Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. Here, we report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states and that this is independent from its effect on mood. Indeed, FKBP51 knock out mice but also mice with silencing of FKBP51 restricted to the spinal cord showed reduced hypersensitivity in a number of persistent pain models. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the specific FKBP51 inhibitor SAFit2 intrathecally administered reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knock out mice. This suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. In conclusion, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long term pain states. *To whom correspondence should be addressed: ucgasmg@ucl.ac.uk. Author contributions: SMG and MM designed the experiments, analyzed the data and wrote the manuscript. MM conducted all the behavioral experiments. MM and SMG conducted the RTqPCR and the glucocorticoid experiments. SG, MM and KKT conducted the immunohistochemical experiments. SMG and LVA conducted the DNA methylation studies. CGB designed the primers for the DNA methylation study. MBC provided the FKBP5 KO mice. FX and FH provided SAFit2.

Exposure to moderate levels of ethanol during brain development has a number of effects on social behavior but the molecular mechanisms that mediate this are not well understood. Gaining a better understanding of these factors may help to develop therapeutic interventions in the future. Zebrafish offer a potentially useful model in this regard. Here, we introduce a zebrafish model of moderate prenatal ethanol exposure. Embryos were exposed to 20mM ethanol for seven days (48hpf-9dpf) and tested as adults for individual social behavior and shoaling. We also tested their basal anxiety with the novel tank diving test. We found that the ethanol-exposed fish displayed reductions in social approach and shoaling, and an increase in anxiety in the novel tank test. These behavioral differences corresponded to differences in hrt1aa, slc6a4 and oxtr expression. Namely, acute ethanol caused a spike in oxtr and ht1aa mRNA expression, which was followed by down-regulation at 7dpf, and an up-regulation in slc6a4 at 72hpf. This study confirms the utility of zebrafish as a model system for studying the molecular basis of developmental ethanol exposure. Furthermore, it proposes a putative developmental mechanism characterized by ethanol-induced OT inhibition leading to suppression of 5-HT and up-regulation of 5-HT1A, which leads, in turn, to possible homeostatic up-regulation of 5-HTT at 72hpf and subsequent imbalance of the 5-HT system.