Blocking sensory nerve fibers eased pain responses in mice
Research could be useful for managing neurological complications in clEDS patients
Abnormally high sensitivity of a type of sensory nerve fibers is behind the heightened pain responses to harmless light touch that were observed in a mouse model of classical-like Ehlers-Danlos syndrome (clEDS), a study shows.
This abnormal pain sensation, called mechanical allodynia, is a main symptom of neuropathic pain — pain related to nerve damage — that has been described by people with clEDS and other types of Ehlers-Danlos syndrome (EDS). Treating the mice with a molecule that blocks these sensory nerve fibers — called A-fibers — eased mechanical allodynia.
The findings shed light on the mechanisms that may underly chronic pain in people with EDS and “will be useful for managing neurological complications in patients,” the researchers wrote.
The study, “Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome,” was published in Scientific Reports.
In clEDS, mutations in the TNXB gene lead to a deficiency in tenascin-X (TNX), a protein that helps maintain the structure of the connective tissues that support muscles, joints, skin, and other organs.
As in other forms of EDS, clEDS patients experience fragile connective tissues, soft and easily bruised skin, and overly mobile joints. Pain also is very common, being reported by about 90% of all EDS patients.
This can include a range of different types of pain or altered sensations. Previous studies reported that clEDS patients experience chronic pain in the joints, muscles, and abdomen, as well as fatigue, burning or prickling sensations, and symptoms of damage to nerves outside the brain and spinal cord.
The mechanisms underlying pain in EDS are still being studied. But heightened sensitivity in the nerve cells that transmit sensory information to the brain (sensory nerves) may lead to increased or abnormal pain perception.
A team of researchers in Japan showed previously that a mouse model of clEDS genetically engineered to lack the TNXB gene exhibited increased sensitivity to normally painless tactile stimuli, or mechanical allodynia.
A type of sensory nerves called A-fibers were found to be overly sensitive to stimulation in these mice, suggesting they could contribute to the mechanical allodynia in clEDS.
Current research is revealing
Now, the same team investigated the effects of blocking signaling of these A-fibers on pain responses in the clEDS mouse model.
As in their previous report, the mouse model exhibited signs of mechanical allodynia and heightened sensitivity in the alpha and delta subtypes of A-fibers relative to healthy mice. Particularly, the mice were quicker to retract their paw in response to light touch.
Also, the sensitivity of C-fibers, a type of smaller sensory nerves that transmit signals more slowly than A-fibers, did not appear affected in the mouse model. While A-fibers are linked to pressure sensations and fast, sharp pain, C-fibers are associated with temperature and chemical sensations, as well as dull aches and pains.
The researchers then treated the mice with certain molecules thought to silence A-fiber signaling. This included QX-314, which blocks certain channel proteins involved in nerve cell firing, as well as flagellin, which activates a molecule called toll-like receptor 5 (TLR5) that helps QX-314 enter into the A-fiber nerve cells.
Reduced sensitivity of the A-fibers
Treatment with both QX-314 and flagellin, injected directly into the paws, led to diminished mechanical allodynia, which was accompanied by signs of reduced sensitivity of the A-fibers.
Moreover, the combination treatment prevented nerve cell activation in the dorsal horn of the spinal cord, which is involved in sensory pain responses.
Interestingly, QX-314 alone also was able to ease mechanical allodynia and reduce A-fiber sensitivity in the clEDS mouse model, but not in healthy mice — where only the QX-314-flagellin combo was able to make the nerve fibers less sensitive.
This suggested that TLR5 proteins in mice with clEDS-like disease may be constitutively activated, or always on an active state, allowing QX-314 to easily enter nerve fibers. Indeed, treating the mice with a molecule that blocks TLR5 signaling reversed QX-314’s ability to affect pain responses on its own.
Altogether, “these results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of [A-fibers], and it is induced by constitutive activation of TLR5,” the researchers wrote.