Nociceptive transmission to rat primary somatosensory cortex--comparison of sedative and analgesic effects

Abstract

CO(2)-laser C-fibre evoked cortical potentials (LCEPs) is a potentially useful animal model for studies of pain mechanisms. A potential confounding factor when assessing analgesic effects of systemically administered drugs using LCEP is sedation. This study aims to clarify: 1) the relation between level of anaesthesia and magnitude of LCEP, 2) the effects of a sedative and an analgesic on LCEP and dominant EEG frequency 3) the effects of a sedative and analgesic on LCEP when dominant EEG frequency is kept stable. LCEP and EEG were recorded in isoflurane/nitrous-oxide anaesthetized rats. Increasing isoflurane level gradually reduced LCEPs and lowered dominant EEG frequencies. Systemic midazolam (10 μmol/kg) profoundly reduced LCEP (19% of control) and lowered dominant EEG frequency. Similarly, morphine 1 and 3 mg/kg reduced LCEP (39%, 12% of control, respectively) and decreased EEG frequency. When keeping the dominant EEG frequency stable, midazolam caused no significant change of LCEP. Under these premises, morphine at 3 mg/kg, but not 1 mg/kg, caused a significant LCEP reduction (26% of control). In conclusion, the present data indicate that the sedative effects should be accounted for when assessing the analgesic effects of drug. Furthermore, it is suggested that LCEP, given that changes in EEG induced by sedation are compensated for, can provide information about the analgesic properties of systemically administrated drugs.

Figure 1. The effect of different Isoflurane concentrations (%) on LCEP (a) and EEG (b).

Frequency distribution (FFT = fast Fourier transformation) of sampled EEG (c). (a–c) show averaged LCEP, raw data EEG sweeps and FFT from a single animal. (d) Normalized grand mean and standard deviation of averaged LCEP area under curve (AUC) and EEG dominant frequency recordings from five rats. 100% corresponds to the mean LCEP AUC at 0.9% isoflurane.

Figure 2. An overview of the stimulation protocol.

LCEP stimulation was performed every 10 minutes. The first LCEP (t = 0) and the first LCEP after drug were not included in the data analysis (see methods). “EEG” mark the time period during which 2 separate EEG recordings were made.

Figure 3. The effect of Midazolam on LCEP and EEG.

Normalized grand mean and standard deviation of averaged LCEP area under curve and EEG dominant frequency recordings is shown. “With comp” represents experiments with adjustment of volatile anaesthesia to keep a stable dominant EEG frequency after drug. “before” represents baseline measurements before drug and “after” represents LCEPs elicited after drug administration. The results from student's t-test are also shown. See methods section for details.

Figure 4. The effect of Morphine on LCEP and EEG. Normalized grand mean and standard deviation of averaged LCEP area under curve and EEG dominant frequency recordings is shown.

“With comp” represents experiments with adjustment of volatile anaesthesia to keep a stable dominant EEG frequency after drug. “before” represents baseline measurements before drug and “after” represents LCEPs elicited after drug administration. Left part of the figure shows data from 1 mg/kg and right part shows data from 3 mg/kg Morphine. The results from student's t-test are also shown. See methods section for details.