The neurotransmitter serotonin, 5-hydroxytryptamine (5-HT), is a pleiotropic agent in the brain that has important roles in cognition. An important serotonin receptor in the brain, 5-HT2A, is also expressed in peripheral tissues; however, functional roles for serotonin signaling outside of the central nervous system are not well defined. In this issue, the article by Yu et al. shows that functionally selective activation of the 5-HT2A receptors in smooth muscle produces a profound suppression of tumor necrosis factor α (TNF-α)-mediated inflammatory responses. The authors examine the effect of a highly selective 5-HT2A agonist, (R)-DOI [(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane], in a well established model system for the study of inflammatory responses, primary cultures of rat aortic smooth muscles. It was found that (R)-DOI potently suppressed TNF-α-triggered expression of inflammatory markers, such as intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), interleukin-6 expression, nitric-oxide synthase activity, and nuclear factor-κB (NF-κB) nuclear translocation. The authors made two surprising discoveries. First, (R)-DOI blocks TNF-α effects with an IC50 of 10 to 20 pM. Second, it can do so when administered hours after TNF-α treatment. Such potency is unprecedented, and the observation of efficacy, even when administered after initiation of an inflammatory response, opens the door to possible treatments of numerous pathologies, such as atherosclerosis, rheumatoid arthritis, or Alzheimer's disease. The super potency of (R)-DOI is also an excellent example of selective, functional receptor activation. Although other agents with similar agonist affinity for 5-HT2A suppress TNF-α effects, they do not exhibit the potency of (R)-DOI. It is known that (R)-DOI preferentially activates the phospholipase-Cβ protein kinase C (PKC) axis as opposed to activation of phospholipase-A2, although the results also implicate participation of a nontraditional PKC. Thus, it remains to be seen whether the potent inflammatory effects seen here also involve nontraditional effector coupling of the G-protein-coupled 5-HT2A. Regardless, the study provides important insights into 5-HT2A function in the periphery while also opening the door to a new and exciting avenue for development of novel anti-inflammatory agents.
See article at J Pharmacol Exp Ther 2008, 327:316-323.
- The American Society for Pharmacology and Experimental Therapeutics