salicylates and Tinnitus

This review has the purpose to summarize concentration-effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine-induced increase in hearing threshold and its recovery can be analysed according to 'the psychophysical power function'. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half-maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self-attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Aspirin; Dose-Response Relationship, Drug; Hair Cells, Auditory, Outer; Hearing Loss, Sensorineural; Humans; Mechanotransduction, Cellular; Molecular Structure; Quinine; Salicylates; Severity of Illness Index; Tinnitus

Manganese enhanced magnetic resonance imaging (MEMRI) is a method used primarily in basic science experiments to advance the understanding of information processing in central nervous system pathways. With this mechanistic approach, manganese (Mn(2+)) acts as a calcium surrogate, whereby voltage-gated calcium channels allow for activity driven entry of Mn(2+) into neurons. The detection and quantification of neuronal activity via Mn(2+) accumulation is facilitated by "hemodynamic-independent contrast" using high resolution MRI scans. This review emphasizes initial efforts to-date in the development and application of MEMRI for evaluating tinnitus (the perception of sound in the absence of overt acoustic stimulation). Perspectives from leaders in the field highlight MEMRI related studies by comparing and contrasting this technique when tinnitus is induced by high-level noise exposure and salicylate administration. Together, these studies underscore the considerable potential of MEMRI for advancing the field of auditory neuroscience in general and tinnitus research in particular. Because of the technical and functional gaps that are filled by this method and the prospect that human studies are on the near horizon, MEMRI should be of considerable interest to the auditory research community. This article is part of a Special Issue entitled .

Topics: Animals; Auditory Perception; Brain; Calcium Channels; Contrast Media; Disease Models, Animal; Humans; Ion Channel Gating; Magnetic Resonance Imaging; Manganese; Membrane Potentials; Noise; Predictive Value of Tests; Salicylates; Tinnitus

To elucidate the role of auditory cortex in tinnitus.. Neurophysiological findings in cat auditory cortex following noise trauma or the application of salicylate and quinine, all expected to induce tinnitus, were reviewed. Those findings were interpreted in the context of what is expected from studies in humans, specifically in the brains of people with tinnitus.. Tinnitus is an auditory percept to which several central structures in the auditory system may contribute. Because the central auditory system has both feed-forward connections and feedback connections, it can be described as a set of nested loops. Once these loops become activated in a pathological fashion, as they may be in tinnitus, it becomes hard to assign importance to each contributing structure. Strongly interconnected networks, that is, neural assemblies, may be determining the quality of the tinnitus percept.. It is unlikely that tinnitus is the expression of a set of independently firing neurons, and more likely that it is the result of a pathologically increased synchrony between sets of neurons. There is clear evidence for this from both evoked potentials and from neuron-pair synchrony measures.

Topics: Animals; Auditory Cortex; Auditory Pathways; Cats; Humans; Nerve Net; Noise; Pitch Perception; Quinine; Risk Factors; Salicylates; Sound Spectrography; Tinnitus

Tinnitus is a pathology, which severely impairs the quality of life, and for which no efficient therapy exists. One reason is the lack for clear understanding of the molecular mechanisms of this pathology. For example, the anatomical site and the molecular pathways responsible for the generation of tinnitus are still under debate. This is due, in part, to the difficulty to induce and measure tinnitus in animals. This paper summarizes the recent discoveries provided by the use of salicylate as a model of tinnitus. The first is the demonstration that salicylate acts at the periphery by activating on cochlear NMDA receptors that are not "normally" implicated in the transmission of auditory message to the brain. The second discovery is the clear demonstration that strong relationships exist between anxiety and perception of tinnitus. Interestingly, application of NMDA antagonists onto the round window membrane abolished tinnitus, even in animals receiving a treatment with the anxiogenic serotonergic agent meta-chlorophenylpiperazine (mCPP). In addition to classical psychotherapeutic treatments, targeting cochlear NMDA receptors, by local infusion of drugs into the middle ear to reach the cochlea, may represent a promising therapeutic strategy to cure incapacitating tinnitus, even in depressed or chronically anxious patients.

Topics: Animals; Anxiety; Disease Models, Animal; Humans; Salicylates; Tinnitus

Large doses of aspirin produce reversible hearing loss and tinnitus. These effects have been attributed to the salicylate ion, the active component of aspirin. Salicylate acts as a competitive antagonist at the anion-binding site of prestin, the motor protein of sensory outer hair cells. This provides an explanation for the hearing loss induced by aspirin. However, the molecular mechanism of salicylate-induced tinnitus remains obscure. One physiological explanation is that salicylate ototoxicity is likely to originate in an alteration to arachidonic acid metabolism. Arachidonic acid potentiates NMDA receptor currents. We therefore tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Tinnitus was assessed with a behavioural test based on an active avoidance paradigm. Results showed that the tinnitus induced by salicylate may be suppressed by the introduction of NMDA antagonists into the cochlear fluids. To determine if the activation of NMDA receptors was linked to cyclooxygenase inhibition, we investigated the effect of mefenamate (a potent cyclooxygenase inhibitor). Since NMDA antagonists also blocked mefenamate-induced tinnitus, we suggest that salicylate-induced tinnitus is mediated by cochlear NMDA receptors through the inhibition of cyclooxygenase activity. Target cochlear NMDA receptors may therefore present a therapeutic strategy for the treatment of tinnitus.

Topics: Animals; Cochlea; Cyclooxygenase Inhibitors; Disease Models, Animal; Excitatory Amino Acid Antagonists; Receptors, N-Methyl-D-Aspartate; Salicylates; Tinnitus

Early after the development of aspirin, almost 150 years ago, its auditory toxicity has been associated with high doses employed in the treatment of chronic inflammatory diseases. Tinnitus, loss of absolute acoustic sensitivity and alterations of perceived sounds are the three auditory alterations described by human subjects after ingestion of large doses of salicylate. They develop over the initials days of treatment but may then level off, fluctuate or decrease, and are reversible within a few days of cessation of treatment. They may also occur within hours of ingestion of an extremely large dose. Individual subjects vary notably as to their susceptibility to salicylate-induced auditory toxicity. Tinnitus may be the first subjective symptom, and is often described as a continuous high pitch sound of mild loudness. The hearing loss is slight to moderate, bilaterally symmetrical and affects all frequencies with often a predominance at the high frequencies. Alterations of perceived sounds include broadening of frequency filtering, alterations in temporal detection, deterioration of speech understanding and hypersensitivity to noise. Behavioral conditioning of animals provides evidence for mild and reversible hearing loss and tinnitus, similar to those observed in humans. Anatomical examinations revealed significant alterations only at outer hair cell lateral membrane. Electrophysiological investigations showed no change in endocochlear resting potential, and small changes in the compound sensory potentials, cochlear microphonic and summating potential, at low acoustic levels. Measures of cochlear mechanical responses to sounds indicated a clear loss of absolute sensitivity and an associated broadening of frequency filtering, both of a magnitude similar to audiometric alterations in humans, but at extremely high salicylate levels. Otoacoustic emissions demonstrated changes in the mechano-sensory functioning of the cochlea in the form of decrease of spontaneous emissions and reduced nonlinearities. In vitro measures of isolated outer hair cells showed reduction of their fast motile responses which are thought to be at the origin of cochlear absolute sensitivity and associated fine filtering. Acoustically evoked neural responses from the eighth nerve to the auditory cortex showed reversible and mild losses of absolute sensitivity and associated broadening of frequency filtering. There is no evidence of a direct alteration of cochlear efferent innervation. Evi

