Peter J. Stienen

Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog

The sedative and analgesic effects of continuous rate infusion (CRI) of dexmedetomidine (DEX) were investigated in Beagle dogs (n=8) using auditory and somatosensory evoked potentials (AEPs and SEPs) recorded before, during and after a CRI of saline or DEX (1.0, 3.0, 5.0 μg/kg bolus, followed by 1.0, 3.0, 5.0 μg/kg/h CRI, respectively). The results showed a significant reduction in AEP at doses of 1.0 μg/kg/h and above and a significant reduction of the SEP at doses of 3.0 and 5.0 μg/kg/h. Neither the AEP nor the SEP was further reduced at 5.0 μg/kg/h when compared to 3.0 μg/kg/h, although a slower return towards baseline values was observed at 5.0 μg/kg/h. The mean plasma levels (±SEM) of DEX during infusion were 0.533±0.053 ng/mL for the 1.0 μg/kg/h dose, 1.869±0.063 ng/mL for the 3.0 μg/kg/h dose and 4.017±0.385 for the 5.0 μg/kg/dose. It was concluded that in adult dogs, a CRI of DEX had a sedative and analgesic effect that could be described quantitatively using neurophysiological parameters. Sedation was achieved at lower plasma levels than required for analgesia, and DEX had a longer (but not larger) effect with infusion rates above 3.0 μg/kg/h.

Evaluation of methods for eliciting somatosensory-evoked potentials in the awake, freely moving rat.

To standardise the method of eliciting somatosensory-evoked potentials (SEPs), SEPs were generated by electrical stimulation of different stimulus sites and recorded bilaterally from the primary somatosensory cortex (S1) and from midline in awake, freely moving rats. Increasing stimulus intensity enhanced amplitudes of all SEPs. At supramaximal stimulation, SEPs following vibrissae and tail stimulation (V-SEP and Ta-SEP, respectively) but not following trunk stimulation (Tr-SEP), fulfilled our criterion of signal-to-noise ratio >or=4. The first V-SEP component coincided with a stimulus artefact, disqualifying these recordings for a standard stimulation protocol. The Ta-SEP generated stable and reproducible recordings and was considered to be the preferred technique. Early components of the contralateral S1 recorded V-SEP and Tr-SEP occurred at latencies different from the other recordings. Increasing stimulus repetition rate (SRR) decreased amplitudes of all SEPs. At the highest obtainable SRR, the amplitude between the V-SEP second positive and second negative components in all recordings was 70-80% of the amplitude at 0.1 Hz, whereas peak amplitudes of subsequent components and those of the Tr-SEP and Ta-SEP were 20-50%. These results indicate that the different SEP components might be generated by different ascending neural pathways.

Evaluation of analgesic and sedative effects of continuous infusion of dexmedetomidine by measuring somatosensory- and auditory-evoked potentials in the rat

OBJECTIVE To study, the analgesic and sedative effects of different constant rate infusions (CRI) of dexmedetomidine, in the rat, by measurement of specific electroencephalographic parameters. The recorded parameters were somatosensory-evoked potentials (SEPs) and auditory-evoked potentials (AEPs), which have been shown to be related to analgesia and sedation respectively. ANIMALS Nine male Wistar rats (HsdCpb:Wu, Harlan Netherlands BV, body weight 300-350 g). METHODS Somatosensory-evoked potentials were recorded from the primary somatosensory cortex and the vertex location (SI/Vx-SEPs). Auditory-evoked potentials were recorded from the primary auditory cortex and vertex location (AI/Vx-AEPs). Primary somatosensory cortex and vertex location recorded SEPs and AI/Vx-AEPs were recorded alternately, during CRI of dexmedetomidine (4.0, 10.0, 20.0 microg kg(-1) hour(-1)) and a control (saline). RESULTS The primary somatosensory cortex-evoked potentials were not affected by the dexmedetomidine CRI, but the other three parameters were significantly affected; although the AI-SEP to a lesser extent than the Vx-SEP and Vx-AEP. A maximum effect on the Vx-AEP was reached at lower doses than on the Vx-SEP. CONCLUSIONS Based on the present findings, it is suggested that CRI of dexmedetomidine provided profound sedation at low doses, whereas higher doses are needed to provide concurrent analgesia. CLINICAL RELEVANCE A constant rate infusion of dexmedetomidine can be a valuable adjunct in the provision of sedation and/or analgesia. However, analgesia cannot be produced without sedation, and sedation is not necessarily accompanied by comparative degrees of analgesia.

Differences between primary somatosensory cortex- and vertex-derived somatosensory-evoked potentials in the rat

The somatosensory-evoked potential (SEP) elicited by high-intensity stimulation potentially provides a reliable indicator of analgesic efficacy since it reflects the level of activation of the nociceptive system. In the present study, components in the 10-30-ms latency range of SEPs recorded over the primary somatosensory cortex (SI-SEPs) and vertex (Vx-SEP) in the rat were characterized and compared. SEPs were elicited by electrical tail-base stimulation, and SI-SEPs and Vx-SEPs were recorded simultaneously. Responses to increasing stimulus intensity and stimulus frequency while awake and responses to bolus injection of fentanyl, thiopental, and ketamine were investigated. The SI-SEP positive component (P) occurring at 12 ms after stimulation (P12) showed a significantly lower intensity threshold and was significantly less affected by increasing stimulus frequency and by administration of the different drugs when compared to the Vx-SEP P15. The fact that a single stimulus modality results in different signal characteristics dependent on the recording site supports the view that different neural mechanisms involved in primary processing of somatosensory information are responsible for the generation of the SI-SEP P12 and Vx-SEP P15, respectively. This differentiation between SI-SEPs and Vx-SEPs potentially has distinct consequences using the SEP to evaluate nociception and analgesia in the rat model.

