Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
Opioid analgesic tolerance (OAT), among other central side effects, limits opioids’
indispensable clinical use for managing chronic pain. Therefore, there is an existing
unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs)
containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate
in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs),
particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic
subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine
antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model.
In spinal tissues of rats treated with a morphine–NFPS combination, NFPS alone, or
vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions
were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed
in glycine and glutamate contents of cerebrospinal fluids from animals treated with
a morphine–NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors
are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an
increase in opioid efficacy. This study, to the best of our knowledge, shows for the
first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are
required to decipher the exact mechanisms.
