JUN 08, 2016 12:12 PM PDT

A New Class of Pain Relievers

WRITTEN BY: Cassidy Reich
Pain is a very important biological process because it tell us that something is wrong. There are a variety of types of pain and they all give us different pieces of information. The various pain sensors and pathways are what allow us to differentiate between pain from heat and pain from an abrasion. Just like pain is an important biological process, pain management is an important part of medicine and patient care. Painkillers can be very general in the molecular mechanisms of their analgesic effects and can have unfortunate off-target effects. Targeting the specific pain pathway for a particular type of pain holds a lot of promise as a drug development strategy.

In that vein, researchers at Duke University have recently published a study in Scientific Reports that details the efficacy of a novel small compound that targets not one, but two important pain receptors.

         Parent compound GSK205 and its derivatives. 16-8 is the lead compound from this library.
Transient receptor potential Vanilloid 4 (TRPV4) is an ion channel in the TRP family that has been heavily implicated in pain and inflammation. TRPV4 is widely expressed, but is particularly important in trigeminal (head and neck) pain due to its activity in the sensory neurons in the trigeminal and dorsal root ganglion. In addition to trigeminal pain, TRPV4 has been implicated in arthritis/osteoarthritis because of its involvement in cartilage maintenance.The pain and inflammation from pancreatitis has also been shown to rely on TRPV4 signaling. Treating pancreatitis is difficult and the condition is extremely painful, so more effective pain management is needed. Targeting TRPV4 would have clinical relevance for a number of conditions.

The researchers decided to target TRPV4 by rationally designing drugs based off the scaffold of a TRPV4-selective drug GSK205. GSK205 is not a very potent TRPV4 inhibitor so they were looking for a more effective compound. They tested their compounds in two in vivo models of different kinds of pain. The trigeminal formalin model was used to test the efficacy of the TRPV4 inhibitors on reducing general trigeminal pain. The caerulein-induced pancreatitis model is a model of visceral pain and inflammation. In particular, one of the compounds tested, designated as 16-8, was effective at reducing pain and inflammation in both in vivo models. 16-8 is also very potent, able to bind TRPV4 at sub-μM concentrations as determined by a heterologous cellular channel activity assay.

What is most interesting about this compound is that it also inhibits another TRP channel, TRPA1. TRPA1 has been implicated along with TRPV4 in pain and inflammation from pancreatitis and in trigeminal pain. These two channels are not exactly the same though. TRPA1 is associated more with pain and itch and TRPV4 is associated with skin irritation and head-neck pain. Co-involvement of TRPV4 and TRPA1 has been shown in so many conditions, such as nervous system disorders and degenerative or inflammatory musculoskeletal conditions.

16-8 is so unique because it inhibits both TRPV4 and TRPA1, targeting the synergistic pain and inflammation caused by these two channels. A dual-action drug like 16-8 could be approved for a lot of conditions in lots of different formulations and drug delivery systems. Transdermal formulation for skin application, intra-thecal administration for neurological conditions, intra-articular injections for arthritis, and so on. A drug like this has the potential to help a lot of people and be a blockbuster on the market.   

Sources: EurekAlert and Science Reports   
About the Author
Cassidy is a curious person, and her curiosity has led her to pursue a PhD in Pharmacology at the New York University Sackler Institute of Biomedical Sciences. She likes to talk about science way too much, so now she's going to try writing about it.
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