Effects of norketamine enantiomers in rodent models of persistent pain

NMDA-receptor antagonists are potential drugs for chronic pain treatment, in particular for neuropathic pain involving central sensitization processes. Clinical use of available NMDA antagonists, such as ketamine, is limited for this indication due to its side effects (psychotomimetic, sedative, motor). There is a need for novel NMDA-receptor antagonist(s) with better analgesia/toxicity profile(s). One such potential candidate is norketamine, a primary metabolite of ketamine. S(+) and R(−)norketamine were characterized utilizing rodent models of persistent pain: the chronic constriction nerve injury model of peripheral neuropathy (CCI) and the formalin-injection model of tonic inflammatory pain (formalin test). Side effects (motor coordination, stereotypic behaviors, locomotor activity) were also assessed. (±)Ketamine served as a reference NMDA-receptor antagonist in some studies. Norketamine alleviated, in a dose-dependent fashion, mechanical and thermal hyperalgesia (CCI), and blocked formalin-induced flinches (2nd phase). It had less effect on tactile allodynia (CCI). Efficacy was demonstrated after parenteral and oral administration. The antinociceptive properties resided primarily in the S(+) enantiomer. Antinociception was not accompanied by significant side effects. The present findings suggest that norketamine, in particular the S(+) enantiomer, might be a useful NMDA-receptor antagonist for treatment of chronic pain involving central sensitization.