chronic itch , which is defined as itch lasting more than 6 weeks , is a prevalent problem that occurs in ~10% of the population ( mollanazar et al . , 2015 ) . chronic itch conditions negatively affect quality of life , and yet there are no therapies that are both efficacious and selective for itch . the lack of effective treatment is partly attributable to a poor understanding of the mechanisms that underlie it . although antihistamines are frequently prescribed as a treatment for itch , they are typically ineffective because most types of chronic itch are not histamine - mediated ( mollanazar et al . , 2015 ) . unfortunately , while there are numerous mediators that can cause itch , the factors that are responsible in most circumstances of chronic itch are largely unknown . human psychophysical studies have shown that application of serotonin into the skin causes itch ( weisshaar et al . , 2004 ) . in rodents , serotonin is a key component of mast cells , and it is a potent mediator of itch . however , until recently , the mechanisms through which serotonin causes itch have remained uncertain . many pruritogens bind to metabotropic receptors on primary sensory neurons ; however , these receptors must be coupled to ionotropic channels via intracellular signaling pathways in order to allow sufficient current influx to generate action potentials . several groups have shown that the cation channels trpv1 and trpa1 are coupled to different pruritogen receptors and that they are critical for different forms of itch transmission ( ross , 2011 ) . more specifically , trpv1 is required for histaminergic itch , whereas trpa1 is required for several types of non - histaminergic itch , such as that induced by chloroquine , bam8 - 22 , il-31 , endothelin-1 , thymic stromal lymphopoietin , and bile acids . until recently , whether serotonin receptors were likewise coupled to trps remained unknown . understanding serotonin - mediated itch has been complicated by the fact that there are numerous serotonin receptors that are expressed on primary afferents , as well as on immune mediators that could be involved in itch . it was previously hypothesized that the primary pathway through which serotonin causes itch is via stimulation of histamine release from mast cells . however , contrary to this idea , antihistamines failed to reduce serotonin - induced itch sensation in humans ( hosogi et al . , 2006 ) . a recent study has demonstrated that one way in which serotonin induces itch is via direct activation of 5-ht7 ( encoded by htr7 ) , which is expressed on subsets of primary sensory afferents ( morita et al . , 2015 ) . in this study , mice lacking either htr7 or trpa1 showed substantially reduced scratching behavior in response to an intradermal injection of a 5-ht7-selective agonist . furthermore , htr7 and trpa1 knockout mice scratched considerably less in a model of atopic dermatitis . however , it seemed likely that this was only part of the serotonin - itch story , because the 5-ht2-selective agonist , -methyl-5ht , is a potent pruritogen in mice . as reported in this issue of jid , the study by carstens and colleagues ( 2015 ) provides further insight into the molecular players involved in serotonin - evoked itch by defining a trpv4-dependent pathway that is likely to be downstream of 5-ht2-mediated itch . the original goal of this study was to investigate a possible role for trpv4 in itch . trpv4 is upregulated in the skin of individuals with certain itch conditions ( moore et al . , 2013 ; yang et al . , 2015 interestingly , trpv4 knockout mice displayed a significant reduction in scratching behavior in response to serotonin , but not to histamine , chloroquine , or sligrl ( akiyama et al . a trpv4 antagonist also reduced substantially the amount of serotonin - evoked scratching , supporting the idea that trpv4 is critical to serotonin signaling in normal mice . importantly , the authors showed that the change in response to serotonin in the trpv4 knockout mice was specifically a decrease in serotonin - evoked itch behaviors , and not a change in serotonin - evoked pain behaviors . this study demonstrates that trpv4 is a key downstream component of serotonin - evoked itch ( figure 1 ) . in order to link serotonin to trpv4 and the activation of sensory neurons serotonin - mediated activation was dependent on trpv4 , as a trpv4 antagonist reduced significantly the calcium response to the application of serotonin . in support of this finding , the authors demonstrated that the proportion of neurons that responded to serotonin was reduced significantly in trpv4 knockout mice . interestingly , the proportion of neurons responding to other types of pruritogens did not change in mice lacking trpv4 , indicating that trpv4 plays an important and specific role in responses to serotonin in primary sensory neurons . to identify the receptor through which serotonin acts , akiyama et al . the 5-ht2 antagonist , but not the 5-ht1 antagonist , reduced serotonin - evoked scratching . this finding raises the possibility that 5-ht2 , acting via trpv4 , is key mediator of serotonin - evoked itch . thus , there appear to be at least two distinct pathways through which serotonin mediates itch : a trpa1-dependant pathway that mediates 5-ht7-mediated itch , as well as a trpv4-dependent pathway that likely mediates 5-ht2-mediated itch . what remains to be tested is whether these receptors are expressed on distinct or overlapping populations of primary sensory afferents .
previous studies have revealed that trpv1 and trpa1 function downstream of many itch receptors , where they mediate inward current to trigger action potentials in primary afferents . although other trp channels , such as trpv4 , are expressed in primary afferents , whether or not they play an analogous role in itch was previously unknown . 
 now , akiyama et al . 
 provide evidence that trpv4 is a key mediator of serotonin - induced itch . 
 this finding is important because it uncovers an unanticipated role for trpv4 in itch , thereby identifying a novel therapeutic target .