Research paperEffects of isoflurane on auditory evoked potentials in the cochlea and brainstem of guinea pigs
Introduction
Experimental electrophysiological recordings of the auditory system are frequently performed under deep anesthesia. General anesthesia is essential when invasive surgery is needed and can be necessary to prevent movement of the animal to minimize artifacts during recordings. Volatile anesthetics such as isoflurane, can be preferable above injection anesthetics since the anesthetic regime can be regulated precisely and adapted swiftly in answer to an altered physiological status of the animal. This can be especially advantageous in sensitive animals such as guinea pigs, which are notoriously difficult for achieving a safe and effective general anesthesia (Wolfensohn and Lloyd, 1994). Anesthetics, including the volatile anesthetics, affect the physiological status of the animal which has to be taken into account when interpreting electrophysiological data in the anesthetized animal.
The acoustically evoked brainstem response (ABR), compound action potential (CAP) and cochlear microphonic (CM) are routinely recorded in anesthetized animals to assess the functionality of the auditory pathway. With regard to the ABR, general anesthetics such as barbiturates (Shapiro et al., 1984, Drummond et al., 1985, Church and Shucard, 1987), ketamine (Church and Gritzke, 1987) and the halogenated volatiles (Dubois et al., 1982, Sainz et al., 1987, Santarelli et al., 2003) typically increase its latency, especially of later peaks, without affecting the amplitude. Nitrous oxide (Manninen et al., 1985), and the opioids morphine and fentanyl (Samra et al., 1984, Samra et al., 1985) do not affect the ABR. Effects of general anesthetics on the peripheral auditory system are less well characterized and reported effects are variable. Pentobarbital and ketamine have been reported to increase threshold and latency of the CAP at high stimulus frequencies (Cazals et al., 1980). Pentobarbital has also been shown to reduce CM amplitude (Samara and Tonndorf, 1981). In contrast, a later study examining the effect of various anesthetics including pentobarbital and ketamine showed no effects on either CAP amplitude or latency (Brown et al., 1983). The NMDA antagonist 2-amino-5-phosphonovalerate (a ketamine-like compound) has been shown to suppress the amplitude and increase the latency of CAPs, without affecting CM amplitude (Puel et al., 1991). Finally, benzodiazepines were shown to increase CAP amplitude, but decrease the CM (Velluti and Pedemonte, 1986).
This study evaluated the effects of isoflurane on auditory evoked potentials. Isoflurane is a general inhalation anesthetic that induces sedation, hypnosis, immobility and amnesia. Isoflurane has a broad pharmacological profile and affects many neurotransmitter receptor systems including the GABAergic, glycinergic, acetylcholinergic, serotoninergic and glutamatergic system (reviewed by Eger (2004) and Grasshoff et al. (2005)).
Much attention has focussed on the effects of isoflurane on the auditory cortical system and especially the auditory middle latency response (MLR) has received attention. Numerous studies have shown that isoflurane decreases MLR amplitude and increases MLR latency (e.g. Thornton et al., 1992, Schwender et al., 1997, Leistritz et al., 2002). Effects of isoflurane on the auditory brainstem response (ABR) have also been well documented. Several studies on the effects of isoflurane in humans have shown an increased latency of the late ABR peaks. ABR amplitude was unaffected in these studies (Manninen et al., 1985, Sebel et al., 1986, Lloyd-Thomas et al., 1990). In rats isoflurane has been shown to increase the latency of all ABR peaks including peak I (Santarelli et al., 2003). Since the early peak I of the ABR is thought to represent auditory nerve activity (Legatt, 2002), this indirectly indicates that the auditory nerve response is delayed in rats, but not in humans. Effects of isoflurane on the auditory nerve and cochlear responses using direct CAP recordings have not yet been reported. Isoflurane was shown to suppress the amplitude of evoked otoacoustic emissions, indicating an effect on cochlear hair cells (Ferber-Viart et al., 1998).
In this study we examined the effects of various concentrations of the volatile anesthetic isoflurane using electrocochleography and ABR recordings in guinea pigs. We report effects of isoflurane on the amplitude, threshold and latency of the CAP and ABR, and on the amplitude and threshold of the CM.
Section snippets
Animals and surgery
Seven healthy female albino guinea pigs (strain: Dunkin Hartley; supplier: Harlan Laboratories) were used that weighed 300–600 g at the time of recording. Surgical procedures on these animals were approved by the Animal Ethical Committee of the Academic Biomedical Centre of the University of Utrecht under numbers 05.02.021 and 2007.I.02.025. Animals were housed according to the standards of the animal care facility of the University of Utrecht.
Animals were equipped with chronically implanted
Effects of isoflurane on CAP and CM in individual animals
CAP and CM data were obtained in five animals. Fig. 1 shows CAP recordings at 11.3 kHz in a representative animal in the awake condition and when artificially ventilated with 3% isoflurane. Isoflurane clearly decreased CAP amplitudes. Fig. 2 displays the effects of isoflurane on CAP and CM in individual animals to illustrate inter-animal variability. Cochlear responses were evoked with 11.3 kHz tones of 63 dB SPL and are shown as a function of isoflurane concentration. In four out of five animals
Discussion
We have shown that isoflurane affects the auditory system from periphery (CAP, CM) to brainstem (ABR) in the guinea pig. On average, isoflurane dose-dependently suppressed the amplitude and increased the threshold of the CAP. Effects on CM amplitude were more variable, but at high concentrations CM was invariably suppressed. Isoflurane dose-dependently increased CAP latency. Effects were most pronounced at high frequencies (Fig. 3, Fig. 4) and were typically significant at 2.5–3% isoflurane.
Acknowledgements
This work was funded by the Heinsius-Houbolt fund, Wassenaar, The Netherlands.
The authors wish to thank Rik Mansvelt-Beck and Josine Verhaal for technical assistance and are grateful to René van de Vosse for data acquisition and analysis software and technical assistance.
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