Editorial Views  |   August 2019
Central Sensitization, N-methyl-d-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development
Author Notes
  • From the Department of Anesthesiology and Critical Care Medicine (S.N.R., E.S., Y.G.), and the Department of Neurological Surgery (Y.G.), Johns Hopkins University, School of Medicine, Baltimore, Maryland.
  • This editorial accompanies the article on p. 356.
    This editorial accompanies the article on p. 356.×
  • Accepted for publication April 3, 2019.
    Accepted for publication April 3, 2019.×
  • Address correspondence to Dr. Raja: sraja2@jhmi.edu
Article Information
Editorial Views / Central and Peripheral Nervous Systems / Pain Medicine
Editorial Views   |   August 2019
Central Sensitization, N-methyl-d-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development
Anesthesiology 8 2019, Vol.131, 233-235. doi:10.1097/ALN.0000000000002808
Anesthesiology 8 2019, Vol.131, 233-235. doi:10.1097/ALN.0000000000002808
The best available pharmacologic therapies for chronic pain leave much to be desired in terms of both effectiveness and tolerability. Additionally, the opioid epidemic that currently ravages the United States has highlighted an unmet need and spurred the urgent search for safer and more effective analgesics. Researchers are now working to develop targeted therapies based on advances in our understanding of the molecular mechanisms and pathophysiology of acute and chronic pain. One such mechanism is the concept of “central sensitization,” a key component of postinjury pain hypersensitivity that was proposed over three and a half decades ago.1,2  Intense noxious inputs induce a prolonged state of neuronal hyperexcitability in the central nervous system, particularly in the spinal dorsal horn. Among the neurochemical mechanisms that contribute to this central sensitization, activation of the N-methyl-d-aspartate (NMDA) receptor plays a pivotal role,3  and NMDA antagonists were proposed as potential analgesics.4  However, no new drugs targeting this site have shown beneficial clinical effects or been approved for pain treatment in decades. Hence, there is renewed interest in utilizing clinically available drugs of this class, such as ketamine and dextromethorphan, for pain management. In this issue of Anesthesiology, Martin et al.5  use a human freeze injury model of cutaneous hypersensitivity to demonstrate that the noncompetitive NMDA antagonist dextromethorphan decreases both primary (at the site of tissue injury) and secondary (outside the injury site) hyperalgesia—surrogate measures of peripheral and central sensitization. These observations raise the intriguing question of whether human pain models can facilitate the translation of mechanism-based targets identified in animal models to clinically effective drugs.