Studies using cytokine ko mice to investigate pain behavior have given ample evidence for the algesic effect of pro-inflammatory cytokines: for instance, mice with an innate lack of IL-1 or IL6 display reduced pain behavior – either naive or after nerve injury. The investigation of the innate lack of anti-inflammatory cytokines and systems in pain development and maintenance has given complementary results: IL-10 deficiency is associated with enhanced pain behavior; the lack of the co-inhibitory molecule B7-H1 leads to mechanical hypersensitivity, increased pro-inflammatory cytokine gene expression and prolonged pain behavior after CCI. Here we show that naive IL-4 ko mice have tactile hypersensitivity. Having excluded innate differences in the expression of the other major pro- and anti-inflammatory cytokines in naive IL-4 ko mice, we consider it very likely that the lack of IL-4 and the tactile hypersensitivity are causally related. It is not surprising that IL-4 deficiency leads to tactile hypersensitivity and spares thermal sensitivity. Thermal and tactile sensations follow separate spinal pathways and can be affected separately. It is known that depending on modality and status pain behavior in cytokine ko mice is differentially controlled. For example, lesion of dorsal column neurons can selectively attenuate tactile allodynia. Why lack of IL-4 leads to mechanical allodynia in the naive animal is not clear yet. It is well known that pro-inflammatory cytokines like IL-1 or TNF can influence electrical excitability of nociceptive neurons. Few studies have investigated the potential role of IL-4 in cell excitability. In an early study IL-4 was shown to activate ion channels on B-lymphocytes. IL-4 also induces rapid and big increases in the activity of large-conductance, calcium-activated potassium channels in smooth muscle cells. IL-4 also affects the electrical properties of spinal neurons by modifying the function of ion currents. One possibility to explain mechanical allodynia in naive IL-4 ko mice might therefore be that IL-4 ko mice have a reduction in their central inhibitory neurotransmission. In pilot experiments the analysis of spinal single unit recordings gave first indications towards an increased firing frequency of lamina V sensory neurons in IL-4 ko mice upon stimulation with an innocuous von-Frey hair. Naive IL-4 ko mice are hypersensitive to mechanical stimulation and no further drop of the mechanical withdrawal thresholds is observed after CCI. This is mostly due to the fact that the mechanical withdrawal thresholds are already very low at baseline and a further reduction LEE011 citations exceeds the sensitivity of behavioral tests. The exclusive increase of pro- but especially anti-inflammatory cytokines in the ipsilateral spinal cord of IL-4 ko mice may also play a role. IL-4 and IL-10 expression can attenuate mechanical allodynia. The lack of IL-4 alone with obviously no compensatory change in cytokine expression, as in the naive mice, leads to the phenotype of tactile hypersensitivity.