Itch(pruritus)is a common intractable symptom of several skin diseases,such as atopic dermatitis and xerosis,and other systemic liver and kidney diseases.Toll-like receptors(TLRs)are well-known for mediating innate immunity by recognition of exogenous pathogen-associated molecular patterns(PAMPs) and endogenous danger-associated molecular patterns(DAMP).Recently,we have demonstrated TLRs,such as TLR3 and TLR7,are also expressed in primary sensory neurons located in dorsal root ganglia and mediate acute and/or chronic itch in mice,emphasizing unexpected functions for neuronal TLRs in peripheral and central nerve system.In this study,we further examined the role of TLR4 in itch and pain in mice.We found that spontaneous scratching behavior in an experimental dry skin model was substantially decreased in Tlr4-/-mice.In contract,acute scratching behavior induced by histamine and chloroquine was not affected in Tlr4-/-mice.In addition,touch-evoked scratching behavior under acute and chronic itch condition was also reduced in Tlr4-/-mice.Intrathecal injection of TLR4 antagonist lipopolysaccharide,derived from Rhodobacter sphaeroides(LPS-RS),had no effects on acute itch,but significantly reduced dry skin-induced chronic itch in mice.Interestingly,intrathecal injection of TLR4 agonist lipopolysaccharide (LPS)suppressed acute itch,but significantly increased dry skin-induced chronic itch.Furthermore,acute nociceptive pain,including mechanical and thermal pain was not affected in Tlr4-/-mice,whereas formalin-induced second-phase spontaneous pain was reduced in Tlr4-/-mice.Our findings demonstrate critical role of TLR4 in regulating itch and pain in mice and targeting TLR4 receptor may provide novel anti-itch or anti-pain strategy.