The myriad pain pathophysiology has intrigued and challenged humanity for centuries. In this regard, the traditional pain therapies such as opioids and nonsteroidal anti-inflammatory drugs have been highly successful in treating acute and chronic pain. However, their drawback includes adverse events such as psychotropic effects, addiction potential, and gastrointestinal toxicities, to mention a few. These factors combined with the likelihood of an increase in chronic pain conditions due to an aging population calls for the development of novel mechanism-based or "site-specific" agents to target novel pain pathways. In this regard, rapid progress has been made in understanding the molecular mechanisms of novel pain targets such as cannabinoid receptors, fatty acid hydrolase, voltage-gated and ligand-gated ion channels such as P2 receptors, transient receptor potential channels and glial cell modulators. Accordingly, preclinical studies indicate that the site-specific/selective agents exhibit sufficient efficacy and reduced side effects such as lack of psychotropic effects indicating their clinical potential. This review provides a brief summary of some "at-site" pain targets and their role in the pain pathophysiology, and describes the efforts in developing some small molecules as novel pain therapeutics.
Keywords: P2X receptors; cannabinoid receptors; glial cells; nonsteroidal anti-inflammatory drugs; opioids; transient receptor potential channels.