Topics: Adolescent; Adult; Aged; Animals; Auditory Threshold; Chinchilla; Cochlea; Female; Hearing Loss, High-Frequency; Hearing Loss, Sensorineural; Hearing Tests; Humans; Male; Mice; Middle Aged; Pitch Perception; Rats; Salicylates; Speech Perception; Tinnitus

Salicylates and most NSAIDS in high doses cause mild to moderate temporary hearing loss, either flat or greater in the high frequencies. Hearing loss is accompanied by tinnitus and suprathreshold changes. Salicylates may or may not exacerbate hearing loss and cochlear damage induced by noise. The mechanism of salicylate ototoxicity seems to be multifactorial. Morphologic studies suggest that no permanent cochlear damage occurs with salicylate ototoxicity. Electrophysiologic, morphologic, and in vitro data conclusively demonstrate that salicylate affects outer hair cells. In addition, salicylates appear to decrease cochlear blood flow. Salicylates and NSAIDs inhibit PG-forming cyclooxygenase, and recent studies suggest that abnormal levels of arachidonic acid metabolites consisting of decreased PGs and increased LTs may mediate salicylate ototoxicity. As with salicylate, quinine ototoxicity appears to be multifactorial in origin. The mechanism includes vasoconstriction and decreases in cochlear blood flow, as measured by laser Doppler flowmetry, motion photographic studies, and histologic studies. Reversible alterations of outer hair cells also appear to play an important role, as demonstrated by histology, electron microscopy, isolated hair cell studies, and cochlear potential evaluations. Unlike with salicylate, however, the role of prostaglandins in quinine ototoxicity has not been clearly demonstrated. Also, one of quinine's principal actions, antagonism of calcium-dependent potassium channels, has yet to be investigated for its potential role in ototoxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cochlea; Hearing Loss; Humans; Quinine; Salicylates; Tinnitus

Aspirin, the prototype of the salicylates, is a ubiquitous agent. The availability of aspirin, other salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) as prescription and over-the-counter medications means there is a wealth of clinical experience with these agents. Among the documented adverse effects of aspirin is the potential for ototoxicity. Tinnitus and hearing loss, usually reversible, are associated with acute intoxication and long term administration of salicylates. A range of measured serum concentrations are reported as correlating with documented ototoxicity (19.6 to > 67 mg/dl). Most case reports are based on total serum salicylate concentrations whereas unbound serum salicylate concentrations appear to reflect more closely the risk of ototoxicity. The pathophysiology of toxicity may be related to biochemical and subsequent electrophysiological changes in the inner ear and eighth cranial nerve impulse transmission. Localised drug accumulation and vasoconstriction in auditory microvasculature may be mediated by the antiprostaglandin activity of these agents. Ototoxicity, although not life-threatening, may add to the morbidity of patients taking salicylates or NSAIDs in therapeutic and toxic doses.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Hearing Loss; Humans; Salicylates; Tinnitus

There are few physiological data available on the origin and nature of tinnitus. It is not even known whether tinnitus associated with cochlear pathology is a manifestation of increased or decreased activity in the cochlear nerve. In previous investigations of cochlear pathology, the spontaneous neural activity has generally been found to be depressed. In the present experiments, an animal model has been established by the administration of sodium salicylate in doses producing blood concentrations that evoke tinnitus in humans. Under these conditions, changes occur in cochlear nerve-fibre thresholds and tuning, similar to those obtained in other types of cochlear pathology. However, under salicylate, the distribution of spontaneous discharge shifts significantly to higher rates than normal. These changes are accompanied in some, but not all, fibres by changes in the temporal patterns of discharge suggestive of excitation. In the second animal model studied, a normal guinea-pig that had a naturally occurring continuous tonal emission, analogous to that recently recorded in human "physiological" tinnitus, was investigated in detail. The emitted signal was recorded in the ear-canal acoustic pressure and in the round-window potential. Several lines of evidence point to the signal as being cochlear in origin, including: its resistance to muscular paralysis and section of the stapedius muscle; the effects of changes in middle-ear pressure; its reversible elimination by hypoxia; and its suppression by tones of higher frequency.

Topics: Acoustic Stimulation; Action Potentials; Aged; Animals; Cats; Cochlear Nerve; Disease Models, Animal; Ear, Middle; Guinea Pigs; Humans; Lidocaine; Oxygen; Pressure; Salicylates; Time Factors; Tinnitus

Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies.. To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes.. Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678). 3 private practices and 14 universities in the United States.. Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (< or = 225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks.. After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy.. Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes.. Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline (P = 0.009). Mean HbA1c changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated.. The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time.. Salsalate lowers HbA1c levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation.. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Topics: Adolescent; Adult; Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastrointestinal Diseases; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Prodrugs; Salicylates; Tinnitus; Young Adult

Tinnitus or subjective hearing loss, or both, were reported by 61 of 134 (45%) patients with rheumatoid arthritis (RA) taking regular salicylates and by 73 of 182 (40%) untreated healthy subjects. In the patients with RA mean salicylate levels were not higher in those with tinnitus than in those without tinnitus, but levels were significantly higher in those with subjective hearing loss than in those with no symptoms. Twenty five per cent of the patients with RA had tinnitus or subjective hearing loss with salicylate levels less than 1.42 mmol/l. Audiometric responses in 31 patients correlated poorly with symptoms. Tinnitus and subjective hearing loss may be too non-specific to be reliable as tools for adjusting the salicylate level into the therapeutic range.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Aspirin; Audiometry; Clinical Trials as Topic; Hearing Loss, Sensorineural; Humans; Middle Aged; Salicylates; Tinnitus

Topics: Acetanilides; Acetates; Anti-Inflammatory Agents; Humans; Rheumatic Diseases; Salicylates; Tinnitus

Topics: Acetanilides; Acetates; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Clinical Trials as Topic; Humans; Salicylates; Tinnitus

In a double-blind between-patient study of aspirin and benorylate carried out in 72 outpatients with rheumatoid arthritis, benorylate 4 g twice daily was shown to be an effective analgesic and anti-inflammatory drug, its effects being indistinguishable from those of aspirin 1.2 g four times daily. Compared with the pretreatment values both drugs produced a statistically significant improvement (P < 0.01) in functional grade, overall pain, articular index, and grip strength at the end of the first and second weeks. The overall incidence of side effects was less with benorylate, though this difference was not significant at the 5% level.

Topics: Adolescent; Adult; Aged; Analgesics; Aniline Compounds; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Clinical Trials as Topic; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Movement; Pain; Phenols; Physical Examination; Salicylates; Tinnitus

Topics: Adult; Aged; Aspirin; Clinical Trials as Topic; Deafness; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Salicylates; Time Factors; Tinnitus

Topics: Aspirin; Clinical Trials as Topic; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Heartburn; Humans; Photography; Placebos; Salicylates; Tinnitus

Tinnitus is a widespread and serious clinical and social problem. Although oxidative injury has been suggested to be one of pathological mechanisms in auditory cortex, whether this mechanism could be applied to inferior colliculus remains unclear. In this study, we used an online electrochemical system (OECS) integrating in vivo microdialysis with selective electrochemical detector to continuously monitor the dynamics of ascorbate efflux, an index of oxidative injury, in inferior colliculus of living rats during sodium salicylate-induced tinnitus. We found that OECS with a carbon nanotubes (CNTs)-modified electrode as the detector selectively responses to ascorbate, which is free from the interference from sodium salicylate and MK-801 that were used to induce tinnitus animal model and investigate the N-methyl-d-aspartate (NMDA) receptor mediated excitotoxicity, respectively. With the OECS, we found that the extracellular ascorbate level in inferior colliculus significantly increases after salicylate administration and such increase was suppressed by immediate injection of NMDA receptor antagonist MK-801. In addition, we found that salicylate administration significantly increases the spontaneous and sound stimuli evoked neural activity in inferior colliculus and that the increases were inhibited by the injection of MK-801. These results suggest that oxidative injury may occur in inferior colliculus following salicylate-induced tinnitus, which is closely relevant to the NMDA-mediated neuronal excitotoxicity. This information is useful for understanding the neurochemical processes in inferior colliculus involved in tinnitus and its related brain diseases.

