Processing of pain and itch information by modality-specific neurons within the anterior cingulate cortex in mice

Hyoung-Gon Ko 1,2 ,HyunsuJung 3,4,9, Seunghyo Han1,9, Dong Il Choi4,9,
Chiwoo Lee4,9, Ja Eun Choi4,JihaeOh4,ChuljungKwak3,DaeHeeHan3,
Jun-Nyeong Kim1,SanghyunYe 4,JiahLee4,JaehyunLee4,KyungminLee 5,
Jae-Hyung Lee 6,MinZhuo7,8 & Bong-Kiun Kaang3,

Pain and itch are aversive sensations with distinct qualities, processed in
overlapping pathways and brain regions, including the anterior cingulate
cortex (ACC), which is critical for their affective dimensions. However, the
cellular mechanisms underlying their processing in the ACC remain unclear.
Here, we identify modality-specific neuronal populations in layer II/III of the
ACC in mice involved in pain and itch processing. Using a synapse labeling
tool, we show that pain- and itch-related neurons selectively receive synaptic
inputs from mediodorsal thalamic neurons activated by pain and itch stimuli,
respectively. Chemogenetic inhibition of these neurons reduced pruriception
ornociception without affecting the opposite modality. Conversely, activation
of these neurons did not enhance stimulus-specific responses but commonly
increased freezing-like behavior. These findings reveal that the processing of
itch and pain information in the ACC involves activity-dependent and
modality-specific neuronal populations, and that functionally distinct ACC neuronal subsets process pain and itch

Neuronal substance P-driven MRGPRX2-dependent mast cell degranulation products differentially promote vascular permeability

 https://doi.org/10.3389/fimmu.2024.1477072

Cell. 2024 Oct 24:S0092-8674(24)01149-8.

 doi: 10.1016/j.cell.2024.10.001. Online ahead of print.

Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch

Jun Yang ¹, Tianjun Zhao ², Junping Fan ³, Huaibin Zou ⁴, Guangyi Lan ⁵, Fusheng Guo ¹, Yaocheng Shi ³, Han Ke ³, Huasheng Yu ⁶, Zongwei Yue ¹, Xin Wang ⁷, Yingjie Bai ⁷, Shuai Li ⁸, Yingjun Liu ⁸, Xiaoming Wang ⁸, Yu Chen ⁹, Yulong Li ¹⁰, Xiaoguang Lei ¹¹

• PMID: 39476841
• DOI: 10.1016/j.cell.2024.10.001

Abstract

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

Keywords: 3-sulfonated bile acids; MRGPRX4; OCA; bile acids; cholestatic pruritus; cryo-EM structure; deoxycholic acid; farnesoid X receptor; liver diseases; non-alcoholic steatohepatitis.