Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord

Abstract It has been known that 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 Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.

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

10.1101/489831 ◽

2018 ◽

Cited By ~ 2

Author(s):

Rita Bardoni ◽

Devin M. Barry ◽

Hui Li ◽

Kai-Feng Shen ◽

Joseph Jeffry ◽

...

Keyword(s):

Neural Mechanisms ◽

Projection Neurons ◽

List Type ◽

Inhibitory Effects ◽

Spinal Neurons ◽

Chronic Itch ◽

Spinal Mechanism ◽

Itch Sensation ◽

Neurokinin 1

AbstractA 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 Aδ 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.HighlightsActivation of GRPR neurons evokes itch and is dependent upon NK1R activationGRPR neurons receive both direct and indirect inputs from C/Aδ fibersCounter-stimuli inhibit GRPR neurons via GABAergic signalingIncreased excitability of GRPR neurons in chronic itch condition

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The neurokinin-1 receptor is expressed with gastrin-releasing peptide receptor in spinal interneurons and modulates itch

10.1101/2020.07.14.199471 ◽

2020 ◽

Author(s):

Tayler D. Sheahan ◽

Charles A. Warwick ◽

Louis G. Fanien ◽

Sarah E. Ross

Keyword(s):

Dorsal Horn ◽

Projection Neurons ◽

Spinal Neurons ◽

Neurokinin 1 Receptor ◽

Peptide Receptor ◽

Gastrin Releasing Peptide ◽

Dorsal Horn Neurons ◽

Endogenous Expression ◽

Neurokinin 1

AbstractThe neurokinin-1 receptor (NK1R, encoded by Tacr1) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. Thus, we leveraged a newly developed Tacr1CreER mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of Tacr1CreER spinal neurons increases itch behavior, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization to characterize the endogenous expression of Tacr1 throughout the superficial and deeper dorsal horn, as well as the lateral spinal nucleus.Retrograde labeling studies from the parabrachial nucleus show that less than 20% of superficial Tacr1CreER dorsal horn neurons are spinal projection neurons, and thus the majority of Tacr1CreER are local interneurons. We then use a combination of in situ hybridization and ex vivo two-photon Ca2+ imaging of the spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn neurons. These findings are the first to describe a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry.

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