Five (5) Beagle dogs and twelve (12) cynomolgus monkeys were used to generate representative data with the model, and their response to the positive control drug (PTZ) (see the Experimental methods section). At onset of treatment, Beagle dogs were 10 months old and cynomolgus monkeys were 2 years old. Prophylactic antibiotics (Baytril, Bayer Health Care, Toronto, ON, Canada; 0.1 mL/kg, 50 mg/mL; Penicillin G procaine, Vetoquinol, Lavaltrie, QC, Canada; 0.4 mL, 300 000 IU/mL) were administered by intramuscular (IM) injection prior to surgery and daily for at least two days. Preemptive analgesia was attained via a transdermal Fentanyl patch

(Sandoz, QC, Canada; 12.5 μg/h) over three days. An antibiotic, Cefazolin (Novopharm, Markham, ON, Canada; 0.4 mL/kg, 80 mg/mL) was applied to the skull surgical site. A local anesthetic (Bupivacaine, INCB018424 concentration Hospira, Montreal, QC, Canada, 0.25%, 0.5 mL; or Lidocaine, Vetoquinol, Lavaltrie, QC, Canada; 20 mg/mL, 0.5 mL) was injected (0.1–0.2 mL) in 6–10 subcutaneous (SC) sites distributed over the skull surgical site to ensure a multimodal analgesia. Animals were placed on a heating pad and inhaled a mixture of oxygen (O2) and isoflurane (AErrane, Baxter Corporation, Mississauga, ON, Canada). Respiratory rate was maintained between 8 and 20 breaths/min with an inspiratory airway pressure between 18 and 25 cm GSK126 nmr H2O using a mechanical ventilator (Hallowell

EMC, Pittsfield, MA, USA). Heart rate, pulse oximetry (SpO2) and body temperature were monitored continuously during anesthesia. A longitudinal incision

was performed lateral but close to the linea alba, and the internal abdominal oblique muscle was separated from the aponeurosis of the transversus abdominis. The telemetry transmitter was placed between the internal abdominal oblique muscle and the aponeurosis of the transversus abdominis muscle. The rectus abdominis was sutured with a simple continuous suture and EEG electrodes were tunneled subcutaneously to a small skin incision in the neck. Electroencephalographic leads (TL11M2-D70-EEE, Data Science International, Phosphoprotein phosphatase St.-Paul, MN, USA) were secured on to the skull bones to monitor three standard bipolar derivations (C3-O1, C4-O2 and Cz-Oz) using the 10–20 electrode system. A linear groove was done in the cranial cortical bone to secure the electrodes with surgical glue (Vetbond, 3M, St-Paul, MN, USA) and acrylic. Electromyographic (EMG) recording was obtained using electrodes sutured to longitudinal muscles in the neck area and recorded continuously with the telemetry transmitter. A period of three weeks was allowed between surgery and the start of experimental procedures. An additional ten (10) cynomolgus monkeys (3.5–6 years old), maintained under the same environmental conditions as described above, were surgically prepared with the same telemetry transmitters (TL11M2-D70-EEE, Data Science International, St.