Topics: Ascorbic Acid; Disease Models, Animal; Dizocilpine Maleate; Electrochemical Techniques; Inferior Colliculi; Oxidative Stress; Salicylates; Sodium Salicylate; Tinnitus

As a common debilitating disorder worldwide, tinnitus requires objective assessment. In the auditory brainstem response (ABR) test, auditory potentials can be evoked by acoustic or optoacoustic (induced by laser light) stimulations. In order to use the ABR test in the objective assessment of tinnitus, in this study, acoustic ABR (aABR) and optoacoustic ABR (oABR) were compared in the control and tinnitus groups to determine the changes caused by sodium salicylate (SS)-induced tinnitus in rat. In both aABR and oABR, wave II was the most prominent waveform, and the amplitude of wave II evoked by oABR was significantly higher than that of aABR. Brainstem transmission time (BTT), which represents the time required for a neural stimulation to progress from the auditory nerve ending to the inferior colliculus, was significantly shorter in oABR. In the tinnitus group, there was a significant increase in the threshold of both ABRs and a significant decrease in the amplitude of wave II only in the oABR. Based on our findings, the ABR test has the potential to be used in the assessment of SS-induced tinnitus, but oABR has the advantages of producing more prominent waveforms and significantly reducing the amplitude of wave II in tinnitus.

Topics: Acoustics; Animals; Evoked Potentials, Auditory, Brain Stem; Rats; Salicylates; Sodium Salicylate; Tinnitus

High doses of salicylate induce tinnitus in humans and experimental animals. The Dorsal Cochlear Nucleus is implicated with the genesis of tinnitus, and increased activity in this nucleus is seen in animal models of tinnitus. Incubation of brainstem slices containing the DCN with millimolar salicylate reduces the spontaneous firing of glycinergic cartwheel neurons and glycinergic neurotransmission on fusiform neurons, the principal neuron of this nucleus. However, the mechanism of salicylate mediating this effect is not known. Recently, we have shown that K

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Cochlear Nucleus; KATP Channels; Neurons; Rats; Salicylates; Tinnitus

The anti-inflammatory drug salicylate induces tinnitus in animals and man. Salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input. Systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing in the inferior colliculus (3-6 h post drug), with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 µM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing. Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus. Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.

Topics: Animals; Arginine; Guinea Pigs; Humans; Inferior Colliculi; Nitric Oxide; Nitric Oxide Synthase Type I; Receptors, N-Methyl-D-Aspartate; Salicylates; Tinnitus

To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein (

Topics: Animals; Disease Models, Animal; Humans; Neuroblastoma; Rats; Rats, Sprague-Dawley; Resveratrol; Salicylates; Tinnitus; Tumor Necrosis Factor-alpha

High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca

Topics: Animals; Cell Line, Tumor; Glutamic Acid; Humans; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, N-Methyl-D-Aspartate; Salicylates; Tinnitus; Valproic Acid

Tinnitus and hyperacusis are debilitating conditions often associated with aging or exposure to intense noise or ototoxic drugs. One of the most reliable methods of inducing tinnitus is with high doses of sodium salicylate, the active ingredient in aspirin. High doses of salicylate have been widely used to investigate the functional neuroanatomy of tinnitus and hyperacusis. High doses of salicylate have been used to develop novel behavioral methods to detect the presence of tinnitus and hyperacusis in animal models. Salicylate typically induces a hearing loss of approximately 20 dB which greatly reduces the neural output of the cochlea. As this weak neural signal emerging from the cochlea is sequentially relayed to the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex, the neural response to suprathreshold sounds is progressively amplified by a factor of 2-3 by the time the signal reaches the auditory cortex, a phenomenon referred to as enhanced central gain. Sound-evoked hyperactivity also occurred in the amygdala, a region that assigns emotional significance to sensory stimuli. Resting state functional magnetic imaging of the BOLD signal revealed salicylate-induced increases in spontaneous neural activity in the inferior colliculus, medial geniculate body, and auditory cortex as well as in non-auditory areas such as the amygdala, reticular formation, cerebellum, and other sensory areas. Functional connectivity of the BOLD signal revealed increased neural coupling between several auditory areas and non-auditory areas such as the amygdala, cerebellum, reticular formation, hippocampus, and caudate/putamen; these strengthened connections likely contribute to the multifaceted dimensions of tinnitus. Taken together, these results suggest that salicylate-induced tinnitus disrupts a complex neural network involving many auditory centers as well as brain regions involved with emotion, arousal, memory, and motor planning. These extra-auditory centers embellish the basic auditory percepts that results in tinnitus and which may also contribute to hyperacusis.

Topics: Acoustic Stimulation; Animals; Evoked Potentials, Auditory; Hyperacusis; Neuroanatomy; Rats; Rats, Sprague-Dawley; Salicylates; Tinnitus

Salicylate intoxication is a cause of tinnitus and comorbidly associated with anxiety in humans. In a previous work, we showed that salicylate induces anxiety-like behavior and hippocampal type 2 theta oscillations (theta2) in mice. Here we investigate if the anxiogenic effect of salicylate is dependent on age and previous tinnitus experience. We also tested whether a single dose of DMT can prevent this effect. Using microwire electrode arrays, we recorded local field potential in young (4-5- month-old) and old (11-13-month-old) mice to study the electrophysiological effect of tinnitus in the ventral hippocampus (vHipp) and medial prefrontal cortex (mPFC) in an open field arena and elevated plus maze 1h after salicylate (300mg/kg) injection. We found that anxiety-like behavior and increase in theta2 oscillations (4-6 Hz), following salicylate pre-treatment, only occurs in young (normal hearing) mice. We also show that theta2 and slow gamma oscillations increase in the vHipp and mPFC in a complementary manner during anxiety tests in the presence of salicylate. Finally, we show that pre-treating mice with a single dose of the hallucinogenic 5-MeO-DMT prevents anxiety-like behavior and the increase in theta2 and slow gamma oscillations after salicylate injection in normal hearing young mice. This work further support the hypothesis that anxiety-like behavior after salicylate injection is triggered by tinnitus and require normal hearing. Moreover, our results show that hallucinogenic compounds can be effective in treating tinnitus-related anxiety.

