Papers of the Week

N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.