Pain and itch are aversive sensations, eliciting distinct defense responses to ward off external threats. Specifically, pain triggers a withdrawal reflex to avert additional harm, while itch incites a scratching response to rid the skin surface of irritants. These two sensations have traditionally been viewed as antagonistically controlled phenomena, with pain inhibiting itch and, conversely, itch being provoked by pain suppression [1].

The underlying neural mechanisms of these pain-itch interactions have been explored, with significant findings revealing their operation at the spinal cord level. However, despite the progress made at the spinal cord level, minimal research exists thus far regarding the involvement of supraspinal regions in the neural processing of these interactions [2].

The present study utilized optogenetic techniques combined with an acute itch and pain model to reveal that orexin-producing neurons (orexin neurons) in the lateral hypothalamus suppress pain while promoting itch. This demonstrates that these neurons control the two sensations in opposite directions.

Orexin neurons have been known to project from the hypothalamus to various brain regions, forming neural circuits and serving diverse functions. Our research also reveals that the neural circuit of orexin neurons projecting from the hypothalamus to the periaqueductal gray is crucial for the opposing control of itch and pain, using optogenetic terminal inhibition techniques.

Furthermore, experiments using chronic itch model mice, which reflect pathological pruritus observed in clinical settings, revealed that orexin neurons also contribute to worsening chronic itch conditions. This suggests that hypothalamic orexin neurons could be a new target for developing treatments for chronic itch.

Our results shed light on the neural control mechanisms responsible for the mysterious interaction where itch and pain mutually cancel each other out, answering why these sensations behave as they do.

The findings from our research are expected to lead to new perspectives in developing analgesic and antipruritic drugs.

[1] M. Schmelz, Itch and pain, Neurosci. Biobehav. Rev. 34 (2010) 171–176, https:// doi.org/10.1016/j.neubiorev.2008.12.004.

[2] Kaneko, T. & Kuwaki, T. The opposite roles of orexin neurons in pain and itch neural processing. Peptides 160, 170928 (2023).