In addition at the spinal level

In addition, at the spinal level, results from colocalization experiments demonstrate that GABA-C receptors are present in the substantia gelatinosa and that they are presynaptically located. Neurons located in the substantia gelatinosa are differentially activated by afferent noxious and non-noxious stimuli such that the latter controls onward information flow through PAD mechanisms [35]. Modulation of PAD can have significant implications for analgesia. For instance, it has been established that opiates and related compounds, act at least in part by potentiating PAD [35], [37]. Ablation of α2-GABA-A receptors not only reverses the modulation of PAD by diazepam but also its spinal anti-hyperalgesic affects in a model of inflammatory pain [44], further strengthening the observation that effects of diazepam are largely due to its facilitatory action on presynaptic inhibition [42]. Similarly, blockade of GABA-ergic inhibition in the spinal cord produces hyperalgesia and tactile allodynia [20], [31], [40]. Alternatively, strategies such as targeted FPH1 to specifically enhance GABA-ergic inhibition in the spinal dorsal horn have been successful in alleviating neuropathic pain associated with spinal cord injury [19]. The presence of GABA-C receptors in this system could add a greater flexibility to pain modulation via PAD. While they may act independently or in conjunction with GABA-A receptors, targeting GABA-C receptors offers specific therapeutic advantages. For instance, GABA-C receptors exhibit a ten-fold increased sensitivity to GABA [1]. They desensitize less rapidly and have longer mean open times, in addition to a smaller Cl− conductance, compared to GABA-A receptors [11], [12], [15]. These characteristics are particularly useful since GABA-C receptor- mediated GABA-ergic inhibition can be achieved at levels of GABA that are too low for the activation of GABA-A receptors. Novel centrally acting anti-nociceptive agents can, therefore, be developed without any potentially unwanted side-effects associated with drugs acting on GABA-A receptors.
Acknowledgements
Introduction Formation of structure and function of the brain is genetically programmed but also modified by environmental factors during development. Maternal separation is widely used as an animal model to study the mechanism underlying the relationship between early-life environmental factors and the development of brain and behaviors. Prolonged maternal separation for 3 or more hours per day during the first two postnatal weeks has been found to produce increased anxiety and depression-like behaviors, and exaggerated hypothalamic-pituitary-adrenal (HPA)-axis response to stress in adulthood (Levine, 2000; Meaney, 2001; Pryce and Feldon, 2003). In contrast, postnatal handling (brief maternal separation) is a manipulation that briefly (3–15 min) separates rat or mouse pups from their mother daily during the postnatal period (e.g. postnatal day 1 (P1)-P10 or P1-P21) (Levine et al., 1956, 1962; Plotsky and Meaney, 1993; Fenoglio et al., 2005). Many studies have reported that postnatal handling has beneficial effects on the offspring behavior. For example, postnatal handling lowers anxiety levels in mice (Moles et al., 2004) and rats (Vallée et al., 1997; Caldji et al., 2000) and improves spatial learning and memory in mice (Zaharia et al., 1996; Anisman et al., 1998) and rats (Vallée et al., 1999; Fenoglio et al., 2005), although the effects on anxiety-like behavior and spatial learning and memory are not necessarily consistent between mice and rats and even among different mouse strains (Zaharia et al., 1996; Millstein and Holmes, 2007). Therefore, we first confirmed effects of the postnatal handling on the offspring behavior under our experimental paradigm. The brain mechanisms which mediate effects of postnatal handling on adult behavior have been studied focusing on glucocorticoids in the HPA axis, but other potential mechanisms of molecular regulation have been less investigated (Raineki et al., 2014). In the present study, to clarify the brain mechanisms, we focused on some molecules which may link postnatal handling during development and behaviors of the adult offspring.