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1Department of Otolaryngology, People's Hospital, Faculty of Medicine, Wuhan University, Wuhan, China; and 2Department of Surgery–Otolaryngology, University of Kentucky Medical Center, Lexington, Kentucky
Submitted 15 September 2004; accepted in final form 1 December 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). These emissions provide evidence for an active mechanical amplification of sounds in the inner ear (Kim 1980; Norton 1992; Rosowski et al. 1984; Wilson 1980). Many experimental data (Fitzgerald et al. 1993; Frolenkov et al. 1998; Grosh et al. 2004; Probst 1990; Whitehead et al. 1992a, b), including genetic studies (Cheatham et al. 2004a; Liberman et al. 2002), indicate that these active cochlear mechanics mainly originate from outer hair cells (OHCs). In the mammalian cochlea, OHCs have electromotility that can actively enhance the basilar membrane vibration in response to acoustic stimulation (Brownell et al. 1985). Elimination of OHC electromotility can induce hearing loss and also result in elimination or decrease in otoacoustic emissions (Harris 1990; Liberman et al. 2002; Lonsbury-Martin and Martin 1990). Hence, otoacoustic emission measurement provides a reliable noninvasive test to examine OHC and cochlear functions in vivo.
Salicylate (aspirin) is a widely used drug in clinics. It has been known that salicylate can cause reversible tinnitus and hearing loss (Boettcher and Salvi 1991; Brien 1993; Cazals 2000; Matz 1990; Myers and Bernstein 1965). Electrophysiological and histological studies suggest that salicylate mainly acts on cochlear OHCs to influence hearing function. Salicylate can reversibly eliminate OHC electromotility. OHCs perfused with salicylate solution show vesiculation of subsurface cisternae in their lateral walls and a reversible reduction in the turgidity, axial stiffness, electromotility, and motility-associated nonlinear capacitance (Dieler et al. 1991; Kakehata and Satons-Sacchi 1996; Lue and Brownell 1999; Shehata-Dieler et al. 1991; Tunstall et al. 1995). A recent experiment further revealed that salicylate can competitively bind the motor protein prestin with its external voltage sense of Cl– ions to inhibit OHC electromotility (Oliver et al. 2001; Zheng et al. 2000). In in vivo recording, salicylate reversibly eliminated spontaneous otoacoustic emissions (SOAEs) and reduced distortion product otoacoustic emissions (DPOAEs) acutely after administration (Fitzgerald et al. 1993; Janssen et al. 2000; Kujawa et al. 1992; Long and Tubis 1988; Martin et al. 1988; McFadden and Plattsimer 1984; Wier et al. 1988). These effects are consistent with hearing loss observed in the clinic after treatment with a high dose of salicylate.
However, it is difficult to reconcile these changes with salicylate-induced tinnitus generation. Tinnitus is a virtual auditory sense without a corresponding acoustic stimulus, showing hypersensitivity in the auditory system. Many factors can act on central and peripheral auditory systems to induce tinnitus (Baguley 2002; Jastreboff 1990; Kaltenbach 2000; Lockwood et al. 2002; Salvi et al. 2000). In the clinic, repetitive administration of a relatively high dose of salicylate can uniformly cause tinnitus perception (for review, see Cazals 2000). Daily treatment with salicylate can also induce animals to develop tinnitus (Guitton et al. 2003; Jastreboff and Sasaki 1986; Jastreboff et al. 1988a, b). It has been reported that salicylate increases the spontaneous activity of the auditory nerves (Evans and Borerwe 1982; Stypulkowski 1990) and changes the average spectrum of cochleoneural activity (Cazals et al. 1998; Martin et al. 1993; Schreiner and Snyder 1987). Increased spontaneous neural activities also occurred in the inferior colliculus (Chen and Jastreboff 1995; Jastreboff and Sasaki 1986; Manabe et al. 1997) and the auditory contex (Ochi and Eggermont 1996). However, the precise mechanism still remains unclear. In this experiment, we adopted recording of DPOAEs in awake guinea pigs to examine the effect of salicylate on cochlear and OHC functions. The data showed that a single injection of salicylate could reduce the amplitude of distortion product of 2f1-f2 in otoacoustic emissions, but long-term administration of salicylate progressively raised the distortion product. This suggested that the long-term administration of salicylate may paradoxically enhance OHC electromotility. The data also provide evidence that OHCs may play an important role in salicylate-induced tinnitus generation.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Adult guinea pigs (250 
300g) of either sex with normal pinna reflex and no middle ear infections were used in the experiments. During the DPOAE measurement, the guinea pig was placed in a box in a double-wall soundproof cabin without anesthesia, and its head was gently fixed with a nose ring. Before measurement, animals were trained one or two times to accustom them to the testing environment. Most animals were quiet during the recording. The testing would be repeated if the recording was unstable.
