(2R,6R)-hydroxynorketamine reverses mechanical and thermal pain hypersensitivity produced by the chemotherapeutic agent oxaliplatin in rats

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of a number of anticancer drugs, like oxaliplatin, leading to chronic sensory hypersensitivity and neuropathic pain. This study investigated the efficacy of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, in a rat model of CIPN induced by oxaliplatin. Rats treated with oxaliplatin developed long-lasting mechanical and thermal hypersensitivity, as assessed by the Von Frey test and the hot plate test, respectively. A single injection of (2R,6R)-HNK (30 mg/kg, s.c.) significantly reversed both mechanical and thermal hypersensitivity for up to 24 h. Furthermore, repeated treatment with (2R,6R)-HNK (30 mg/kg/day) for 7 days produced sustained analgesia on mechanical hypersensitivity that persisted up to 14 days after treatment cessation. In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. Locomotor activity was not affected by (2R,6R)-HNK treatment, although duloxetine caused a transient decrease. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN.