“
“GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-alpha 2 and -alpha 3 receptor function within the spinal cord. As yet, a lack of clinically LXH254 cell line suitable tool compounds has prevented this concept being tested in humans.

Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary mechanical hypersensitivity. The subtype-selective PAM NS11394 (0.3-10 mg/kg), and the non-selective PAM diazepam (1-5 mg/kg) variously reduced capsaicin-induced secondary mechanical hypersensitivity (180 min post-injection). However, the low efficacy subtype-selective PAM TPA023 (3-30 mg/kg) was completely ineffective. This was surprising as both NS11394 and TPA023 robustly selleck chemicals llc attenuated late phase (6-30 min post-injection) capsaicin-induced flinching, a pain-like behaviour that is putatively driven by peripheral and central sensitizing mechanisms. Diazepam also attenuated capsaicin-induced nocifensive behaviours, albeit at doses

previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human volunteer studies. (C) 2012 Elsevier Ltd. All rights reserved.”
“Background. Adverse childhood experiences have been described as one of the major environmental risk factors for depressive disorder. Similarly, the deleterious impact of early traumatic experiences on depression seems to be moderated by individual genetic variability. Serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) modulate the effect of childhood adversity on adult depression, although inconsistencies across studies have been found. Moreover,

the gene x environment (G x E) interaction concerning the different types of childhood adversity remains poorly understood. The aim of this study was to analyse the putative SN-38 supplier interaction between the 5-HTT gene (5-HTTLPR polymorphism), the BDNF gene (Val66Met polymorphism) and childhood adversity in accounting for adult depressive symptoms.

Method. A sample of 534 healthy individuals filled in self-report questionnaires of depressive symptomatology [the Symptom Check List 90 Revised (SCL-90-R)] and different types of childhood adversities [the Childhood Trauma Questionnaire (CTQ)]. The 5-HTTLPR polymorphism (5-HTT gene) and the Val66Met polymorphism (BDNF gene) were genotyped in the whole sample.

Results. Total childhood adversity (beta=0.27, p<0.001), childhood sexual abuse (CSA; beta=0.17, p<0.001), childhood emotional abuse (beta=0.