Distortion product measurement
A cubic distortion component of 2f1-f2 in DPOAEs was measured using a CELESTA 503 Cochlear Emission Analyzer (Madsen, Denmark). Two plastic tubes that were 5 cm long and had a 3-mm ID were inserted into the external ear canal and sealed with an earplug. Two pure tones (f1 and f2) were simultaneously delivered into the ear. The ratio of f2 versus f1 (f2/f1) was 1.22. The test frequency was presented by a geometric mean of f1 and f2 [f0 = (f1 x f2)1/2] from f0 = 0.75–8 kHz. The intensity of f1 (L1) was set at 5 dB SPL (0 dB SPL re. 20 µPa) higher than that of f2 (L2). The distortion product was recorded from the L1/L2 level of 15/10–70/65 dB SPL in a step of 5 dB SPL. One hundred fifty responses were averaged. The recording was set to be automatically stopped when the amplitude of the 2f1-f2 component was lower than 2 SD of the noise floor level.
Salicylate administration and experiment procedure
Sodium salicylic acid was purchased from Sigma (St. Louis, MO) and freshly dissolved in saline to a concentration of 200 mg/ml. In the acute effect study, a single dose of sodium salicylate (200 mg/kg) was administered to 10 guinea pigs through intramuscular injection. The equivalent volume of saline was given to five guinea pigs at the same time as control. The distortion product of 2f1-f2 was measured at 30 min prior to the injection and at 2, 4, and 8 h after the injection. In the long-term administration experiment, sodium salicylate of 200 mg/kg was intramuscularly injected into eight guinea pigs at 9:00 A.M. and 6:00 P.M. every day for 14 days. Three other guinea pigs were given injection of the equivalent volume of saline as a control group. The distortion product of 2f1-f2 was measured at 30 min prior to the injection at 9:00 A.M. The day of beginning injection was referred to day 0. Distortion product otoacoustic emissions were measured at days –7 and –3 prior to the administration of salicylate, days 0, 3, 7, 10, and 14 in the injection period, and the first, second, third, and fourth week after cessation of the injection (see Fig. 3).
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The statistical analyses were performed using commercial software, SPSS v10.0 (SPSS, Chicago, IL). A level of P < 0.01 was accepted as a statistical significance.
This work was approved and carried out in conformity with all applicable regulations and institutional use rules for the use of animals in research.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In this experiment, we measured DPOAEs in awake guinea pigs to study the effects of salicylate on the cochlear function. Figure 1 shows the distortion product of 2f1-f2 in the normal awake guinea pigs (35 ears). The distortion product of 2f1-f2 shows an increase for the test frequency (f0) from 0.75 to 8 kHz (Fig. 1A). The inset in Fig. 1A is a recording spectrum showing that the amplitude of 2f1-f2 was about 50 dB SPL at f0 of 8 kHz, and the primary sound pressure levels were 70/65 dB SPL. The recording also had a good repeatability. The distortion product audiograms (DP-gram) were almost identical in the repeated recordings at different days (Fig. 1A). The distortion product of 2f1-f2 increased with stimulus sound intensity (Fig. 1B). There is a notch visible at 60/55 dB SPL in the I/O function. The recording noise levels were about –20 dB SPL and were flat in the test intensity range from L1/L2 of 20/15 to 70/65 dB SPL.
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A single salicylate injection could reduce distortion products in acoustic emissions. Figure 2 shows the reduction in otoacoustic emissions after the single injection of salicylate. The reduction in the distortion product of 2f1-f2 was significant at 2 h after the injection of salicylate (Fig. 2). The acute reduction in the distortion product of otoacoustic emissions for salicylate injection was reversible. Eight hours after the injection, the distortion product level had almost recovered to the initial normal level. In the control group with saline injection, the distortion product had no alteration and remained stable during the whole test period (empty circles in Fig. 2).
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In contrast with the acute effect of short-term application of salicylate, long-term application of salicylate induced an increase in the distortion product of 2f1-f2 (Figs. 3, 4–5). Figure 3 shows the audiogram of 2f1-f2 in long-term administration of salicylate measured from f0 of 0.75–8 kHz. The distortion product of 2f1-f2 progressively increased during the salicylate treatment at every test frequency (Figs. 3 and 4). After daily injection of salicylate for 14 days, the distortion product raised about 2–3.5 dB SPL, which was significantly different from the normal level (P < 0.01, ANOVA). The increase was reversible. After cessation of the injection of salicylate, the raised distortion product level slowly reduced (Fig. 3). Four weeks after cessation of the injection, the distortion product returned to the normal control level and was completely recovered (Figs. 3 and 4A). In the control group with saline injection, there was no change in the distortion product of 2f1-f2 (data not shown).
