Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways

Background and purpose: Sensory nerves regulate central and local reflexes such as airway plasma protein leakage, bronchoconstriction and cough. Sensory nerve activity may be enhanced during inflammation such that these protective effects become exacerbated and deleterious. Cannabinoids are known to inhibit airway sensory nerve function. However, there is still controversy surrounding which receptor is involved in eliciting these effects. Experimental approach: We have adopted a pharmacological approach, including using a novel, more selective CB(2) receptor agonist, GW 833972A (1000-fold selective CB(2)/CB(1)), and receptor selective antagonists to investigate the inhibitory activity of cannabinoids on sensory nerve activity in vitro and in vivo in guinea-pig models of cough and plasma extravasation. Key results: Depolarization of human and guinea-pig isolated vagus nerves in vitro induced by capsaicin was inhibited by GW 833972A. This compound also inhibited the depolarization of guinea-pig vagus by hypertonic saline or prostaglandin (PG)E(2). In vivo, GW 833972A inhibited citric acid-induced cough in guinea-pigs but not plasma extravasation, and this effect was blocked by a CB(2) receptor antagonist. Conclusions and implications: This confirms and extends previous studies highlighting the role of CB(2) receptors in the modulation of sensory nerve activity elicited both by the exogenous ligands capsaicin and hypertonic saline but also by endogenous modulators such as PGE(2) and low pH stimuli. These data establish the CB(2) receptor as an interesting target for the treatment of chronic cough.