Mice Without FMRP Protein Perceive Pain Differently

The fragile X mental retardation protein (FMRP) — missing or at low levels in people with fragile X syndrome — plays a key role in regulating chronic visceral pain, according to a study.

Insufficient FMRP might explain some of the self-injurious behavior seen among people with fragile X syndrome.

The study, “FMRP acts as a key messenger for visceral pain modulation,” was published in the journal Molecular Pain.

Fragile X is characterized by intellectual and developmental disabilities. Patients may exhibit self-harm behaviors, meaning purposeful and repeated self-inflicted bodily injuries, that may be linked to lower pain sensitivity.

FMRP normally regulates the expression of proteins found at synapses — sites of near contact where nerve cells communicate. This led researchers from the Fourth Military Medical University, in Xi’an, China, to wonder if an FMRP deficiency would disrupt normal signals in visceral pain, which arises from internal organs within the thoracic, abdominal, or pelvic cavities.

The investigators tested this hypothesis in mice with and without FMRP by injecting them with zymosan, a yeast-derived compound that causes painful inflammation.

Results showed that whereas the mice with FMRP showed expected pain-related behaviors, those lacking this protein were insensitive to zymosan. (Zymosan is is a component of the cell wall in yeast and has been used to induce inflammation and discomfort in animal models by binding to immune cells.)

Molecular results backed up this finding.

A previous study from the same group had found that the AC1 protein, which is implicated in pain, grows more active inside the anterior cingulate cortex (ACC) of mice experiencing pain. Notably, the ACC is a brain region with a key role in central sensitization, which refers to an abnormal state of responsiveness of the pain regulation system.

In response to zymosan, levels of AC1, the activated form of the CREB protein (which regulates gene activity) and of a receptor component (GluN2B) for the excitatory chemical messenger glutamate, all rose in the ACC of control mice but not in animals with no FMRP. As these changes were associated with higher levels of FMRP in the ACC of control animals, the present results strongly support the role of FMRP in chronic pain processing, the team wrote.

The researchers found these same effects mirrored in human neuronal cells under conditions mimicking a molecular pain response.

To further investigate the role that FMRP might play at the molecular level, the investigators dialed the level of FMRP up and down within human neuronal cells.

They found that levels of the proteins AC1, CREB, and GluN2B rose all fell when FMRP production was lower, and all rose when it was overproduced. “These data indicate that FMRP is a key regulator for GluN2B and AC1 in chronic visceral pain,” they wrote.

“Our findings demonstrate that FMRP is required for NMDA GluN2B and AC1 upregulation,” the researchers concluded, “and GluN2B/AC1/FMRP forms a positive feedback loop to modulate visceral pain.”