Roles of orexinergic and noradrenergic neuronal activity in ketamine-induced analgesia: A study using an orexin/ataxin-3 transgenic rat model

Orexin, a neuropeptide, physiologically interacts with locus coeruleus noradrenergic (LC-NA) activity. We hypothesized that this interaction affects ketamine-induced acute analgesia. We assessed ketamine-induced acute analgesia in transgenic (TG) and wild-type (WT) rats with genetically degraded orexinergic neurons using hotplate and tail-flick tests. We examined the effect of the LC-NA toxin, N -(2-Chloroethyl)- N -ethyl-2-bromobenzylamine hydrochloride (DSP4) on ketamine-induced acute analgesia in separate WT and TG groups. Rats received intra-peritoneal ketamine and intracerebroventricular (ICV) treatments, including saline, orexin, orexin + SB-334867 (an orexin type-1 receptor antagonist), or SB-334867. We measured orexin and noradrenaline levels in the brain regions of untreated WT and TG rats (n = 7 and 5, respectively). TG exhibited a decreased percentage of maximum possible effect area under the curve (AUC) for hotplate latency (WT: 1315.0 ± 1026.0; TG: 439.6 ± 831.5; P = 0.016) but not tail-flick latency (WT: 1203.0 ± 332.4; TG: 1127.0 ± 512.4; P = 0.732). Orexin (10 nmol, ICV) increased hotplate latency AUC in DSP4-free WT (control: 220.2 ± 227.2; orexin 10: 1575.0 ± 760.2; P = 0.004), DSP4-free TG (control: 119.9 ± 197.1; orexin 10: 866.5 ± 213.2; P = 0.001), DSP4-treated WT (control: −20.0 ± 350.5; orexin 10: 775.4 ± 485.2; P = 0.048), and DSP4-treated TG (control: −181.3 ± 272.6; orexin: 1038.0 ± 652.6; P = 0.040) rats. AUC with orexin 10 was lower in DSP4-treated WT rats than in DSP4-free WT rats (1575.0 ± 760.2 vs. 775.4 ± 485.2; P = 0.025). Co-administration of SB-334867 (20 nmol, ICV) with orexin blocked the effect of orexin on hotplate latency in DSP4-free but not DSP4-treated rats. TG rats had lower noradrenaline contents (pg/mg tissue) in the pons (WT: 341.9 ± 36.3; TG: 279.6 ± 54.4; P=0.038) and cerebral cortex (WT: 1195.1 ± 36.1; TG: 120.1 ± 32.6; P=0.042), but not in the hypothalamus (WT: 895.6 ± 130.4; TG 822.3 ± 1140.3; P=0.373). Orexin levels decreased in all brain regions of TG rats (pons: WT: 7.6 ± 3.2; TG: 1.1 ± 0.3, P = 0.001; hypothalamus: WT: 12.6 ± 2.9; TG: 2.8 ± 1.4, P<0.0001; cerebral cortex: WT: 2.1 ± 0.6; TG: 0.7 ± 0.3, P = 0.001). The role of orexin in ketamine-induced acute analgesia partly depends on LC-NA activity.