Topics: Aging; Animals; Anxiety; Behavior, Animal; Electroencephalography; Evoked Potentials, Auditory, Brain Stem; Hallucinogens; Hearing Loss, Noise-Induced; Hippocampus; Male; Methoxydimethyltryptamines; Mice; Mice, Inbred C57BL; Microelectrodes; Motor Activity; Prefrontal Cortex; Salicylates; Tinnitus

BACKGROUND Over-the-counter medications that contain aspirin are widely used, and patients generally regard them as safe. However, the side effects of salicylate toxicity can be severe, and delay in the diagnosis may increase the risk of mortality. Neurologic symptoms are a common presenting feature of salicylate toxicity in the elderly, and their recognition may allow earlier diagnosis. This report is of a case of a 61-year-old woman who presented with acute focal neurologic deficit associated with salicylate toxicity and who had a previous history of stroke. CASE REPORT A 61-year-old woman presented to the Emergency Department after awakening with left-sided weakness. She had a history of ischemic stroke with an associated seizure disorder. The patient denied recent seizure, and brain magnetic resonance imaging (MRI) showed no evidence of an acute stroke. Following her arrival, she became acutely confused and complained of tinnitus, shortness of breath, and blurred vision. On direct questioning, she gave a history of excessive use of salicylate for the previous two to three weeks. Her initial serum salicylate level was significantly increased at 78.1 mg/dl (upper therapeutic limit, 19.9 mg/dl). She recovered completely following treatment with oral activated charcoal, intravenous sodium bicarbonate, and potassium replacement. CONCLUSIONS This case demonstrates that physicians should consider salicylate toxicity as a possible cause of exacerbation of neurological deficit in elderly patients.

Topics: Charcoal; Delirium; Female; Humans; Middle Aged; Neurologic Examination; Neurotoxicity Syndromes; Paresis; Potassium; Salicylates; Sodium Bicarbonate; Stroke; Tinnitus

Tinnitus is relevant to neural hyperactivity in the central nervous system (CNS). Normal quantity and functioning of the γ-aminobutyric acid (GABA) receptor are crucial for maintaining the balance between excitation and inhibition in the brain. In this study, we applied a rat model of tinnitus via long-term salicylate administration. The combination of the gap pre-pulse inhibition of acoustic startle (GPIAS) and pre-pulse inhibition (PPI) tests were used to detect tinnitus-like behavior, and rats receiving 7 or 14 consecutive days of salicylate administration showed evidence of tinnitus. After positron emission tomography (PET) scan, we found that the metabolic activity was increased after salicylate treatment followed by enhanced GABA

Topics: Animals; Auditory Cortex; Auditory Perception; Cerebral Cortex; gamma-Aminobutyric Acid; Hippocampus; Limbic System; Male; Prefrontal Cortex; Prepulse Inhibition; Rats; Rats, Sprague-Dawley; Receptors, GABA; Receptors, GABA-A; Reflex, Startle; Salicylates; Tinnitus

Early-response auditory evoked potentials (AEPs) in humans are significantly altered in tinnitus. These changes are closely related to that seen in animals, leading to new approaches to study tinnitus based on objective parameters. The purpose of this study was to characterize the AEPs in animals with tinnitus, by assessing early to late latency responses. For behavioral evaluation, rats were trained using positive reinforcement to press a lever in the presence of an auditory stimulus and to not press during silence. The auditory brainstem response (ABR), middle latency response (MLR) and auditory late latency response (LLR) were correlated to the false-positive responses (pressing the lever during silence), after oral administrations of Sodium Salicylate (SS, 350 mg/kg). In the present study, SS significantly increased the hearing thresholds and reduced ABR peak I amplitudes across the frequency range (4-32 kHz). In contrast, increased amplitudes were observed for several peaks in ABR, MLR, and LLR. Moreover, reduced ABR latencies in response to 8, 16 and 24 kHz tone bursts were observed after SS administration. Similarly, the central evaluation also revealed significantly reduced latencies in MLR and LLR during SS administration. In contrast, increased latencies were observed for ABR latencies in response to 32 kHz tone bursts, and at the P1-N1 component of LLR. Correlational analysis revealed that latencies and amplitudes of peaks II and IV (8 and 16 kHz) of ABR, and N2 latency and P2-N2 amplitude of LLR were associated with behavioral tinnitus. We suggest that AEPs can be used in the rat to evaluate the reduced sensory input and the increased central gain in SS-induced tinnitus, as well as reduced latencies (8-16 kHz) to distinguish between hearing loss and tinnitus.

Topics: Acoustic Stimulation; Animals; Auditory Perception; Auditory Threshold; Brain Stem; Evoked Potentials, Auditory; Evoked Potentials, Auditory, Brain Stem; Female; Hearing; Hearing Loss; Noise; Rats; Rats, Sprague-Dawley; Reaction Time; Salicylates; Tinnitus

Increased prevalence of emotional distress is associated with tinnitus and hearing loss. The underlying mechanisms of the negative emotional response to tinnitus and hearing loss remain poorly understood, and it is challenging to disentangle the emotional consequences of hearing loss from those specific to tinnitus in listeners experiencing both. We addressed these questions in laboratory rats using three common rodent anxiety screening assays: elevated plus maze, open field test, and social interaction test. Open arm activity in the elevated plus maze decreased substantially after one trial in controls, indicating its limited utility for comparing pre- and post-treatment behavior. Open field exploration and social interaction behavior were consistent across multiple sessions in control animals. Individual sound-exposed and salicylate-treated rats showed a range of phenotypes in the open field, including reduced entries into the center in some subjects and reduced locomotion overall. In rats screened for tinnitus, less locomotion was associated with higher tinnitus scores. In salicylate-treated animals, locomotion was correlated with age. Sound-exposed and salicylate-treated rats also showed reduced social interaction. These results suggest that open field exploratory activity is a selective measure for identifying tinnitus distress in individual animals, whereas social interaction reflects the general effects of hearing loss. This animal model will facilitate future studies of the structural and functional changes in the brain pathways underlying emotional distress associated with hearing dysfunction, as well as development of novel interventions to ameliorate or prevent negative emotional responses.

Topics: Animals; Disease Models, Animal; Hearing Loss; Male; Maze Learning; Motor Activity; Rats; Rats, Sprague-Dawley; Salicylates; Social Behavior; Sound; Stress, Psychological; Tinnitus

We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).. Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear.. Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope.. BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05).. Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus.

Topics: Animals; Auditory Cortex; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; Salicylates; Synapses; Tinnitus

Tinnitus often results in severe psychological distress. The present study hypothesized that tinnitus acts as a chronic stressor and induces dysregulation of the production of cytokines. The gap pre‑pulse inhibition of acoustic startle paradigm was applied to test tinnitus‑like behavior in rats. Following this, the mRNA and protein expression levels of interferon (IFN)‑γ, tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and N‑methyl D‑aspartate receptor subunit 2A (NR2A) were measured in rats subjected to acute and chronic salicylate treatment, using reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The gap prepulse inhibition of acoustic startle paradigm detected the tinnitus‑like behavior of rats. The expression of TNF‑α and NR2A genes were increased in the auditory cortex (AC) following long‑term administration of salicylate, whereas the expression of IFN‑γ genes decreased; however, the mRNA levels reversed back to normal baseline 14 days following the cease of salicylate administration. IL‑6 gene expression, however, was not fundamentally altered by salicylate treatment. The data demonstrated that chronic salicylate administration induces tinnitus, in part, via dysregulation of cytokines and specific membrane receptors in the AC.

