Sci Rep. 2018 Nov 6;8(1):16402. doi: 10.1038/s41598-018-34594-2.

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.

Koyama S^1,^2,³, LeBlanc BW^1,², Smith KA^1,², Roach C^1,², Levitt J^1,², Edhi MM^1,², Michishita M³, Komatsu T³, Mashita O⁴, Tanikawa A⁴, Yoshikawa S³, Saab CY^5,⁶.

Author information

1: Department of Neurosurgery, Rhode Island Hospital, Providence, RI, USA.
2: Department of Neuroscience, Brown University, Providence, RI, USA.
3: Laboratory for Pharmacology, Asahi KASEI Pharma Corporation, Shizuoka, Japan.
4: Laboratory for Safety Assessment & ADME, Asahi KASEI Pharma Corporation, Shizuoka, Japan.
5: Department of Neurosurgery, Rhode Island Hospital, Providence, RI, USA. carl_saab@brown.edu.
6: Department of Neuroscience, Brown University, Providence, RI, USA. carl_saab@brown.edu.

Abstract

We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.