PET/MR pins down nerve pain at the molecular level

Pain is unavoidable. It alerts sufferers to very real threats via injury and disease and is invaluable for that reason, but it is also vague and imprecise and sometimes just mysterious, especially in cases of chronic pain disorders.

Self-reporting and physical exam are subjective measures that do not get down to any real measurement of pain. Conventional imaging systems, including x-ray, CT and MRI, and electrodiagnostic tests miss the mark when it comes imaging migraines, fibromyalgia, low back pain and other pain disorders because they very often pick up nerve anomalies that don’t correspond at all to patients’ symptoms or the pathology generating the pain.

Scientists from the departments of radiology, chemistry and anesthesia at Stanford University in Stanford, Calif., sought to develop a biomarker that could target and help measure the mechanisms of pain at the molecular level. The ideal going in was to create an agent that could visualize the molecular changes that signal pain generation and potentially use it to gauge wound healing and to assist in drug trials.

The target that researchers are now focused on is not the only route, but it appears to be a good way forward. The route is through the voltage-gated sodium channel, a molecule that is considerably upregulated in pain-sensitive neurons.

“This molecule is in part responsible for 'firing off' electrical signals to the brain thus warning our body of pain, but when present in abnormally high amounts—as it is in the chronic pain patient—it can lead to the nerve firing at higher than normal rates, spontaneous misfires or fire erroneously and randomly in patients with chronic pain, giving rise to the symptoms of chronic pain,” Sandip Biswal, MD, a researcher and associate professor at Stanford told Molecular Imaging.

The researchers found during the course of their study that several peptide radioligands could be used with PET to seek out these channels. One showing particular promise is F-18 saxitoxin (STX), which binds to extracellular isoforms involved in the function of voltage-gated sodium channels. Preliminary findings showed that the technique was feasible and effective for narrowing in on pain with PET/MR. The scientists went on to publish their work Nov. 21 in the Journal of the American Chemical Society.

Preclinical PET/MR evaluations showed that models displayed more F-18 STX uptake at the left injured nerve, but not in uninjured sciatic nerves. Researchers can now differentiate between unrelated nerve anomalies and actual pain-generating conditions.

“Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation,” said Biswal.

If this tracer were to be made available, clinicians would be able to swiftly identify hotspots of excessive voltage-gated sodium channel activity and use that information to personalize treatment, including but not limited to deciding how aggressive treatment should be and predicting areas where chronic pain are likely to develop.

“Pharmaceutical and biotechnology companies can also use this imaging approach to identify ideal candidates for their drug trials and better evaluate the efficacy of their analgesic drug-candidate relatively early in its development,” said Biswal. “This can potentially aid drug developers in more accurately identifying the optimal drug candidates to move forward into advanced clinical trials, thereby saving significant resources.”

The authors expect, if funding comes through, to be imaging humans with the investigational molecular agent within the next year and a half.