The pain of PIP2

A team from The University of North Carolina at Chapel Hill has shown that phosphatidylinositol-4-phosphate 5-kinase type 1g regulates signaling by diverse pain receptors and has identified a small molecule antagonist that targets it.¹ Although the compound alleviates chronic pain in multiple mouse models, the lethality of homozygous mutations of the kinase in mice and humans highlights the need for repeat-dosing studies to better characterize the safety of the approach.

Pain is triggered by the action of specialized sensory neurons known as nociceptors, which are found in skin, muscle and other tissues and are activated by noxious stimuli, including excess heat, chemical stress or physical stress.² Nociceptors detect these inputs by expressing proteins that transmit a signal from the site of the insult to the CNS, causing pain. For example, the nociceptor-expressed ion channel TRPV1 (transient receptor potential vanilloid 1; VR1) is activated by temperature or chemical stresses, triggering a signaling cascade that leads to the sensation of pain...