Background: Ketamine induces neuroapoptosis in neonatal rodents. However, these experimental paradigms were performed without concurrent noxious stimulation, a condition that does not reflect the interaction of anesthesia and surgical stimulation. Noxious stimulation with and without concurrent analgesic drugs has been shown to have divergent patterns of neuronal activation and cell death. We hypothesized that concurrent noxious stimulation would attenuate ketamine-induced caspase-3 activation. Methods: Postnatal day 7 Sprague-Dawley rat pups were randomized to a 6-h exposure to ketamine with and without peripheral noxious stimulation by intraplantar injection of complete Freund's adjuvant. A cohort of naïve rat pups with and without complete Freund's adjuvant injections served as control subjects. Neuroapoptosis was measured by cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining. In order to determine if concurrent noxious simulation altered the expression of cell survival and cell cycle proteins, levels of protein kinase B and glycogen synthase kinase-3β and cyclin D1 were measured. Results: Ketamine induced a significant increase in cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining with increases in cyclin D1 levels. Concurrent noxious stimulation with ketamine attenuated caspase-3 activation and maintained cyclin D1 levels. Phosphorylation of protein kinase B and glycogen synthase kinase-3β was not definitively altered under these conditions. Conclusion: The administration of ketamine with concurrent noxious stimulation results in the attenuation of the neuroapoptotic response. These findings suggest that concurrent surgery and procedural pain attenuates ketamine-induced neuroapoptosis.

AIM: To systematically evaluate the effect of intraperitoneal local anesthetic on pain characteristics after laparoscopic cholecystectomy (LC). METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library. Randomized controlled trials in English that compared the effect of intraperitoneal administration of local anesthetics on pain with that of placebo or nothing after elective LC under general anesthesia were included. The primary outcome variables analyzed were the combined scores of abdominal, visceral, parietal, and shoulder pain after LC at multiple time points. We also extracted pain scores at resting and dynamic states. RESULTS: We included 39 studies of 3045 patients in total. The administration of intraperitoneal local anesthetic reduced pain intensity in a resting state after laparoscopic cholecystectomy: abdominal [standardized mean difference (SMD) = -0.741; 95%CI: -1.001 to -0.48, P < 0.001]; visceral (SMD = -0.249; 95%CI: -0.493 to -0.006, P = 0.774); and shoulder (SMD = -0.273; 95%CI: -0.464 to -0.082, P = 0.097). Application of intraperitoneal local anesthetic significantly reduced the incidence of shoulder pain (RR = 0.437; 95%CI: 0.299 to 0.639, P < 0.001). There was no favorable effect on resting parietal or dynamic abdominal pain. CONCLUSION: Intraperitoneal local anesthetic as an analgesic adjuvant in patients undergoing laparoscopic cholecystectomy exhibited beneficial effects on postoperative abdominal, visceral, and shoulder pain in a resting state.

Previous randomized controlled trials regarding the effectiveness of perioperative midazolam in preventing postoperative nausea and vomiting (PONV) have produced conflicting results. Consequently, the present systematic review was performed to assess the effect of perioperative administration of midazolam on PONV. The MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials databases were searched to identify all randomized controlled trials that investigated the effectiveness of midazolam under general anesthesia. The primary end points were defined as postoperative nausea (PON), postoperative vomiting (POV), and PONV. From 16 studies, 1433 patients were included in the final analysis. Compared with the control group, patients who received midazolam showed a lower overall incidence of PON (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.40-0.65; I = 35%; number needed to treat [NNT] = 6; number of included studies [n] = 11), POV (RR, 0.46; 95% CI, 0.33-0.65; I = 0%; NNT = 8; n = 10), and PONV (RR, 0.45; 95% CI, 0.36-0.57; I = 31%; NNT = 3; n = 7). Perioperative administration of midazolam was effective in preventing PON, POV, and PONV.

Ginseng saponin has long been used as a traditional Asian medicine and is known to be effective in treating various kinds of pain. Ginsenoside Rf is one of the biologically active saponins found in ginseng. We evaluated ginsenoside Rf's antinociceptive and anti-inflammatory effects, and its mechanism of action on adrenergic and serotonergic receptors, in an incisional pain model. Mechanical hyperalgesia was induced via plantar incision in rats followed by intraperitoneal administration of increasing doses of ginsenoside Rf (vehicle, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2 mg/kg). The antinociceptive effect was also compared in a Positive Control Group that received a ketorolac (30 mg/kg) injection, and the Naïve Group, which did not undergo incision. To evaluate the mechanism of action, rats were treated with prazosin (1 mg/kg), yohimbine (2 mg/kg), or ketanserin (1 mg/kg) prior to receiving ginsenoside Rf (1.5 mg/kg). The mechanical withdrawal threshold was measured using von Frey filaments at various time points before and after ginsenoside Rf administration. To evaluate the anti-inflammatory effect, serum interleukin (IL)-1β, IL-6, and tumor necrotizing factor-α levels were measured. Ginsenoside Rf increased the mechanical withdrawal threshold significantly, with a curvilinear dose-response curve peaking at 1.5 mg/kg. IL-1β, IL-6, and tumor necrotizing factor-α levels significantly decreased after ginsenoside Rf treatment. Ginsenoside Rf's antinociceptive effect was reduced by yohimbine, but potentiated by prazosin and ketanserin. Intraperitoneal ginsenoside Rf has an antinociceptive effect peaking at a dose of 1.5 mg/kg. Anti-inflammatory effects were also detected.

Ketamine-induced neuroapoptosis has been attributed to diverse stress-related mechanisms. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional kinase that is active in neuronal development and linked to neurodegenerative disorders. We hypothesized that ketamine would enhance GSK-3β-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3β, would attenuate this response in vivo. Protein levels of cleaved caspase-3, protein kinase B (AKT), GSK-3β, and cyclin D1 were measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 h exposure to ketamine. A cohort of rat pups was randomized to a 6 h exposure to ketamine with and without lithium. Neuroapoptosis was measured by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and phosphorylated forms of AKT, GSK-3β, and cyclin D1 (cell cycle protein) were also measured. Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which corresponded to decreases in phosphorylated AKT and GSK-3β. Co-administration of lithium with ketamine attenuated this response. Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3β phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3β is activated during this ketamine-induced neuroapoptosis.