became anxiolytic in the Vogel conflict test and the social interaction test when co-administered with acetaminophen; the effect was blocked by the CB1 antagonist AM251. Small amounts of acetaminophen are also metabolized via the cytochrome P-450 pathway into N-acetyl-p-benzoquinone imine. Intrathecal administration of NAPQI activates TRPA1 and imparts antinociception in the mouse hot-plate test, and a similar action is found for D9-tetrahydrocannabiorcol. These effects are lost in Trpa1 mice. In summary, preclinical studies indicate that acetaminophen enhances the activity of eCBs and synthetic cannabinoids in rodents. Why acetaminophen fails to elicit cannabimimetic effects in humans is unknown. Acetaminophen-cannabinoid drug interactions may be species-specific; Gould et al. demonstrated strain-specific differences in mice. They suggested that other indirect actions of acetaminophen, including 5-HT receptor agonism, may outweigh any CB1 mediated effects in some mouse strains. Glucocorticoids. The distribution of glucocorticoid receptors and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoidmediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects. In a rat model of spinal nerve injury, the GR receptor agonist dexamethasone increased CB1 density after spinal nerve injury, which suggests that CB1 is a downstream target for GR actions. Glucocorticoid administration also induced CB1 expression in bone in mice and rats. The acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain. Electrophysiological studies of rat hypothalamic slices demonstrated that adding dexamethasone or corticosterone to slice baths caused a rapid suppression of synaptic activity, characterized as glucocorticoid-induced, eCB-mediated suppression of synaptic excitation. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19630521 GSE was blocked by CB1 antagonists, indicating that eCB release mediated GSE. A follow-up study demonstrated that GSE correlated with increased levels of AEA and 2-AG. The same group found no changes in AEA and 2-AG PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19632393 after exposure of cerebellar slices to dexamethasone. In hypothalamic slices, GSE could be blocked by leptin, suggesting that GSE is a nutritional state-sensitive mechanism. Dexamethasone enhanced order SB366791 eCBmediated GSE by inhibiting COX2 in dorsal raphe serotonin neurons. Corticosterone administration increased AEA levels in several rat limbic structures, but not the prefrontal cortex. 2-AG levels were only elevated in the hypothalamus. The same group conducted an ex vivo study of the rat medial prefrontal cortex. Bath application of corticosterone to mPFC slices suppressed GABA release onto principal neurons in the prelimbic region, which was prevented by application of the CB1 antagonist AM251. This indicates local recruitment of eCB signaling, probably through 2-AG. A previous study of rats receiving a single dose of corticosterone detected no change in 2-AG and a reduction of AEA in hippocampal homogenates. Corticosterone increased hippocampal levels of 2-AG in rats; the impairment of contextual fear memory by corticosterone was blocked by the CB1 antagonist AM251. Chronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus and mouse hippocampus and amygdala. Chronic corticosterone adm