Inhibiting the function of a protein called sortilin — an important regulator of nerve damage-induced pain in mice — may represent a potentially effective strategy for treating chronic pain in humans, including those with multiple sclerosis, a study in mice suggests.
The researchers say more work is needed to determine if it is possible to block sortilin locally in the spinal cord.
These findings were reported in a study, “Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain,” published in the journal Science Advances.
Neuropathic pain is a specific type of pain that is triggered by damage to nerve cells and fibers. This damage-induced pain can be caused by an injury or by chronic diseases, including diabetes and multiple sclerosis.
Damage to nerve cells can make these cells become “uninhibited,” sending pain signals in the absence of an actual painful stimulus. The pain sensation itself can come in many forms, such as burning, pricking, stinging, tingling, freezing, or as a stabbing feeling, and is often chronic and disabling. In MS, it typically occurs in the legs as a persistent and burning pain.
“Once nerve damage has occurred, and the nerve cells go into overdrive, molecules are released which start a domino effect that ultimately triggers pain,” Mette Richner, PhD, professor at Aarhus University and lead author of the study, said in a press release.
Evidence shows that a natural molecule called neurotensin has analgesic, or painkilling, effects in experimental models, acting as a “brake” for the pain signals. Now, researchers have demonstrated that sortilin protein, which is also known as neurotensin receptor 3 (NTSR3), can regulate neurotensin analgesic signals.
In other words, neurotensin acts as a “brake” for the pain signals, and sortilin drives these pain signals by inhibiting neurotensin — essentially acting as a “brake for the brake,” the researchers said. At the molecular level, this stops the body’s pain development.
“The [pain signals’] domino effect can be inhibited by a particular molecule in the spinal cord called neurotensin, and our studies show that the neurotensin is ‘captured’ by sortilin,” Richner said.
The researchers evaluated mice that had been genetically engineered to lack the gene that encodes sortilin. These animals were protected against neuropathic pain induced by nerve damage, the team found. However, when they treated the mice with inhibitors of neurotensin, which blocked the molecule, they became sensitive again to induced-neuropatic pain.
Further experiments revealed that a chemical inhibitor of sortilin could delay the onset of induced-neuropatic pain in mice.
Taken together, these data suggest that sortilin is not only important for neuropathic pain, but it also may be a target for treatments that could reduce this pain in people. “Targeting sortilin might … provide a novel strategy to overcome spinal disinhibition,” the researchers said.
“Our research is carried out on mice, but as some of the fundamental mechanisms are quite similar in humans and mice, it still gives an indication of what is happening in people suffering from chronic pain,” said Christian Vaegter, PhD, researcher at Aarhus University and co-senior author of the study.
“[H]ere, at the molecular level, … we’ve now added a crucial piece to a larger puzzle,” Richner said.
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