Topics: Animals; Auditory Cortex; Behavior, Animal; Biomarkers; Cytokines; Disease Models, Animal; Gene Expression; Inflammation Mediators; Male; Phenotype; Rats; Salicylates; Tinnitus

Behavioral screening remains a contentious issue for animal studies of tinnitus. Most paradigms base a positive tinnitus test on an animal's natural tendency to respond to the "sound" of tinnitus as if it were an actual sound. As a result, animals with tinnitus are expected to display sound-conditioned behaviors when no sound is present or to miss gaps in background sounds because tinnitus "fills in the gap." Reliable confirmation of the behavioral indications of tinnitus can be problematic because the reinforcement contingencies of conventional discrimination tasks break down an animal's tendency to group tinnitus with sound. When responses in silence are rewarded, animals respond in silence regardless of their tinnitus status. When responses in silence are punished, animals stop responding. This study introduces stimulus classification as an alternative approach to tinnitus screening. Classification procedures train animals to respond to the common perceptual features that define a group of sounds (e.g., high pitch or narrow bandwidth). Our procedure trains animals to drink when they hear tinnitus and to suppress drinking when they hear other sounds. Animals with tinnitus are revealed by their tendency to drink in the presence of unreinforced probe sounds that share the perceptual features of the tinnitus classification. The advantages of this approach are illustrated by taking laboratory rats through a testing sequence that includes classification training, the experimental induction of tinnitus, and postinduction screening. Behavioral indications of tinnitus are interpreted and then verified by simulating a known tinnitus percept with objective sounds.

Topics: Animals; Evoked Potentials, Auditory, Brain Stem; Generalization, Response; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Salicylates; Sound; Tinnitus

Topics: Administration, Topical; Female; Humans; Middle Aged; Nausea; Salicylates; Tinnitus; Warts

Tinnitus is associated with neural hyperactivity in the central nervous system (CNS). Salicylate is a well-known ototoxic drug, and we induced tinnitus in rats using a model of long-term salicylate administration. The gap pre-pulse inhibition of acoustic startle test was used to infer tinnitus perception, and only rats in the chronic salicylate-treatment (14 days) group showed evidence of experiencing tinnitus. After small animal positron emission tomography scans were performed, we found that the metabolic activity of the inferior colliculus (IC), the auditory cortex (AC), and the hippocampus (HP) were significantly higher in the chronic treatment group compared with saline group (treated for 14 days), which was further supported by ultrastructural changes at the synapses. The alterations all returned to baseline 14 days after the cessation of salicylate-treatment (wash-out group), indicating that these changes were reversible. These findings indicate that long-term salicylate administration induces tinnitus, enhanced neural activity and synaptic ultrastructural changes in the IC, AC, and HP of rats due to neuroplasticity. Thus, an increased metabolic rate and synaptic transmission in specific areas of the CNS may contribute to the development of tinnitus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Auditory Cortex; Hippocampus; Inferior Colliculi; Positron-Emission Tomography; Salicylates; Synapses; Tinnitus

This study demonstrates a new strategy to develop in vivo electrochemical biosensors through rational design and simple formation of bioelectrochemically multifunctional film (BMF). The BMF is rationally designed by first efficiently incorporating oxidase, ferrocene mediator, and graphene oxide into polymaleimidostyrene/polystyrene (PMS/PS) matrix to form a homogeneous mixture and then simply formed by drop-coating the mixture onto solid conducting substrate. By using the as-formed BMF, electrochemical biosensors could be constructed with a technical simplicity and high reproducibility. To illustrate the BMF-based biosensors for in vivo applications, we directly couple the biosensors to in vivo microdialysis to establish an online electrochemical system (OECS) for in vivo monitoring of glucose in rat auditory cortex during salicylate-induced tinnitus model. The OECS with the BMF-based biosensor as the detector shows a linear response toward glucose within a concentration range from 50 to 500 μM with a detection limit of 10 μM (S/N = 3). Additionally, the OECS is stable and does not suffer from the interference from the electroactive species endogenously coexisting in the brain microdialysate. With the BMF-based OECS, the basal level of glucose in the microdialysate continuously sampled from rat auditory cortex is determined to be 120 ± 10 μM (n = 5). After the rats were administrated with salicylate to induce transient tinnitus, the microdialysate glucose concentration in the rat auditory cortex remarkably increased to 433 ± 190 μM (n = 5) at the time point of 1.5 h. This study essentially offers a new, technically simple and reproducible approach to development of in vivo electrochemical biosensors, which is envisaged to be relatively useful for understanding of the molecular basis of brain functions.

Topics: Animals; Auditory Cortex; Biosensing Techniques; Disease Models, Animal; Electrochemical Techniques; Equipment Design; Glucose; Graphite; Metallocenes; Oxides; Oxidoreductases; Rats; Salicylates; Tinnitus

Although the activity of tinnitus-related ion co-transporter are known, their mRNA expressions has seldom been reported. We aimed to investigate the mRNA expressions of tinnitus-related ion co-transporter genes, and treatment effects of Spirulina.. The mRNA expressions of K(+)-Cl(-) co-transporter (KCC2) and Na-K-2Cl co-transporter 1 (NKCC1) genes in the cochlea and brain of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate. The effects of spirulina water extract on these gene expressions were investigated.. Compared to the control group, the tinnitus scores increased significantly, however, the salicylate-induced tinnitus could be reduced significantly by spirulina water extract. The tinnitus group had higher of borderline significance mRNA expression of KCC2 gene in the cochlear, significantly higher in the temporal lobes and in the frontal lobes. Meanwhile, compared to the tinnitus group, the spirulina group had significantly lower mRNA expression of KCC2 gene in the cochlear, temporal lobes, frontal lobes and parahippocampus/hippocampus. However, the NKCC1 mRNA expression was not significantly different between three groups in the cochlea and these brain areas.. Salicylate-induced tinnitus might be associated with increased mRNA expression of KCC2 gene, but not with mRNA expressions of NKCC1 gene in the cochlear and some tinnitus-related brain areas. Spirulina reduced the expression of KCC2 genes in salicylate-induced tinnitus.

Topics: Animals; Brain; Cochlea; Disease Models, Animal; Gene Expression; K Cl- Cotransporters; Male; Mice; Salicylates; Solute Carrier Family 12, Member 2; Spirulina; Symporters; Tinnitus

The purpose of this study was to investigate the mRNA expression of the dopamine receptor 1A (DR1A) and cannabinoid receptor 1 (CR1) genes in mice with tinnitus. Sixteen 3-month-old male SAMP8 mice were randomly and equally divided into two groups (8 mice in each group): a control (saline-treated) group and a tinnitus (salicylate-treated) group. The mRNA expression of the DR1A and CR1 genes in the cochleae and brains of the mice was evaluated after tinnitus had been induced by intraperitoneal injection of sodium salicylate (300 mg/kg body weight). The results showed that 4-day salicylate treatment (unlike 4-day saline treatment) caused a significant increase in the tinnitus score and in mRNA expression of the DR1A gene in the cochlea, the brainstem and inferior colliculus, the hippocampus and parahippocampus, and the temporal lobe, but not the frontal lobe. Conversely, 4-day salicylate treatment caused significantly lower mRNA expression of the CR1 gene in the cochlea and all the brain areas tested. In summary, salicylate-induced tinnitus may be associated with increased mRNA expression of the DR1A gene - but with decreased mRNA expression of the CR1 gene - in the cochlea and in many tinnitus-related brain areas.

