NMDAR-hypofunction in regions like the prefrontal cortex and the resulting neuroplasticity deficits altering frontocortical circuitry integral to pain perception have been strongly implicated in supraspinal, centralized, chronic pain. Enhancing activity in hypoactive regions might decrease activity in hyperactive regions like the insula and the anterior cingulate cortex (ACC) through modulations of activity across circuitry.  

Comparing placebo to post-NYX-2925 treatment resulted in reductions of Glx/tCr (glutamate and glutamine/ratio to total creatine) levels in dorsal ACC at rest and in posterior insular cortex (pIns) following an evoked-pain stimulus: sensitivity to pain was associated with greater pain-evoked release of Glx/tCr in the pIns during placebo. Increased pre-treatment pain-evoked Glx-release in the pIns was associated with reductions in sensitivity to pressure-evoked pain following 20mg and 200mg NYX-2925. NYX-2925 (20mg) reduced connectivity between dACC to primary somatosensory cortex and precuneus. NYX-2925 (200mg) improved pain, fatigue, severity of symptoms, and patient-reported function. NYX-2925 was safe and well tolerated.