ, Wan L, Zhang XY, Yuan L, Lin JK, Wang M, Zhou L, Xu XH, Sun YG. Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation (2019) Neuron 101(1):45-59.e9. doi: 10.1016/j.neuron.2018.11.010
Objective: To determine the neural mechanism promoting the itch-scratching cycle.
Summary: Ablation of Tac1+ but not SST+ neurons decreases itch-induced scratching behavior. l/vlPAG Tac1+ neurons Induce Scratching Behavior via a Descending Pathway.
Dose: To ablate the spinal GRPR+ neurons, mice were intrathecally injected with Bombesin-SAP or Control Blank-SAP (400 ng/5 mL).
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.
REVIEW: Barry DM, Munanairi A, & Chen Z-F. Spinal Mechanisms of Itch Transmission. (2018). Neurosci Bulletin, 34 (1):156-164.
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. Circuit dissection of the role of somatostatin in itch and pain (2018) 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.
Mu D, Sun YG. (2017) Itch Induces Conditioned Place Aversion in Mice. Neurosci Lett 658:91-96. PMID: 28842279
Yu YQ, Barry DM, Hao Y, Liu XT, Chen ZF. (2017) Molecular and Neural Basis of Contagious Itch Behavior in Mice. Science 355(6329):1072-76. PMID: 28280205 (read summary)
Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, Krasnow MA, Feldman JL. (2016) The peptidergic control circuit for sighing. Nature 530(7590):293-297. PMID: 26855425 (Targeting Trends 16q2)
Akiyama T, Nguyen T, Curtis E, Nishida K, Devireddy J, Delahanty J, Carstens MI, Carstens E. (2015) A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156(7):1240-1246. (Targeting Trends 15q3)
Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. (2015) Gate Control of Mechanical Itch By a Subpopulation of Spinal Cord Interneurons. Science 350(6260):550-54. PMID: 26516282 (Targeting Trends 17q1)
Akiyama T, Tominaga M, Takamori K, Carstens MI, Carstens E. (2014) Role of spinal bombesin-responsive neurons in nonhistaminergic itch. J Neurophysiol 112(9):2283-2289. (Targeting Trends 15q1)
Zhao ZQ, Wan L, Liu XY, Huo FQ, Li H, Barry DM, Krieger S, Kim S, Liu ZC, Xu J, Rogers BE, Li YQ, Chen ZF. (2014) Cross-Inhibition of NMBR and GRPR Signaling Maintains Normal Histaminergic Itch Transmission. J Neurosci 34(37):12402-12414. (Targeting Trends 14q4)
Sasaki A, Adhikari S, Andoh T, Kuraishi Y. (2013) BB2 bombesin receptor-expressing spinal neurons transmit herpes-associated itch by BB2 receptor-independent signaling. Neuroreport 24(12):652-656. (Targeting Trends 13q3)
Han N, Zu JY, Chai J. (2012) Spinal bombesin-recognized neurones mediate more nonhistaminergic than histaminergic sensation of itch in mice. Clin Exp Dermatol 37(3):290-295. (Targeting Trends 12q2)
Mishra SK, Holzman S, Hoon MA. (2012) A nociceptive signaling role for neuromedin B. J Neurosci 32(25):8686-8695. (Targeting Trends 12q4)
Jeffry J, Kim S, Chen ZF. (2011) Itch signaling in the nervous system. Physiology (Bethesda) 26(4):286-292. (Targeting Trends 11q4)
Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF. (2011) Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids. Cell 147(2):447-458. (Targeting Trends 12q1)
Chen Z-F, Sun Y-G, Zhao Z-Q, Meng X-L, Yin J, Liu X-Y. (2009) Ablation of GRPR+ Neurons in the Spinal Cord by Bombesin-Saporin Knocks Out Itch Sensation in Mice Without Affecting Pain Circuit. Targeting Trends 10(4).
Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular Basis of Itch Sensation. Science 325:1531-1534. (Targeting Trends 09q4)