Biology subjects

Barry, D. M.

Publications and source records attributed to Barry, D. M..

3 recordsLinked to original sources

bioRxiv2021

BNP facilitates NMB-mediated histaminergic itch via NPRC-NMBR crosstalk

B-type natriuretic peptide (BNP) binds to its two cognate receptors NPRA and NPRC, encoded by Npr1 and Npr3, respectively, with equal potency and both are expressed in the spinal cord. Moreover, natriuretic peptides (NP) signal through the inhibitory cGMP pathway, raising the question of how BNP may transmit itch information. We report that Npr3 is highly restricted to laminae I-II of the dorsal horn, and partially overlaps with neuromedin B receptor (NMBR) that encodes histaminergic itch. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not gastrin releasing peptide (GRP) that encodes nonhistaminergic itch. Consistently, BNP evoked Ca2+ response in NMBR/NPRC HEK 293 cells and BNP-saporin that ablated both Npr1 and Npr3 neurons impaired histamine-, but not CQ-evoked, itch. These results reveal a previously unknown mechanism by which BNP changes its inhibitory mode of action to the facilitation of itch through a novel NPRC-NMBR cross-talk. Our studies suggest that neuropeptides encode histaminergic and nonhistaminergic itch not only through distinct modes but also in synergy.

neuroscience↗

bioRxiv2018

Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

A myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and A{delta} fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.\n\nHighlightsO_LIActivation of GRPR neurons evokes itch and is dependent upon NK1R activation\nC_LIO_LIGRPR neurons receive both direct and indirect inputs from C/A{delta} fibers\nC_LIO_LICounter-stimuli inhibit GRPR neurons via GABAergic signaling\nC_LIO_LIIncreased excitability of GRPR neurons in chronic itch condition\nC_LI

neuroscience↗

bioRxiv2018

Exploration of Sensory and Spinal Neurons Expressing GRP in Itch and Pain

Gastrin-releasing peptide (GRP) is a putative itch-specific neurotransmitter, but definite evidence in the dorsal root ganglion (DRG) and spinal cord is lacking. We generated and validated a Grp-Cre knock-in (GrpCre-KI) mouse line whereby Grp neurons are genetically labeled. Cre-dependent marking analysis revealed exclusive innervation of the upper epidermis of the skin by GRP fibers. Importantly, optical stimulation of Grp fibers expressing channel rhodopsin (ChR2) in the skin evoked itch but not pain-related scratching behaviors, while conditional deletion of Grp in sensory neurons attenuated non-histaminergic itch. In contrast, intersectional genetic ablation of spinal Grp neurons did not affect itch nor pain transmission. Our study demonstrates a role of GRP in sensory neurons in itch and suggests that GRP sensory neurons are dedicated to itch transmission. GrpCre-KI mice provide a long-sought avenue for investigating peripheral coding mechanism of itch and further interrogation of itch-nerve fibers in the skin under chronic pruritus.\n\nHighlightsO_LIValidated expression of a Grp-Cre knock-in line in sensory neurons that innervate the skin\nC_LIO_LIOpto-activation of Grp sensory neurons evokes itch behavior\nC_LIO_LIConditional deletion of Grp in sensory neurons reduces non-histaminergic itch behavior\nC_LIO_LIIntersectional ablation of Grp spinal neurons does not affect itch or pain behaviors\nC_LI

neuroscience↗