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Jul 10, 2014
 |  BC Innovations  |  Targets & Mechanisms

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.

Although distinct receptors are responsible for detecting different stimuli, a common feature of nociception is that inflammation or injury can sensitize cells to these inputs. Indeed, most non-opioid drugs that are approved to treat pain rely on blocking inflammatory signaling rather than acting on any individual receptor.

A UNC team led by Mark Zylka and Jian Jin set out to identify and target additional pathways that could broadly modulate the activity of pain receptors.

Zylka told SciBX, "Tissue injury causes the release of diverse molecules that activate receptors on sensory neurons and cause pain. Given this molecular diversity, efforts to treat pain by blocking individual receptors have failed."

Zylka is an associate professor of cell biology and physiology at UNC, and Jin is associate director of medicinal chemistry in the Center for Integrative Chemical Biology and Drug Discovery...

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