Lipid kinases as therapeutic targets for chronic pain

Abstract

Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long-term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability [98; 28]. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, focus has shifted towards targeting downstream convergence points of nociceptive signaling [98]. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets as these molecules are required for signaling downstream of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Furthermore, PIP2 regulates the activity of various ion channels [80]. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons.

Targeting AMPK for the Alleviation of Pathological Pain

“…For instance, AMPK is a core regulator of phospholipid biosynthesis and metabolism, but this aspect of AMPK function has been almost entirely ignored in the context of neuronal excitability. This area of investigation offers great opportunity for new discovery because it is well known that lipids are key regulators of channel, G-protein coupled receptor, and kinase function in nociceptors (Piomelli et al 2014; Loo et al 2015) and other neurons. Here, we propose that basic cell biology studies on the role of AMPK in neuronal excitability can greatly enhance our understanding of the target and how it can be manipulated to achieve effects that are relevant for pain therapeutics.…”

Conditional deletion of Pip5k1c in sensory ganglia and effects on nociception and inflammatory sensitization

“…Phosphatidylinositol 4,5-bisphosphate, also known as PI(4,5)P 2 or PIP 2 , has important roles in cell signaling and is immediately downstream of many pronociceptive signaling pathways, despite only accounting for 0.5% to 1% of the phospholipid molecules in cells. 6 , 7 Type 1 phosphotidylinositol 4-phosphate 5-kinases (PIP5KIs) synthesize PIP 2 by phosphorylating the large pools of phosphatidylinositol 4-phosphate in cells. There are three Pip5k1 genes, two of which are ubiquitously expressed ( Pip5k1a and Pip5k1b ), while the third (phosphatidylinositol 4-phosphate 5-kinase type 1 gamma, Pip5k1c ) is expressed predominantly in neuronal tissues.…”

“…There are three Pip5k1 genes, two of which are ubiquitously expressed ( Pip5k1a and Pip5k1b ), while the third (phosphatidylinositol 4-phosphate 5-kinase type 1 gamma, Pip5k1c ) is expressed predominantly in neuronal tissues. 6 , 8 , 9 We previously found that global heterozygous deletion of Pip5k1c reduced PIP 2 in dorsal root ganglia (DRG) and reduced pain signaling and inflammatory sensitization. 10 While these studies suggested that it might be possible to reduce pronociceptive signaling by selectively inhibiting a lipid kinase that generates PIP 2 in DRG neurons, whether the decrease observed in pain behavior was due to a reduction in the enzyme expression specifically in sensory neurons or globally throughout the nervous system was unresolved.…”

Human EAG channels are directly modulated by PIP2 as revealed by electrophysiological and optical interference investigations

“…Acting as a multifunctional molecule, PIP 2 plays pivotal roles in normal and pathological cellular functions 18 19 20 . For instance, PIP 2 is implicated in cell proliferation and neurological diseases 21 22 23 . Consequently, the lipid kinases including phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol-4-phosphate 5-kinases (PIP5KIs) responsible for PIP 2 synthesis are considered to be potential therapeutic targets for various disorders involving altered neuronal excitability such as chronic pain 19 22 24 25 26 .…”

“…For instance, PIP 2 is implicated in cell proliferation and neurological diseases 21 22 23 . Consequently, the lipid kinases including phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol-4-phosphate 5-kinases (PIP5KIs) responsible for PIP 2 synthesis are considered to be potential therapeutic targets for various disorders involving altered neuronal excitability such as chronic pain 19 22 24 25 26 . In addition, the degradation of PIP 2 is subject to dynamic regulation by many important neuronal transmitters via G protein-coupled receptor (GPCR)-induced phospholipase C (PLC) activation, which in turn affects many important downstream targets including a wide array of ion channels 19 27 28 .…”