Development of a rat model to assess analgesic efficacy using somatosensory-evoked potentials

Abstract

General anaesthesia is a reversible and controllable condition in which the perception of sensory stimuli by the central nervous system is suppressed. From the perspective of the subject undergoing anaesthesia, suppression of perception of noxious stimuli (analgesia) is of crucial importance. However, to date, there is no gold standard to assess the adequacy of analgesia in either man or animal. The experiments described in this thesis, together present a rat model for assessing the efficacy of the electro-encephalographic (EEG) somatosensory-evoked potential (SEP) as indicator of analgesia. The SEP has the distinct advantage over behavioural approaches (e.g. hot plate, tail flick) and other EEG parameters that it represents directly the neural substrate of pain (nociception). Somatosensory-evoked potentials are fragments of the EEG recorded time-locked after stimulation of peripheral somatosensory fibres. Since SEPs evoked by high intensity stimulation, represent neural processing of noxious stimuli and with neural processing of noxious stimuli being affected by anaesthetic drugs, the drug-induced changes in SEP waveforms are considered to be related to an altered nociceptive state. Therefore, the SEP is a potential indicator of analgesic efficacy during general anaesthesia. Although SEPs and the effect of anaesthetic drugs on SEPs, have been widely studied in anaesthesiological studies in rats, a stringent and uniform definition for eliciting and recording SEP and of SEP components, is lacking. This results in poor understanding of which neural structures generate these potentials and consequently obstruct the interpretation of SEPs in the rat model in relation to nociception and analgesia. Using the SEP in the rat as a model to assess the efficacy of analgesia, necessitates 1) a stringent definition of the stimulation/recording procedure and of SEP components with respect to generator sources, 2) a true interpretation of drug-induced changes of SEPs during anaesthesia and 3) an objective reference to validate SEPs in relation to nociception and analgesia in rats. These fundamental aspects were elaborated in the combined experiments described in this thesis. In light of the results described in this thesis, it is suggested that stimulation of, and recording in, awake, freely behaving animals provide the distinct advantage that SEPs containing a truly noxious component can be generated. In contrast to most SEP studies using (lightly) anaesthetised rats, the present technique is useful for creating baseline data prior to studying antinociceptive effects of analgesic drugs on SEPs. In addition, the amplitude of a specific SEP component appeared to be of special interest in relation to nociception and analgesia. Its relatively low sensitivity to lower stimulus intensities, its relatively high sensitivity to increasing stimulus frequency, its increased sensitivity to anaesthetic drugs and the high correlation with unpleasant sensory and emotional experiences, suggests this component to involve a functional mechanism related to discrimination between relevant and irrelevant stimuli being potentially indicative of analgesic efficacy. Although this SEP component appears to be promising to assess analgesic efficacy, there is a great need for follow-up studies elucidating what neural structures are involved in the generation of this SEP component.