Cannabidiol Does Not Impair Anabolic Signaling Following Eccentric Contractions in Rats.

Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD (p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p < .001) and tended to be higher in the CBD group (p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.

Molecular dynamics simulations of dihydro-ß-erythroidine bound to the human α4ß2 nicotinic acetylcholine receptor.

BACKGROUND AND PURPOSE: The heteromeric α4ß2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state. EXPERIMENTAL APPROACH: The competitive antagonist dihydro-ß-erythroidine (DHßE) was modelled by replacement of the agonist nicotine in the α4ß2 nAChR experimental structure. DHßE is used both in vitro and in vivo for its ability to block α4ß2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 µs. Electrophysiological studies of mutated receptors were performed to validate the simulation results. KEY RESULTS: The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state. CONCLUSIONS AND IMPLICATIONS: Our model suggests that the side chains of α4 L257 (9') and α4 L264 (16') are the main constrictions in the transmembrane pore. The involvement of position 9' in channel gating is well established, but position 16' was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation. The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.