Response After Repeated Ketamine Injections in a Rat Model of Neuropathic Pain

Ketamine, an N-methyl-D-aspartate antagonist, reduces pain by decreasing central sensitization and pain windup. However, chronic ketamine use can cause tolerance, dependency, impaired consciousness, urinary symptoms, and abdominal pain. This study aimed to investigate the effects of repeated ketamine injections and ketamine readministration after discontinuation in a rat model of neuropathic pain. To induce neuropathic pain, partial sciatic nerve ligation (PSNL) was performed in 15 male Wistar rats, and these animals were divided into three groups: PSNL (control), PSNL + ketamine 5 mg/kg (K5), and PSNL + ketamine 10 mg/kg (K10; n=5 each). Ketamine was injected intraperitoneally daily for 4 weeks, discontinued for 2 weeks, and then readministered for 1 week. Following PSNL, the mechanical withdrawal threshold was determined weekly using the Von Frey. The K10 group showed a significant increase in the mechanical withdrawal threshold, presented here as the target force (in g), at 21 and 28 days compared to the time point before ketamine injection (mean±SE, 276.0±24.0 vs. 21.6±2.7 and 300.0±0.0 vs. 21.6±2.7, respectively; P<0.01) and at 14, 21, and 28 days compared to the control group (108.2±51.2 vs. 2.7±1.3, 276.0±24.0 vs. 2.5±1.5, and 300.0±0.0 vs. 4.0±0.0, respectively; P<0.05). However, in the K10 group, the ketamine effects decreased significantly at 7 days after readministration compared to those after 28 days of repeated injections (P<0.05). In the K10 group, repeated ketamine injections showed a significant increase in antinociceptive effect for >2 weeks, but this ketamine effect decreased after drug readministration.