Somatosensory-evoked potentials indicate increased unpleasantness of noxious stimuli in response to increasing stimulus intensities in the rat

Recently, it has been shown in rats that specific characteristics of somatosensory-evoked potentials (SEPs) recorded from different sites on the scalp correlate differently to the amount of unpleasantness experienced by the animal following noxious stimulation. It was shown that the SEP recorded from vertex (Vx-SEP) did correlate with the unpleasantness, whereas the SEP recorded from the primary somatosensory cortex (SI-SEP) did not. In the present study, we further investigated the relationship between the Vx-SEP, SI-SEP and the unpleasantness of noxious stimuli. Therefore, different groups of rats were subjected to a SEP fear-conditioning paradigm in which the unconditioned stimulus (US), represented by noxious stimuli applied to evoke SEPs, was paired to a conditioned stimulus (CS) represented by a tone. Different stimulus intensities of the US were applied in the different groups. After CS-US presentation, CS-induced fear-conditioned behaviour was analysed in relation to the characteristics of the Vx- and SI-SEP during CS-US presentation. Results showed that increasing stimulus intensities led to increased SEP amplitudes, which were paralleled by an increased amount of CS-induced fear-conditioned behaviour. No differences between Vx-SEP and SI-SEP were found. The increase in the SEPs in parallel with the increased amount of fear-induced behaviour further supports the SEP to be a potentially valuable tool for studying acute pain and analgesia in animals.

Nociception-related somatosensory evoked potentials in awake dogs recorded after intra epidermal electrical stimulation

At present, the specific neurophysiologic methodology of recording pain‐related evoked potentials is considered a most promising approach to objectively quantify pain in man. This study was designed to characterise and evaluate the use of somatosensory evoked potentials to study nociception in a canine model. To this aim, somatosensory evoked potentials were evoked by intra‐epidermal electrical stimulation and recorded from the scalp in 8 beagle dogs. Characteristics determined were: (1) the conduction velocities of the peripheral nerve fibres involved, (2) the stimulus intensity response characteristics and (3) the evaluation of possible disturbance of the signals by muscular activity from the hind paw withdrawal reflex (EMG artefact). The results showed (1) the conduction velocities to be in the A‐delta fibre range (i.e. fibres involved in nociception), (2) an increase in amplitude and a decrease in latency of the evoked potential following increasing stimulus intensities and (3) the absence of EMG artefact in the signals. These data indicate that the evoked potentials recorded, are related to nociception and thus are suited to quantitatively characterise the perception of noxious stimuli making this model useful for pain‐ and analgesia‐related research.

The α2-adrenoceptor agonist dexmedetomidine suppresses memory formation only at doses attenuating the perception of sensory input

It was investigated whether continuous rate infusion of the alpha(2)-adrenoceptor agonist dexmedetomidine can suppress memory formation by mechanisms other than reducing perception of sensory input in a fear-conditioning paradigm. Different groups of rats infused with either saline or dexmedetomidine (2.0, 4.0 or 10.0microg/kg bolus, followed by 2.0, 4.0 or 10.0microg/kg/h continuous rate infusion respectively), were subjected to a somatosensory-evoked potential (SEP) fear-conditioning paradigm. This paradigm combined the pairing of an innoxious conditioned stimulus (CS) and a noxious unconditioned stimulus (US), of which the latter was used to generate the SEPs (training phase).The following day, the perception of the US during the training phase was assessed by presenting the CS only and subsequently scoring the resulting duration of freezing behaviour (testing phase). Freezing behaviour was reduced only in those groups which demonstrated reduced SEPs. Based on these findings, it is concluded that dexmedetomidine suppresses memory formation only at doses reducing central nervous system activity in response to sensory input.

Differences between somatosensory-evoked potentials recorded from the ventral posterolateral thalamic nucleus, primary somatosensory cortex and vertex in the rat

Somatosensory-evoked potential (SEP) components recorded over the primary somatosensory cortex (SI) and vertex in the rat within the 10-30 ms latency range were characterised with respect to the anatomy and function of the primary somatosensory pathway. To this aim, these components were compared to SEP components in the similar latency range recorded from the ventral posterolateral thalamic (VPL) nucleus, a nucleus known to be part of the subcortical structure of the primary somatosensory pathway and were described with respect to their stimulus-response characteristics and their response to the mu-opioid agonist fentanyl. The VPL positive (P)11-negative (N)18-P22 and SI P13-N18-P22 differed with respect to peak occurrence (P11 versus P13, respectively) and waveform morphology, but did not differ with respect to stimulus-response characteristics and their response to fentanyl. When compared to the vertex P15-N19-P26, the VPL P11-N18-P22 and SI P13-N18-P22 complex follow a relatively fast acquisition in stimulus intensity-response and were affected significantly less to increasing stimulus frequencies and to fentanyl. These results demonstrated that when compared to the VPL-SEP and SI-SEP, the Vx-SEP was modulated differently by the experimental conditions. It is suggested that this may be related to involvement of neural structures within different functional somatosensory pathways.