The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature.

Expression and function of histamine H4R in central and peripheral nervous system have been a matter of controversy for more than a decade. The scientific discussion is often limited to a few publications postulating the presence of functional H4R on neurons of the central and peripheral nervous system, but the even larger number of reports showing negative data is often neglected. In this article, we critically review the existing literature on H4R in central and peripheral nervous system and discuss the weak points often overlooked by the community. We identified as most important problems (i) insufficient validation or quality of antibodies, (ii) missing knockout controls, (iii) uncritical interpretation of RT-PCR results instead of qPCR experiments, (iv) insufficient controls to confirm specificity of pharmacological tools, (v) uncritical reliance on results produced by a single method and (vi) uncritical reliance on results not reproduced by independent research groups. Additionally, there may be a publication as well as a citation bias favoring the awareness of positive results, but neglecting negative data. We conclude that H4R expression on neurons of the brain is not convincingly supported by the current literature, at least as long as the positive data are not reproduced by independent research groups. Expression and function of H4R on peripheral neurons or non-neuronal cells of the nervous system, specifically on microglia is an interesting alternative hypothesis that, however, requires further verification. This article is part of a Special Issue entitled 'Histamine Receptors'.