Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers

Study Description: This is a randomized, double-blind, placebo-controlled, single-site crossover study. This experimental study will assess the analgesic efficacy and mechanisms of a single infusion of 0.5 mg/kg (2R,6R)-HNK, an enhancer of synaptic glutamate release. We hypothesize that HNK infusion will elicit acute and long-lasting analgesia and that HNK will alter brain responses to noxious stimuli in a pain-specific manner. We will also include a natural history (i.e., No Treatment) control group to isolate placebo effects. The study includes both inpatient and outpatient visits. Objectives: Primary Objective: To evaluate the ability of (2R,6R)-HNK, an enhancer of synaptic glutamate release, to reduce acute pain during quantitative sensory testing (QST). The efficacy of a single infusion of (2R,6R)-HNK will be compared to placebo in a crossover design. Secondary Objectives: * To determine the time course of analgesic efficacy of (2R,6R)-HNK immediately following infusion, after 4-5 hours, and one day later compared to placebo, as assessed by change from baseline on QST outcomes. * To evaluate the effects of (2R,6R)-HNK on nociceptive brain responses, as assessed by brain responses to thermal stimulation in the Neurologic Pain Signature (NPS) in comparison to placebo during functional magnetic resonance imaging (fMRI). * To evaluate whether analgesic effects of (2R,6R)-HNK are specific to pain, by comparing effects of (2R,6R)-HNK relative to placebo on pain-related neural activation and emotion-related neural activation during fMRI scanning. * To evaluate the magnitude of placebo analgesia by comparing the placebo condition with a natural history (No Treatment) control group. Endpoints: Primary Endpoint: Ratings of nociceptive stimuli during QST. Secondary Endpoints: * Ratings of nociceptive stimuli during QST one day after infusion. * Scores on validated acute pain questionnaires (McGill Pain Questionnaire, Brief Pain Inventory, Patient Global Impression of Change). * NPS pattern expression based on fMRI response to painful, relative to nonpainful, stimulation. * FMRI activation in response to unpleasant, relative to neutral, emotional images. * Incidence and nature of adverse events; vital signs; weight and body mass index (BMI) changes; physical examination changes; clinical laboratory evaluations; Electrocardiogram (ECG). Surrogate Markers of Drug Effect, Target Engagement, and Analgesic Response: -Change in peripheral biomarkers, including autonomic nervous system and NPS.