Ketamine normalizes high-gamma power in the anterior cingulate cortex in a rat chronic pain model

Abstract

Chronic pain alters cortical and subcortical plasticity, causing enhanced sensory and affective responses to peripheral nociceptive inputs. Previous studies have shown that ketamine had the potential to inhibit abnormally amplified affective responses of single neurons by suppressing hyperactivity in the anterior cingulate cortex (ACC). However, the mechanism of this enduring effect has yet to be understood at the network level. In this study, we recorded local field potentials from the ACC of freely moving rats. Animals were injected with complete Freund's adjuvant (CFA) to induce persistent inflammatory pain. Mechanical stimulations were administered to the hind paw before and after CFA administration. We found a significant increase in the high-gamma band (60-100 Hz) power in response to evoked pain after CFA treatment. Ketamine, however, reduced the high-gamma band power in response to evoked pain in CFA-treated rats. In addition, ketamine had a sustained effect on the high-gamma band power lasting up to five days after a single dose administration. These results demonstrate that ketamine has the potential to alter maladaptive neural responses in the ACC induced by chronic pain.

Keywords: Anterior cingulate cortex; Chronic pain; Gamma band power; Ketamine; Local field potential.

Fig. 1

Experimental Design. a Pinprick stimulations were conducted in the uninjured paw contralateral to the CFA injection. Local field potentials (LFPs) were recorded from the anterior cingulate cortex (ACC) contralateral to peripheral stimulations. b Location of recording electrodes in the ACC

Fig. 2

Chronic pain increased high-gamma band power in the ACC. a Example of trial-averaged LFP raw trace, in the naïve condition. The panel directly below the raw trace shows trial-averaged time–frequency spectrum, with time 0 denoting the time of pinprick stimulation. b Example of trial-averaged LFP raw trace, post CFA injection. The panel directly below the raw trace shows trial-averaged time–frequency spectrum, with time 0 denoting the time of pinprick stimulation. c Z-score power in the theta frequency band (4–8 Hz) before and after CFA injection. d Z-score power in the alpha frequency band (8–15 Hz) before and after CFA injection. e Z-score power in the beta frequency band (15–30 Hz) before and after CFA injection. f Z-score power in the low-gamma frequency band (30–60 Hz) before and after CFA injection. g Z-score power in the high-gamma frequency band (60–100 Hz) before and after CFA injection (p = 0.0084, Paired t-test). Error bars represent SEM. *p < 0.05, **p < 0.01

Fig. 3

Ketamine inhibited the enhancement of high-gamma band power in CFA-treated rats. a Rats received either a ketamine or saline intraperitoneal injection. b Timeline for CFA, saline, and ketamine injections. c Example of trial-averaged LFP raw trace, in the chronic pain condition two days after saline injection. The panel directly below the raw trace shows trial-averaged time–frequency spectrum, with time 0 denoting the time of pinprick stimulation. d Example of trial-averaged LFP raw trace, in the chronic pain condition two days after ketamine injection. The panel directly below the raw trace shows trial-averaged time–frequency spectrum, with time 0 denoting the time of pinprick stimulation. e Z-score power in the theta frequency band (4–8 Hz) two days after saline or ketamine injection. f Z-score power in the alpha frequency band (8–15 Hz) two days after saline or ketamine injection. g Z-score power in the beta frequency band (15–30 Hz) two days after saline or ketamine injection (p = 0.0229, unpaired t-test). h Z-score power in the low-gamma frequency band (30–60 Hz) two days after saline or ketamine injection (p = 0.0267, unpaired t-test). i Z-score power in the high-gamma frequency band (60–100 Hz) two days after saline or ketamine injection (p = 0.0086, unpaired t-test). Error bars represent SEM. *p < 0.05; **p < 0.01

Fig. 4

Ketamine had a long term effect of inhibition on the high-gamma band power in the ACC in chronic pain state. a Timeline for CFA and ketamine injections. b Example of trial-averaged LFP raw trace, in the chronic pain condition five days after ketamine injection. The panel directly below the raw trace shows trial-averaged time–frequency spectrum, with time 0 denoting the time of pinprick stimulation. c Z-score power in the high-gamma frequency band (60–100 Hz) post CFA injection, two days after ketamine injection, and five days after ketamine injection (p = 0.0140 and p = 0.0322, respectively, One-way ANOVA with Dunnett’s multiple comparisons test). Error bars represent SEM. *p < 0.05