PPARs also may affect pain sensations by modulating glucocorticoid action. Glucocorticoids are steroid hormones released during periods of acute or sustained stress, both physiological and psychological, and signal via the GR (glucocorticoid receptor), another nuclear receptor. Glucocorticoids can pass the blood–brain/spinal barrier and excess levels are detrimental to neuronal survival in the brain, inducing synaptic loss, atrophy of the hippocampus and cognitive deficits. In the CNS, glucocorticoid signaling enhances pain-like behaviors and is up-regulated in parallel with inflammatory cytokines after injury (Blackburn-Munro and Blackburn-Munro, 2003). PPARγ activation inhibits the autonomic and neuroendocrine responses to stress in rats and may explain why activation of this receptor reduces circulating corticosterone levels (Ryan et al., 2012). A 5-day treatment with rosiglitazone attenuates corticosterone levels, heart rate, and expression of c-Fos (a marker of neuronal activation) in the hypothalamus of rats that were subjected to restraint stress (Ryan et al., 2012). Rosiglitazone also decreased circulating corticosterone levels in a mouse model of Alzheimer's disease (Escribano et al., 2009). While the mechanisms through which PPARs attenuate corticosterone remain to be fully elucidated, PPARα activation does
