Characterization of the effects of L-4-chlorokynurenine on nociception in rodents

Abstract Upon systemic administration in rats, the prodrug L-4-chlorokynurenine (4-Cl-KYN) (AV-101) is rapidly absorbed, actively transported across the blood-brain barrier, and converted in astrocytes to 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the GlyB co-agonist site of the NMDA receptor. We examined the effects of 4-Cl-KYN in several rat models of hyperalgesia and allodynia and determined the concentrations of 4-Cl-KYN and newly produced 7-Cl-KYNA in serum, brain and spinal cord. Adult male rats were given 4-Cl-KYN (56, 167, 500 mg/kg), the NMDA receptor antagonist MK-801 (0.1, 0.3, 1.0 mg/kg) or gabapentin (33, 100, 300 mg/kg) intraperitoneally (IP), and were then examined on rotarod, intraplantar formalin-evoked flinching, thermal escape in the normal and carrageenan-inflamed paw, and allodynia following sciatic nerve ligation. Our conclusions show that after systemic delivery, the highest two doses (167 and 500 mg/kg) of 4-Cl-KYN yielded brain concentrations of 7-Cl-KYNA exceeding its IC50 at the GlyB site and resulted in dose-dependent anti-hyperalgesia in the four models of facilitated processing associated with tissue inflammation and nerve injury. Based on the relative dose requirements for analgesic actions and side effect profiles from these experiments, 4-Cl-KYN is predicted to have anti-hyperalgesic efficacy and a therapeutic ratio equal to gabapentin and superior to MK-801.