Topics: Animals; Brain; Cochlea; Disease Models, Animal; Male; Mice; Receptor, Cannabinoid, CB1; Receptors, Dopamine D1; RNA, Messenger; Salicylates; Tinnitus

Tinnitus is one of the leading disorders of hearing with no effective cure as its pathophysiological mechanisms remain unclear. While the sensitivity to sound is well-known to be affected, exactly how intensity coding per se is altered remains unclear. To address this issue, we used a salicylate-overdose animal model of tinnitus to measure auditory cortical evoked potentials at various stimulus levels, and analyzed on single-trial basis the response strength and its variance for the computation of the lower bound of Fisher information. Based on Fisher information profiles, we compared the precision or efficiency of intensity coding before and after salicylate-treatment. We found that after salicylate treatment, intensity coding was unexpectedly improved, rather than impaired. Also, the improvement varied in a sound-dependent way. The observed changes are likely due to some central compensatory mechanisms that are activated during tinnitus to bring out the full capacity of intensity coding which is expressed only in part under normal conditions.

Topics: Acoustic Stimulation; Animals; Evoked Potentials, Auditory; Information Storage and Retrieval; Loudness Perception; Rats; Rats, Sprague-Dawley; Salicylates; Tinnitus

Salicylate's ototoxic properties have been well established, inducing tinnitus and a sensory hearing loss when administered in high doses. Peripherally, acute dosing of salicylate causes frequency dependent reductions in DPOAEs and CAP amplitudes in low (<10 kHz) and high (>20 kHz) frequencies more than mid frequencies (10-20 kHz), which interestingly corresponds to the pitch of behaviourally-matched salicylate-induced tinnitus. Chronic salicylate dosing affects the peripheral system by causing a compensatory temporary enhancement in DPOAE amplitudes and up-regulation of prestin mRNA and protein expression. Despite salicylate's antioxidant properties, cultured cochlea studies indicate it also impairs spiral ganglion neurons (SGNs) by paradoxically causing an upsurge of superoxide radicals leading to apoptosis. Centrally, salicylate alters γ-aminobutyric acid (GABA) and serotonin mediated neurotransmission in the central nervous system (CNS), which results in classical and non-classical auditory regions showing hyperactivity after salicylate administration. In the auditory cortex (AC) and lateral amygdala (LA), neuron characteristic frequencies (CF) shift upward and downward to mid frequencies (10-20 kHz) altering tonotopy following salicylate administration. Additionally, current source density (CSD) analysis showed enhanced current flow into the supergranular layer of the auditory cortex after a high systemic dose of salicylate. In humans, auditory perception changes following salicylate or aspirin, including decreased word discrimination and temporal integration ability. The results of previous studies have partially identified the mechanisms that are involved in salicylate-induced tinnitus and hearing loss, however to date some interactions remain convoluted. This review discusses current knowledge of salicylate ototoxicity and interactions.. Gli effetti ototossici del salicilato sono ben noti ed includono, ad alti dosaggi, acufene ed ipoacusia transitoria. In periferia, la somministrazione acuta di salicilato nell'animale induce una riduzione d'ampiezza dei prodotti di distorsione (DPOAE) e dei potenziali d'azione (CAP), prevalentemente per le basse (<10 kHz) e per le alte (>20 kHz) frequenze; è interessante come questa alterazione corrisponda alla tonalità dell'acufene indotto sperimentalmente. La somministrazione cronica causa invece un aumento transitorio dell'ampiezza dei DPOAEs ed una up-regulation dell'mRNA e dell'espressione proteica della prestina. In vitro la tossicità da salicilato si evidenzia prevalentemente a livello dei neuroni del ganglio spirale (SGNs) inducendo, a dispetto delle ben note proprietà antiossidanti, un rilascio paradosso di radicale superossido che avvia la catena apoptotica. Centralmente, il salicilato altera la trasmissione GABA e serotoninomediata inducendo una iperattività di specifiche popolazioni neuronali. A livello della corteccia uditiva (AC) e dell'amigdala laterale (LA) le frequenze caratteristiche neuronali (CF) variano alterando la tonotopia fisiologica, specialmente per le frequenze centrali (10-20 kHz). Inoltre, l'analisi della densità di corrente (CSD) ha dimostrato un maggior influsso negli strati supragranulari della corteccia uditiva in seguito alla somministrazione di dosi elevate di salicilato per via sistemica.Nell'uomo gli effetti ototossici del salicilato, oltre ad ipoacusia transitoria ed acufene, includono una diminuita discriminazione verbale e difficoltà nell'integrazione temporale. Sebbene diversi lavori in letteratura abbiano identificato i meccanismi fisiopatologici alla base delle alterazioni uditive indotte dal salicilato, ad oggi alcune interazioni rimangono poco chiare.

Topics: Hearing Loss; Humans; Neurotoxicity Syndromes; Salicylates; Tinnitus

Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The present study confirms the role of cochlear NMDA receptors in the induction of salicylate-induced tinnitus.. Il sodio salicilato, principio attivo dell'aspirina, è una molecola in grado di indurre un acufene transitorio mediante l'attivazione dei recettori N-metil-D-aspartato (NMDA) a livello periferico e centrale. L'obiettivo primario di questo studio è di valutare la potenzialità della memantina, inibitore selettivo dei recettori NMDA, nel contrastare l'insorgenza e la persistenza dell'acufene indotto da salicilato in un modello animale. Obiettivo secondario è lo studio degli effetti della memantina sulla funzione uditiva e sulle cellule ciliate esterne. Nel nostro studio sono stati utilizzati 36 ratti divisi in tre gruppi: nel primo gruppo (n = 12) gli animali sono stati trattati con salicilato (300 mg/kg/d, IP), nel secondo (n = 12) con memantina (5 mg/kg/d, IP), nel terzo (n = 12) con entrambi. In tutti gli animali è stato studiato l'acufene con la tecnica GPIAS ad intervalli di 2, 24, 48, 72 e 96 ore dalla prima somministrazione e la funzione uditiva mediante i prodotti di distorsione (DPOAE) ed i potenziali evocati uditivi (ABR). Negli animali trattati con salicilato la nostra metodica ha evidenziato la presenza di un acufene con frequenza vicina ai 16 kHz insorto dopo la prima somministrazione e risoltosi spontaneamente 24 ore dopo l'ultima. Negli animali trattati con salicilato e memantina l'acufene, seppur presente, è risultato significativamente attenuato, prevalentemente durante il secondo giorno di trattamento. Né il salicilato né la memantina hanno causato alterazioni permanenti della funzione uditiva; le variazioni registrate mediante i prodotti di distorsione sono regredite al termine del trattamento. Il nostro studio conferma il ruolo dei recettori NMDA nell'acufene da salicilato e le potenzialità della memantina nel contrastarne l'insorgenza e la persistenza. Data la facile reperibilità del farmaco, già utilizzato nel trattamento della malattia di Alzheimer e del morbo di Parkinson, ed i risultati incoraggianti ottenuti nel modello animale, sono auspicabili ulteriori approfondimenti nell'uomo.

