Identification of a convergent spinal neuron population that encodes itch
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Abstract
Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca 2+ imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca 2+ oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.
In brief
Through population imaging, Sheahan et al. identify a network of neurons in the dorsal horn that is activated by pruritogens and find that kappa opioid receptor signaling inhibits itch through the selective inhibition of GRPR spinoparabrachial neurons.
Highlights
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Itch-inducing agents drive activity in a common population of GRPR-expressing spinal interneurons
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GRPR spinal projection neurons transmit itch from the spinal cord to the brain
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Kappa opioids reduce itch through the inhibition of GRPR spinoparabrachial neurons
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GRPR activation elicits persistent, intrinsic Ca 2+ oscillations
Article activity feed
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cell-intrinsic
I agree that this interpretation makes sense, but the test with TTX might also mean that non-neuronal cells are playing a role in maintaining oscillatory activity, as they can do in the CNS. The pharmacological inhibition of intracellular calcium you use would also block these widely-described mechanisms in astrocytes, for example.
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3minutes gave rise to repeated Ca2+ transients that lasted at least 20 minutes
Did you try application of GRP for shorter than 3 minutes, and if so, did you see less of a persistent response?
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and identify GRPR itch neurons as the primary excitatory cell-type that responds tocompound 48/80.
Similar to the comment above, would you expect to see similar results with a pruritogen other than 48/40, in particular one that does not involve histaminergic itch?
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We found that the total overlap of GRPR:NK1R:SSTR-dspopulation was significantly larger than predicted if the populations were independent (Figures2E and 2F). Dramatic enrichment was also observed in GRPR:NK1R and GRPR-SSTR-dspopulations
Could you use the amount of activity in each cell type, i.e. a few GCaMP spikes vs ongoing oscillations, to enrich this analysis beyond a binary response vs non-response? For example, are more active cells to one peptide more or less likely to be activated by other peptides?
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Figure 2. Diverse itch-causing peptides engage a convergent spinal neuron population
Minor note that "theoretical" is misspelled in panels D and E
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Notably, the order of peptide application didnot influence the response profiles that we observed,
What a cool finding and nice control!
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3000 excitatory neurons, 16%(553/3367 neurons
I see the n's in the legend for Fig. 2, but for clarity, I would recommend putting the n's in the manuscript text for mouse and slice number.
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Given its widespread nature, it is likely that this neural activity was due to acombination of GRPR neurons responding directly to GRP as well as neurons that are activateddownstream of GRPR neuron activity.
Overall, this paper consists of an elegantly structured set of experiments which are technically challenging and really timely. Thank you for the exciting work! One question here: is it possible here to use a blocker of synaptic transmission (but not spiking) to isolate direct vs indirect responses? Similarly, would widespread activation of neurons via high K+ and sucrose allow you to see what proportion of cells are activatable at all in your prep, to better estimate the denominator of these percentages that you present?
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n other words, there appears to be a subset of GRPR neurons that are activated by multiple itch-inducing compounds, which we refer to here as GRPR itch neurons
Have you considered testing an algogen alongside pruritogens to confirm that these neurons are specific to itch?
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