Pain and itch are unpleasant sensations that often accompany infections caused by viral,bacterial,parasitic,and fungal pathogens.Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch.Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns,including Toll-like receptor ligands,N-formyl peptides,and bacterial toxins.Other pathogens are able to silence neuronal activity to produce analgesia during infection.Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future patho gen exposure.Conversely,pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts.Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of hostmicrobe interactions.

Peripheral inflammation is always accompanied by a noxious sensation,either pain or itch,pro-viding a protective warning for the occurrence of pathological changes;however,the mechanisms determining whether pain,itch,or both will be elicited under certain inflammatory statuses are still far from clear.Complete Freund's adjuvant(CFA)contains heat killed and dried Mycobacterium tuberculosis widely used to induce inflammatory pain models,but how CFA treatment affects itch sensation and the possible mechanisms are still unclear.In this study,using itch behavior testing and calcium imaging,we showed that both the behaviors and calcium responses associ-ated with Transient Receptor Potential Vanilloid 1(TRPV1)-mediated histamine-dependent itch and Transient Receptor Potential Ankyrin 1(TRPA1)-mediated histamine-independent itch were signif-icantly suppressed by CFA treatment.Furthermore,to explore the possible cellular mechanisms,high-throughput single-cell RNA sequencing and real-time PCR were used to detect CFA-induced changes of itch-related genes in dorsal root ganglion(DRG)neurons.Our results revealed that although both nociceptive Trpv1+and Trpa1+DRG neurons were increased after CFA treatment,most known pruriceptors,including Hrh1+,Mrgpra3+,Mrgprd+,Htr3a+,Htr1f+,IL31ra+,Osmr+,and Lpar3+DRG neurons,were significantly decreased,which may explain that CFA treatment caused itch suppression.This study indicated that itch sensation was affected after CFA treatment,although negatively,and comprehensive but not specific suppression of different pruriceptors was observed after CFA treatment,suggesting that a unified adaptive change of increased pain and decreased itch will occur simultaneously under CFA-induced inflammatory conditions.