Topics: Animals; Excitatory Amino Acid Antagonists; Male; Memantine; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Salicylates; Tinnitus

Previous studies have shown that sodium salicylate (SS) activates not only central auditory structures, but also nonauditory regions associated with emotion and memory. To identify electrophysiological changes in the nonauditory regions, we recorded sound-evoked local field potentials and multiunit discharges from the striatum, amygdala, hippocampus, and cingulate cortex after SS-treatment. The SS-treatment produced behavioral evidence of tinnitus and hyperacusis. Physiologically, the treatment significantly enhanced sound-evoked neural activity in the striatum, amygdala, and hippocampus, but not in the cingulate. The enhanced sound evoked response could be linked to the hyperacusis-like behavior. Further analysis showed that the enhancement of sound-evoked activity occurred predominantly at the midfrequencies, likely reflecting shifts of neurons towards the midfrequency range after SS-treatment as observed in our previous studies in the auditory cortex and amygdala. The increased number of midfrequency neurons would lead to a relative higher number of total spontaneous discharges in the midfrequency region, even though the mean discharge rate of each neuron may not increase. The tonotopical overactivity in the midfrequency region in quiet may potentially lead to tonal sensation of midfrequency (the tinnitus). The neural changes in the amygdala and hippocampus may also contribute to the negative effect that patients associate with their tinnitus.

Topics: Acoustic Stimulation; Amygdala; Animals; Auditory Perceptual Disorders; Behavior, Animal; Electrodes, Implanted; Evoked Potentials, Auditory; Gyrus Cinguli; Hippocampus; Loudness Perception; Male; Neostriatum; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex, Startle; Salicylates; Tinnitus

To observe the expression of corticotropin-releasing factor-1 receptor in hippocampus of rats model of salicylate induced tinnitus.. Twenty-four rats were randomly divided into three groups, eight for each group. For Group A and Group B, 10% salicylic sodium solution was intraperitoneal injected each day at the dose of 350 mg/kg for 21 days in Group A and 14 days in Group B. Group C received intraperitoneal injection with the same amount of saline solution each day for 14 days. ABR were tested 2 days before, and 2 hours after the first administration and after the last injection. Immunohistochemical test and Western Blot were utilized to detect the expression of CRF1R in hippocampus for each group.. ABR thresholds tested 2 days before the first administration of the 3 groups showed no statistically significant difference (P > 0.05). At the time point of 2 hours after the first injection, the ABR thresholds of Group A and Group B rose by 25.90 dB SPL and 25.03 dB SPL compared with that before the administration, respectively (P < 0. 01). After the last administration, the ABR thresholds of Group A and Group B rose 34.91 dB SPL and 32.62 dB SPI. compared with that before the administration, respectively (P < 0.01). The ABR thresholds of Group C showed no significant statistical difference at all the tested time points (P > 0.05). Immunohistochemical test and Western Blot revealed that the expression level of CRF1R in the hippocampus was A > B > C (P < 0.05).. The expression of CRF1R in the hippocampus of salicylate induced tinnitus rat increased with the injection time, illustrating that CRF1R may participate in the mechanism of tinnitus involving the limbic system.

Topics: Animals; Auditory Threshold; Disease Models, Animal; Hippocampus; Injections, Intraperitoneal; Rats; Receptors, Corticotropin-Releasing Hormone; Salicylates; Tinnitus

Effects of C-phycocyanin (C-PC), the active component of Spirulina platensis water extract on the expressions of N-methyl D-aspartate receptor subunit 2B (NR2B), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase type 2 (COX-2) genes in the cochlea and inferior colliculus (IC) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate. The results showed that 4-day salicylate treatment (unlike 4-day saline treatment) caused a significant increase in NR2B, TNF-α, and IL-1β mRNAs expression in the cochlea and IC. On the other hand, dietary supplementation with C-PC or Spirulina platensis water extract significantly reduced the salicylate-induced tinnitus and down-regulated the mRNAs expression of NR2B, TNF-α, IL-1β mRNAs, and COX-2 genes in the cochlea and IC of mice. The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes.

Topics: Animals; Cochlea; Cyclooxygenase 2; Inferior Colliculi; Interleukin-1beta; Male; Mice; Phycocyanin; Receptors, N-Methyl-D-Aspartate; Salicylates; Spirulina; Tinnitus; Tumor Necrosis Factor-alpha

The aim of this study was to find out the effect of low-level laser therapy (LLLT) on salicylate-induced tinnitus in the rat model. Fourteen Sprague-Dawley rats (8 weeks; 240-280 gm) were divided into 2 groups (study group, control group). Rats of both groups were treated with 400 mg/kg/day of sodium salicylate for 8 consecutive days. Tinnitus was monitored using GPIAS (Gap Prepulse Inhibition of Acoustic Startle) 2 h after first salicylate treatment, and every 24 h during 9 days of treatment. Rats in laser group were irradiated to each ear with wavelength of 830 nm diode laser (165 mW/cm(2)) for 30 min daily for 8 days. During salicylate treatment, rats of study group irradiated with low level laser showed significantly higher GPIAS values throughout the experiment. Therapeutic effect of LLLT is demonstrated in animal tinnitus model by means of GPIAS. Further experimental studies are needed to find possible mechanisms and better methods to improve LLLT efficacy.

Topics: Animals; Low-Level Light Therapy; Rats; Rats, Sprague-Dawley; Reflex, Startle; Salicylates; Tinnitus; Treatment Outcome

The expression of the genes for cyclooxygenase (COX) and NMDA receptor (NR) has seldom been reported in tinnitus. We hypothesized that expression of COX-2 and NR was altered in the cochlea and midbrain in salicylate-induced tinnitus.. Experimental study on mice.. We evaluated the tinnitus score and mRNA expression levels of COX-2 and NR subtype 2B (NR2B) in the cochlea and midbrain in response to intraperitoneal injections of salicylate for 4 days.. At day 4 of tinnitus induction, the mean weights of the whole body and midbrain did not change greatly in both control and salicylate groups. The tinnitus score was not elevated from day 1 to day 4 in the control group, but increased day by day in the salicylate group. The mRNA expression level of COX-2 decreased slightly in the salicylate group in the cochlea (1.1 ± 0.33 vs. 1.3 ± 0.49, P = .0752) and in the midbrain (0.9 ± 0.10 versus 1.0 ± 0.35, P = .0489). Inversely, the expression levels of the NR2B gene increased moderately in the salicylate group in the cochlea (3.7 ± 0.47 versus 2.3 ± 1.13, P < 0.0001) and in the midbrain (1.6 ± 0.64 versus 1.0 ± 0.44, P = .0007).. Salicylate induced tinnitus and altered the expression of the COX-2 and NR2B genes in the cochlea and midbrain of mice. These findings might contribute to further understanding of pathophysiology and therapy of tinnitus.

Topics: Animals; Blotting, Southern; Cochlea; Cyclooxygenase 2; Gene Expression; Male; Mesencephalon; Mice; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salicylates; Tinnitus

