Editors' ChoiceNeuroscience

Treating Chronic Pain

Sci. Signal.  03 Jun 2014:
Vol. 7, Issue 328, pp. ec147
DOI: 10.1126/scisignal.2005541

Low-abundance lipids, such as phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], can function as regulating molecules and can influence the activity of various plasma membrane proteins, which includes inhibiting some channels involved in responding to painful stimuli and activating others, such as the heat-sensitive ion channel receptor TRPV1. PI(4,5)P2 is generated by lipid kinases, including type 1 phosphatidylinositol 4-phosphate 5-kinases (PIP5K1). Wright et al. found that when the activity of a specific PIP5K1 in dorsal root ganglion (DRG) neurons was limited, mice exhibited a reduction in sensitivity to stimuli that can cause chronic pain. At both the mRNA and protein level, PIP5K1C was the most abundant PIP5K1 in DRGs. Although homozygous deficiency of PIP5K1C (PIP5K1C–/–) in mice or humans results in death soon after birth, haploinsufficient (PIP5K1C+/–) mice and humans are apparently normal except for high-frequency hearing loss in mice. The abundance of PI(4,5)P2 was decreased in DRG neurons, but not the brain or spinal cord, from embryonic or adult PIP5K1C+/– mice compared with its abundance in the these tissues of wild-type mice. The increase in intracellular calcium (an indication of neuronal activation) triggered by chemicals that stimulate neuropathic or inflammatory pain was decreased in cultured DRGs from PIP5K1C+/– mice, but calcium signals were restored to those seen in wild-type mouse DRGs by exogenous application of PI(4,5)P2. When these chemicals were injected into the hind paw, PIP5K1C+/– mice spent less time licking their hind paws compared with wild-type mice, but the PIP5K1C+/– mice did not exhibit motor deficits or impaired response to innocuous mechanical touch. Likewise, calcium signals induced by a high concentration of capsaicin, which activates TRPV1 and evokes burning sensations and allodynia (pain to normally nonpainful stimuli), were reduced in cultured DRGs from PIP5K1C+/– mice but were restored by exogenous PI(4,5)P2. PIP5K1C+/– mice had increased tolerance to heat compared with wild-type mice and had decreased sensitivity to mechanical pressure on the hind paw after intraplantar capsaicin injection; these findings together indicate that PIP5K1C enhances sensitivity to pain caused by various stimuli. A screen of a library of kinase-targeted small molecules identified an inhibitor of PIP5K1C (and the related protein PIP4K2C), which bound to these kinases and inhibited their activity in vitro. Wild-type mice injected intrathecally with this inhibitor exhibited decreased sensitivity to heat and to chemical-induced neuropathic or inflammatory pain. The findings indicate that PIP5K1C may be a new target to treat chronic pain.

B. D. Wright, L. Loo, S. E. Street, A. Ma, B. Taylor-Blake, M. A. Stashko, J. Jin, W. P. Janzen, S. V. Frye, M. J. Zylka, The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 82, 836–847 (2014). [PubMed]