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.