Spinal cord microglia drive sex differences in ethanol-mediated PGE2-induced allodynia, 2024, Alexander et al.

Spinal cord microglia drive sex differences in ethanol-mediated PGE2-induced allodynia
Alexander; Reed; Burton

The mechanisms of how long-term alcohol use can lead to persistent pain pathology are unclear. Understanding how earlier events of short-term alcohol use can lower the threshold of non-painful stimuli, described as allodynia could prove prudent to understand important initiating mechanisms. Previously, we observed that short-term low-dose alcohol intake induced female-specific allodynia and increased microglial activation in the spinal cord dorsal horn. Other literature describes how chronic ethanol exposure activates Toll-like receptor 4 (TLR4) to initiate inflammatory responses. TLR4 is expressed on many cell types, and we aimed to investigate whether TLR4 on microglia is sufficient to potentiate allodynia during a short-term/low-dose alcohol paradigm.

Our study used a novel genetic model where TLR4 expression is removed from the entire body by introducing a floxed transcriptional blocker (TLR4-null background (TLR4LoxTB)), then restricted to microglia by breeding TLR4LoxTB animals with Cx3CR1:CreERT2 animals.

As previously reported, after 14 days of ethanol administration alone, we observed no increased pain behavior. However, we observed significant priming effects 3 hours post intraplantar injection of a subthreshold dose of prostaglandin E2 (PGE2) in wild-type and microglia-TLR4 restricted female mice. We also observed a significant female-specific shift to pro-inflammatory phenotype and morphological changes in microglia of the lumbar dorsal horn. Investigations in pain priming-associated neuronal subtypes showed an increase of c-Fos and FosB activity in PKCγ interneurons in the dorsal horn of female mice directly corresponding to increased microglial activity.

This study uncovers celland female-specific roles of TLR4 in sexual dimorphisms in pain induction among nonpathological drinkers.

Link | PDF (Brain, Behavior, and Immunity)

 

In mice.

 

Pretty ingenious experiment. But proving something is sufficient is not much of a value. Proving it necessary is. They can't point to microglia as a key mechanism till they can prove that TLR4 expression on them is necessary for allodynia or female bias. For all we know, TLR4 in guts could do the same thing.