Conditional deletion of Pip5k1c in sensory ganglia and effects on nociception and inflammatory sensitization
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1Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, USA.
Abstract:
Phosphatidylinositol 4-phosphate 5-kinase type 1 gamma (Pip5k1c) generates phosphatidylinositol 4,5-bisphosphate, also known as PI(4,5)P2 or PIP2. Many pronociceptive signaling pathways and receptor tyrosine kinases signal via PIP2 hydrolysis. Previously, we found that pain signaling and pain sensitization were reduced in Pip5k1cþ/ global heterozygous knockout mice. Here, we sought to evaluate the extent to which dorsal root ganglia selective deletion of Pip5k1c affected nociception in mice. Initially, we crossed sensory neuron-selective Advillin-Cre mice with a conditional Pip5k1c knockout (cKO) allele (Pip5k1cfl/fl). However, these mice displayed an early onset proprioceptive deficit. To bypass this early onset phenotype, we used two different tamoxifen-inducible Cre lines (Brn3a-Cre-ERT2 and Advillin-Cre-ERT2) to conditionally delete Pip5k1c in adults. Tamoxifen induced high efficiency deletion of PIP5K1C in dorsal root ganglia and slightly reduced PIP5K1C in spinal cord and brain in Brn3a-Cre-ERT2 Pip5k1cfl/fl (Brn3a cKO) mice while PIP5K1C was selectively deleted in dorsal root ganglia with no changes in spinal cord or brain in Advillin-Cre-ERT2 Pip5k1cfl/fl (Advil cKO) mice. Acute thermosensation and mechanosensation were not altered in either line relative to wild-type mice. However, thermal hypersensitivity and mechanical allodynia recovered more rapidly in Brn3a cKO mice, but not Advil cKO mice, following hind paw inflammation. These data collectively suggest that PIP5K1C regulates nociceptive sensitization in more regions of the nervous system than dorsal root ganglia alone.
Insights
Phosphatidylinositol 4-phosphate 5-kinase type 1 gamma (Pip5k1c) deletion in adult mice reduced pain recovery times. This suggests Pip5k1c in multiple nervous system regions, not just dorsal root ganglia, regulates pain sensitization.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Phosphatidylinositol 4-phosphate 5-kinase type 1 gamma (Pip5k1c) produces phosphatidylinositol 4,5-bisphosphate (PIP2), a key signaling molecule.
- PIP2 hydrolysis is involved in pain signaling pathways and receptor tyrosine kinases.
- Previous studies showed reduced pain signaling in global Pip5k1c knockout mice.
Purpose of the Study:
- To investigate the role of Pip5k1c in nociception by selectively deleting it in dorsal root ganglia (DRG) of adult mice.
- To bypass early-onset phenotypes observed in constitutive knockouts.
- To compare the effects of Pip5k1c deletion in DRG versus broader neural regions.
Main Methods:
- Generated conditional knockout (cKO) mice using tamoxifen-inducible Cre lines (Brn3a-Cre-ERT2 and Advillin-Cre-ERT2) crossed with Pip5k1cfl/fl mice.
- Administered tamoxifen to induce adult-onset deletion of Pip5k1c.
- Assessed nociception, including acute thermal and mechanical sensitivity, and recovery from inflammatory pain.
- Quantified Pip5k1c deletion efficiency in DRG, spinal cord, and brain.
Main Results:
- Tamoxifen-induced Pip5k1c deletion occurred efficiently in DRG for both Brn3a cKO and Advil cKO mice.
- Brn3a cKO mice showed reduced Pip5k1c in spinal cord and brain, while Advil cKO mice had selective DRG deletion.
- No alterations in acute thermosensation or mechanosensation were observed in either cKO line.
- Brn3a cKO mice, but not Advil cKO mice, exhibited faster recovery from thermal hypersensitivity and mechanical allodynia after inflammation.
Conclusions:
- Pip5k1c deletion in DRG alone is insufficient to accelerate pain recovery.
- Pip5k1c plays a role in nociceptive sensitization in regions beyond the dorsal root ganglia.
- Broader deletion of Pip5k1c, including in the spinal cord and brain, is necessary for accelerated pain recovery.
