Abstract
N-methyl-d-aspartate (NMDA) receptors play fundamental roles in pain processing, pain sensitization, and chronic-pain induced depression. The NMDA receptor antagonist, ketamine, is used off-label to treat various chronic pain syndromes. However, because of its risks for causing physical and psychological dependance, psychomimetic side effects, and neurotoxicity, ketamine is of limited clinical usefulness. D-cycloserine (DCS) is a partial agonist of the NMDA receptor, and antagonizes the NMDA receptor when administered at higher doses. Unlike ketamine, DCS does not carry a propensity for dependance or abuse is not neurotoxic, and has extensive history of long term use as an anti-infective agent. These factors suggest that DCS is potentially suitable for treatment of chronic pain.
Anecdotal reports suggest that high doses of DCS can cause psychotomimetic side effects, which is a potential barrier to development as monotherapy. However, preclinical and clinical work suggests that when DCS is administered with a serotonin (5HT) 2A receptor antagonist such as lurasidone, it reduces the risk of these adverse effects. In turn, DCS reduces lurasidone’s propensity to cause akathisia. When DCS and lurasidone are considered as a combined treatment for chronic pain, additional synergies become apparent. 5HT receptor antagonism may block inflammation that underlies peripheral sensitization. Blocking NMDA receptors can stop the development of central sensitization in the dorsal horn of the spinal cord. Moreover, DCS may act at the thalamus, amygdala, and higher brain levels to alter the perception of pain. CS and lurasidone may also act synergistically to treat chronic-pain induced depression. We describe the rationale for the development of DCS and lurasidone as a treatment for chronic pain.