LY-2828360

Cannabinoid CB₂ agonists show therapeutic efficacy without unwanted CB₁-mediated side effects. The G protein-biased CB₂ receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB₂ receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB₂ agonists. Anti-allodynic effects of structurally distinct CB₂ agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB₂^f/f mice and in mice lacking CB₂ receptors in CX3CR1 expressing microglia/macrophages (CX3CR1^CRE/+; CB₂^f/f), but were absent in mice lacking CB₂ receptors in peripheral sensory neurons (Advillin^CRE/+; CB₂^f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB₂^f/f and CX3CR1^CRE/+; CB₂^f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) Advillin^CRE/+; CB₂^f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB₂^f/f mice, but not Advillin^CRE/+; CB₂^f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB₂^f/f or CX3CR1^CRE/+; CB₂^f/f mice of either sex. Our findings have potential clinical implications.

Bisphenol S (BPS) exhibited inhibitory effects on androgen synthesis, but its target of action remains unclear. We investigated the effects of BPS exposure at environmentally relevant concentrations (1 μg/L, 10 μg/L and 100 μg/L) for 48 h on androgen synthesis in rat ovarian theca cells and explored the underlying mechanisms, target site and target molecule. The results showed that BPS exposure inhibited the transcript levels of steroidogenic genes and reduced the contents of androgen precursors, testosterone and dihydrotestosterone. BPS exposure decreased the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2), and the inhibitory effects of BPS on testosterone content and steroidogenic gene expression were blocked by ERK1/2 agonist LY2828360, suggesting that ERK1/2 signaling pathway mediates the inhibitory effects of BPS on androgen synthesis. BPS mainly accumulated on the cell membrane, impermeable BPS-bovine serum albumin exposure still inhibited androgen synthesis, BPS interacted with rat luteinizing hormone receptor (LHR) via formation of hydrogen bonds in the transmembrane region, and the inhibitory effects of BPS on ERK1/2 phosphorylation were blocked by luteinizing hormone (the natural agonist of LHR), indicating that LHR located on the cell membrane is the target of action of BPS. This paper provides a new elucidation of the mechanism of anti-androgenicity of BPS, especially for the non-genomic pathways.