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Effects of salicylate on the I/O function of distortion products
Salicylate also altered the I/O function of distortion product (DP-I/O function). The left column in Fig. 6 shows that the reduction in the acoustic emission for a single injection of salicylate was significant at low and middle sound pressure levels and shifted the DP-I/O function downward. The nonlinearity of the DP-I/O functions was retained. The notch was visible, but its position was shifted to high intensities. Compared with suppression on the I/O function of 2f1-f2 in acute response to single salicylate injection, long-term administration of salicylate raised the distortion product levels and shifted the I/O function upward (right column in Fig. 6). The increase was significant at high sound pressure levels. The notch was also visible but shifted upward.
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2f1-f2) for acute and long-term administration of salicylate. For a single salicylate injection (left column in Fig. 7), the reduction in the distortion product decreased with sound pressure levels. The change was almost linear except there was a notch at 60/55 dB SPL. The slope of change was 0.2–0.35 dB SPL. In the control group with saline injection, no change was detectable (Fig. 7, open circles). For long-term administration of salicylate (right column in Fig. 7), the distortion product increased at low sound pressure levels, became saturated and then slightly decreased at high sound pressure levels. There was also no significant change in the distortion product in the control group with the saline injection (Fig. 7, open circles). This also showed that the recording in long-term repeated measurements was stable.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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It has been well documented that salicylate can reduce otoacoustic emissions. In the clinic, consumption of aspirin uniformly reduced the SOAEs to levels that were unmeasurable or approaching the noise floor of the measurement system (Johnsen and Elberling 1982; Long and Tubis 1988; McFadden and Plattsmier 1984; Ueda et al. 1996). The aspirin also reduced the amplitude of DPOAEs but did not abolish them. Intracochlear perfusion of salicylate reduced basilar membrane movement (Grosh et al. 2004; Murugasu and Russell 1995) and 2f1-f2 distortion products in the ear canal spectrum and in the cochlear microphonic (CM) responses (Fitzgerald et al. 1993; Frank and Kossl 1996; Kujawa et al. 1992). In in vitro recording, perfusion of salicylate also diminished the electronic distortion products evoked by two sinusoidal stimuli in isolated OHCs (Takahashi and Santos-Sacchi 1999; Zhao and Santos-Sacchi 1999).
In this study, single salicylate injection could rapidly reduce the amplitude of 2f1-f2 (Fig. 2); the decrease was significant at low intensity levels (Figs. 6 and 7). This is consistent with previous reports that the degree of amplitude reduction was greater at low primary sound levels (Wier et al. 1988). It has been reported that intraperitoneal injection of 460 mg/kg sodium salicylate can induce a serum concentration of salicylate at 600–700 mg/L and of about 200 mg/L in the cochlear perilymph within 2–4 h in the guinea pig (Jastreboff et al. 1986). In this experiment, we used 200 mg/kg of sodium salicylate intramuscular injection. The salicylate concentration in the cochlear perilymph would be 90 mg/L (Cazals 2000). This concentration of salicylate could reversibly eliminate OHC electromotility in in vitro patch-clamp recording (Dieler et al. 1991; Kakehata and Satons-Sacchi 1996; Shehata-Dieler et al. 1991; Tunstall et al. 1995).
However, long-term administration of salicylate could increase the DPOAE levels (Figs. 3–7). As evidenced by their high emission levels, OHCs are obviously functioning. Although there is a debate on the origination and mechanisms of otoacoustic emissions, there is no doubt that the otoacoustic emissions reflect the active cochlear mechanics. In the mammalian cochlea, OHCs have an electromotility capable of actively enhancing basilar membrane vibration (Brownell et al. 1985), and this electromotility was termed an active cochlear amplifier (Dallos 1992). Knockout of the prestin gene can result in reduction in DPOAEs and hearing loss (Cheatham et al. 2004a; Liberman et al. 2002). It has also been found that Cl– ions work as an external voltage sensor of prestin to trigger cell movement; salicylate can competitively bind prestin with Cl– to eliminate OHC electromotility (Oliver et al. 2001). However, long-term administration of salicylate increased the distortion products (Figs. 3–7). Several mechanisms could be underlying this enhancement. For example, long-term use of salicylate may induce prestin up-regulation and/or relative increase in affinity of prestin with anionic ions (external voltage sensors). It has been reported that prestin is up-regulated in prestin–/+ heterozygous mice (Cheatham et al., 2004b). Long-term use of salicylate may also result in increase in the mechanical nonlinearity associated with stereociliary transduction. Stereocilia mechanics can produce acoustic emissions (Hudspeth 1997; Liberman et al. 2004). Finally, long-term administration of salicylate may also induce alteration in cyclooxygenase activity to affect active cochlear mechanics. Salicylate can inhibit cyclooxygenase activity (Mitchell et al. 1993; Vane 1971; Vane and Botting 1998). However, it has been reported that daily intraperitoneal injections of mefenamate, a potent cyclooxygenase inhibitor, did not change the tinnitus-like behavior in animals (Guitton et al. 2003). It has also been found that intracochlear perfusion of mefenamate had no effect on cochlear function (Puel et al. 1990).