Changes in the gene expressions for tumor necrosis factor-α (TNF-α) and/or interleukin-1β (IL-1β) during tinnitus have not been previously reported. We evaluated tinnitus and mRNA expression levels of TNF-α, IL-1β, and N-methyl D-aspartate receptor subunit 2B (NR2B) genes in cochlea and inferior colliculus (IC) of mice after intraperitoneal injections of salicylate.. Forty-eight 3-month-old male SAMP8 mice were randomly and equally divided into two groups: salicylate-treated and saline-treated. All mice were trained to perform an active avoidance task for 5 days. Once conditioned, an active avoidance task was performed 2 hours after daily intraperitoneal injections of saline, either alone or containing 300 mg/kg sodium salicylate. Total numbers of times (tinnitus score) the mice climbed during the inter-trial silent period for 10 trials were recorded daily for 4 days (days 7 to 10), and then mice were euthanized for determination of mRNA expression levels of TNF-α, IL-1β, and NR2B genes in cochlea and IC at day 10.. Tinnitus scores increased in response to daily salicylate treatments. The mRNA expression levels of TNF-α increased significantly for the salicylate-treated group compared to the control group in both cochlea (1.89 ± 0.22 vs. 0.87 ± 0.07, P < 0.0001) and IC (2.12 ± 0.23 vs. 1.73 ± 0.22, p = 0.0040). mRNA expression levels for the IL-1β gene also increased significantly in the salicylate group compared to the control group in both cochlea (3.50 ± 1.05 vs. 2.80 ± 0.28, p < 0.0001) and IC (2.94 ± 0.51 versus 1.24 ± 0.52, p = 0.0013). Linear regression analysis revealed a significant positive association between tinnitus scores and expression levels of TNF-α, IL-1β, and NR2B genes in cochlea and IC. In addition, expression levels of the TNF-α gene were positively correlated with those of the NR2B gene in both cochlea and IC; whereas, the expression levels of the IL-1β gene was positively correlated with that of the NR2B gene in IC, but not in cochlea.. We conclude that salicylate treatment resulting in tinnitus augments expression of the TNF-α and IL-1β genes in cochlea and IC of mice, and we suggest that these proinflammatory cytokines might lead to tinnitus directly or via modulating the NMDA receptor.

Topics: Animals; Behavior, Animal; Cochlea; Conditioning, Psychological; Gene Expression; Humans; Inferior Colliculi; Interleukin-1beta; Male; Mice; Motor Activity; Random Allocation; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Salicylates; Tinnitus; Tumor Necrosis Factor-alpha

Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10 mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Indoles; Male; Polysorbates; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Salicylates; Surface-Active Agents; Tinnitus

Tinnitus is a non-observable phantom sensation. As such, it is a difficult condition to investigate and, to date, no effective treatment has been developed. To approach this phantom sensation, we aimed to develop a rat behavioral model of tinnitus using salicylate, an active component of aspirin known to induce tinnitus. We also aimed to establish a molecular marker of tinnitus by assessing the expression of transient receptor potential cation channel superfamily V-1 (TRPV1) in the rat auditory pathway during salicylate-induced tinnitus. Animals were trained to perform "an active avoidance task": animals were conditioned by electrical footshock to move to the other side of the conditioning box when hearing a sound. Animals received a single injection of saline or salicylate (400 mg/kg i.p.) and false positive responses were measured 2 h after injection as the number of movements during a silent period. The number of responses in salicylate-treated animals was highest when the conditioned stimulus was 60 dB sound pressure level (SPL) and 16 kHz. This indicates that animals could feel tinnitus 2 h after salicylate injection, equivalent to that induced by 60 dB SPL and 16 kHz. By means of real-time PCR and western blot analysis, TRPV1 expression was significantly upregulated in spiral ganglion cells 2 h after salicylate injection and this upregulation together with the increase in the number of false positive responses was significantly suppressed by capsazepine (10 mg/kg i.p.), a specific antagonist of TRPV1. This suggests that salicylate could induce tinnitus through activation of TRPV1 in the rat auditory pathway.

Topics: Animals; Auditory Pathways; Behavior, Animal; Biomarkers; Capsaicin; Disease Models, Animal; Male; Membrane Transport Modulators; Neuropsychological Tests; Rats; Rats, Wistar; RNA, Messenger; Salicylates; Spiral Ganglion; Time Factors; Tinnitus; TRPV Cation Channels; Up-Regulation

Tinnitus, also called phantom auditory perception, is a major health problem in western countries. As such, a significant amount of effort has been devoted to understanding its mechanisms, including studies in animals wherein a supposed "tinnitus state" can be induced. Here, we studied on the same awake animals the effects of a high-dose of salicylate and of an acoustic trauma both at levels known to induce tinnitus. Recordings of cortical activity (local field potentials) from chronically implanted electrodes in the same animals under each condition allowed direct comparison of the effects of salicylate and trauma (noise trauma was carried out several days after full recovery from salicylate administration). Salicylate induced a systematic and reversible increase in amplitude of cortical responses evoked by tone bursts over a wide range of frequencies and intensities. The effects of noise trauma, though much more variable than those of salicylate, resulted in both increases and decreases in the amplitude of cortical responses. These alterations of cortical response amplitudes likely reflect associated hypoacusis and hyperacusis. The effects of salicylate administration and noise trauma on spontaneous activity were also studied. Fourier analysis did not reveal any increase in power within any given frequency band; rather, both treatments induced a decrease of power spectrum over a relatively broad frequency band (approximately 10-30 Hz). Entropy rate of spontaneous activity, a measure of complexity (temporal correlations), was found to decrease after salicylate but not after acoustic trauma. The present data on evoked potentials confirm salicylate effects at the cortical level and partially extend such effects to acoustic trauma. While the present study showed that both salicylate and noise trauma induced some changes of spontaneous activity in auditory cortex, none of these changes are interpretable in terms of potential neural correlate of tinnitus.

Topics: Acoustic Stimulation; Action Potentials; Animals; Auditory Cortex; Auditory Pathways; Disease Models, Animal; Dose-Response Relationship, Drug; Ear, Inner; Evoked Potentials, Auditory; Guinea Pigs; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Hyperacusis; Neurotoxins; Noise; Salicylates; Tinnitus; Wakefulness

Traditional Chinese medicine (TCM) has been reported to successfully alleviate tinnitus, although well-controlled studies have not been conducted. In this study, we attempted to test a TCM, Er Ming Fang (EMF01) containing Rehmannia glutinosa, Cornus officinalis, Salvia mittiorrhiza, Pueraria, Schisandra chinensis, Poria cocos and Platycodon grandiflorum, on salicylate-induced tinnitus in rats, using a conditioned lick suppression paradigm.. A pilot study examined the effect of 8.75 g/kg and 17.5 g/kg EMF01 (delivered by oral gavage for 20 days) and showed a slight decrease in the suppression ratio (SR) in the 8.75 g/kg group. In order to confirm the possible effect of EMF01 on tinnitus at 8.75 g/kg, a further study was carried out with a larger sample size.. While there were statistically significant differences between the treatment groups, post hoc tests revealed that EMF01 did not have any significant effect on salicylate-induced tinnitus.. While this study does not support the efficacy of EMF01 in the treatment of salicylate-induced tinnitus, further studies should be conducted to determine if it alleviates tinnitus associated with acoustic trauma.

Topics: Animals; Complementary Therapies; Conditioning, Classical; Drugs, Chinese Herbal; Herbal Medicine; Male; Medicine, Chinese Traditional; Rats; Rats, Wistar; Salicylates; Tinnitus

Salicylate and quinine have been shown to reliably induce short-term tinnitus when administered at high doses. The present study compared salicylate and quinine-induced tinnitus in rats using the gap prepulse inhibition of acoustic startle (GPIAS).. Twenty-four rats were divided into 2 groups; the first group (n = 12) was injected with salicylate (300 mg kg d), whereas the second (n = 12) was treated with quinine orally at a dose of 200 mg kg d. Animals were treated daily for 4 consecutive days. All rats were tested for tinnitus and hearing loss before and 2, 24, 48, 72, and 96 hours after the first drug administration. Tinnitus was assessed using GPIAS; hearing function was measured with distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response.. Salicylate treatment induced transient tinnitus with a pitch near 16 kHz starting 2 hours posttreatment, persisting over the 4-day treatment period and disappearing 24 hours later. