Lack of the protein tenascin X (TNX) associated with classical-like Ehlers-Danlos syndrome (EDS) promotes higher pain sensitivity to tactile and chemical stimuli and aggravates inflammatory pain, a study in mice shows.
These findings add knowledge to the mechanisms behind chronic pain in classical-like EDS and may help to identify other therapeutic targets, besides TNX, for the management of pain associated with EDS.
The study, “Mechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome,” was published in the journal Nature Scientific Reports.
Pain is a common and severe symptom among people with EDS. About 68% of EDS patients with chronic pain have neuropathic pain — pain associated with nerve cell dysfunction — with mechanical allodynia as its major symptom. Mechanical allodynia consists of pain caused by harmless tactile stimuli that normally would not drive pain.
Classical-like EDS is caused by a deficiency in TNX, a protein involved in the maintenance of connective tissues. TNX-deficient EDS patients also have chronic joint and muscle pain, burning or prickling sensations in the hands, arms, legs, or feet, and axonal polyneuropathy (damage of the nerves in the body’s extremities).
Despite its substantial negative impact in patients’ lives, the underlying mechanisms of EDS-associated pain remain poorly understood.
Researchers in Japan have now evaluated the role of TNX deficiency in pain in mice lacking TNX, which mimics classical-like EDS in humans.
When the team first analyzed the levels of TNX in healthy mice, they found that TNX was naturally present in several nerve tissues involved in the transmission of pain from peripheral tissues to the spinal cord (from where the information is passed on to the brain).
This supported TNX’s potential role in the pain transmission pathway, which was further confirmed in mice with TNX deficiency.
Mice lacking TNX showed increased pain sensitivity to harmless tactile stimuli (mechanical allodynia) and to chemical stimuli, as well as aggravated inflammatory pain, compared with healthy mice.
The absence of TNX did not affect the mice’s sensitivity to thermal stimuli, such as harmless cold or harmful heat.
Testing with different types of analgesic medications showed that the pharmacological profile of TNX deficiency-induced pain hypersensitivity was similar to that of neuropathic pain.
Further analyses highlighted that TNX deficiency increased the sensitivity of specific sensory nerve fibers that carry information related to touch — A-beta fibers — and pain (mechanical and thermal) — A-delta fibers — to the dorsal horn of the spinal cord.
“The dorsal horn of the spinal cord is an important site for pain transmission, and it constitutes the first relay station for incoming somatosensory information,” the researchers wrote.
Notably, nerve cells in the dorsal horn of mice lacking TNX showed higher levels of activity associated with the maintenance of neuropathic pain.
Based on these findings, researchers suggested that TNX deficiency promoted higher sensitivity to pain through at least two mechanisms: hyper-sensitization of specific sensory fibers and central sensitization.
Central sensitization is characterized by lower pain thresholds, resulting in hypersensitivity to pain and maintenance of pain even in situations without harmful stimuli.
Overall, the results “suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn,” the researchers wrote.
The data suggest that “TNX is a therapeutic target for the management of pathological pain associated with EDS,” the team concluded.
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