Possible mechanisms of salicylate-induced tinnitus generation
Salicylate is a well-known ototoxic drug that can cause reversible tinnitus and hearing loss. Tinnitus often appears as the first or as an only subjective symptom (Day et al. 1989; Mongan et al. 1973). In the clinic, tinnitus often appears during administration of aspirin (salicylate) after several days to several weeks, becomes louder as treatment is continued, and sounds like a high-pitch noise (Day et al. 1989; McCabe and Dey 1965; Mongan et al. 1973; Myers and Bernstein 1965). Behavioral experiments with rats also give evidence of tinnitus occurring after 26 h of treatment, increasing in loudness with duration of treatment, and having a high pitch (Jastreboff and Sasaki 1994). Tinnitus is thought to be associated with increased or enhanced auditory neuronal activities. It has been reported that salicylate could increase spontaneous activity of the inferior colliculus (Chen and Jastreboff 1995; Jastreboff and Sasaki 1986; Manable et al. 1997) and the auditory cortex (Eggermont and Kenmochi 1998; Ochi and Eggermont 1996). These changes may cause generation of tinnitus perception. However, the most substantial pharmacological and pathological effects of salicylate occur in the cochlea (Cazals 2000). At the auditory nerves, salicylate could increase spontaneous activity, broaden tuning curve, and reduce Q10 values (Evans and Borerwe 1982). Cazals et al. (1998) monitored changes in the average spectrum of electrophysiological cochleoneural activity (ASECA) in long-term administration of salicylate. They found that the ASECA rose at 1 kHz during the treatment. The increase was reversible and returned to the normal level after cessation of the treatment. It has been hypothesized that imbalance between inner hair cell and outer hair cell activities can trigger tinnitus happening (Jastreboff 1990). In this experiment, short-term application of salicylate reversibly reduced the distortion product and long-term administration of salicylate increased the amplitude of 2f1-f2 (Figs. 2–7). Both changes could be associated with OHC activity. This further indicates that OHCs may play an important role in salicylate-induced tinnitus generation.
It has been reported that DPOAEs could be measured in tinnitus-affected ears despite the severe hearing loss (Janssen et al. 1998). Enhancement of otoacoustic emissions was also reported in temporary noise-induced tinnitus after exposure of a loud low-frequency tone or in acoustic trauma ears with tinnitus (Attias et al. 1996). Computer modeling showed that the impedance alteration of cochlear micromechnics caused by OHC malfunction was responsible for the generation of inner ear standing waves (Zweig and Shera 1995), which can result in both spontaneous otoacoustic emissions and tinnitus. Recently, the distortion products have been shown capable of directly generating from nonlinearity of voltage dependence of OHC electromotility (Takahashi and Santos-Sacchi 1999) and electro-mechanical coupling between OHCs (Zhao and Santos-Sacchi 1999). The generation of distortion products increased as the amplitude of stimulus voltage increased. In our in vivo recording, the increasing of the 2f1-f2 component was greater at moderate-to-high sound intensities (Figs. 6 and 7). Apparently, OHCs would produce high mechanical distortion when stimulated by high-level stimuli. This can also induce improper excitation for the inner hair cells causing tinnitus.
In summary, we studied the effects of salicylate on cochlear function by measuring DPOAEs in awake guinea pigs in this experiment. We found that long-term administration of salicylate could paradoxically increase the cubic distortion product of 2f1-f2. This finding implied that long-term administration of salicylate could enhance active cochlear mechanics. This also suggested that the salicylate-induced tinnitus might be generated at the OHC level.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: H.-B. Zhao, Dept. of Surgery–Otolaryngology, Univ. of Kentucky Medical Center, 800 Rose St., Lexington, KY 40536-0293 (E-mail: hzhao2{at}uky.edu)
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