An Intra-brainstem Circuit for Pain-induced Inhibition of Itch
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Abstract
Pain and itch are unpleasant and distinct sensations that give rise to behaviors such as reflexive withdrawal and scratching in humans and mice. Interestingly, it has been observed that pain modulate itch through the neural circuits housed in the brain and spinal cord. However, we are yet to fully understand the identities of and mechanisms by which specific neural circuits mediate pain-induced modulation of itch. Independent studies indicate that brainstem nuclei such as the lateral parabrachial nucleus (LPBN) and rostral ventromedial medulla (RVM) are important for the suppression of itch by painful stimuli. Here, using mouse and viral genetics, rabies tracing, chemogenetics, and calcium imaging, we show that the synaptic connections between LPBN and RVM plays an instrumental role in the interactions between pain and itch. Notably, we found that the LPBN neurons that express the gene encoding the substance P receptor, Tacr1 (LPBN Tacr1 ), synapse onto Tacr1-expressing RVM neurons (RVM Tacr1 ). The RVM Tacr1 neurons were found to be nociceptive, sufficient for inhibiting itch, and necessary for pain-induced itch suppression. Moreover, through brain-wide anterograde and retrograde viral tracing studies, we found that the RVM Tacr1 neurons are bidirectionally connected with LPBN, periaqueductal gray (PAG), and lateral hypothalamic area (LHA). Thus, together, our data indicate that the RVM Tacr1 neurons integrate nociceptive information to mediate itch-induced scratching and can mediate the physiological effects of itch through their downstream targets.
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are sufficient to suppress itch
Another reader left a similar comment above, but I wonder if you've considered trying other pruritogens besides chloroquine? Chloroquine is often used to model non-histaminergic itch, but (of course) histaminergic itch is also important, and accounts for a large proportion of itch signaling.
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Hind leg-directed scratching of the nape was characterized as a scratch.
It would be helpful to readers to clarify whether individual scratches were quantified by observers or detected automatically, i.e. more experimental details, please!
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n=7
Clarify in figure that n = mouse number?
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we found that the PSD95-tagRFP and Syn-GFP were closely apposed (Fig. 3G&H), indicating that synaptic connections exist between the RVM and LPBN Tacr1 expressing neurons.
I think some zoomed in images from Fig 3H showing the apposed puncta would really help convince readers that these are indeed closely apposed. In addition, adding a quantifiable metric for distance between the puncta would be very helpful.
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intra-plantar AITC suppressed chloroquine-induced itch
Likely outside the scope of the current study, but it would be interesting to see whether any aspect of this described circuit is specifically dependent on chloroquine-induced itch, or whether administration of other pruritogens would have differing outcomes.
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As predicted, activation of the PBNGrpr neurons (Nagai et al., 2020) (Fig. 1D) suppressed chloroquine-induced scratching behavior in mice, similar to when PBNTacr1 neurons were stimulated.
Do you have DCZ-only and saline controls in animals with an AAV-mCherry control virus?
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We observed the expression of grpr and tacr1 mRNA in the external-lateral part of the LPBN (Fig. 1A top center and right). grpr and tacr1 expressing neurons partially overlapped (Fig. 1A bottom middle).
I'd be interested to see a quantification of this overlap of both populations.
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Thus, a molecularly defined intra-brainstem circuit between the LPBN and the RVM plays a pivotal role in pain modulation of itch.
Very exciting finding!
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Minor point, but I believe this comma should be removed for meaning. Otherwise, the main findings are differently stated than what the data show.
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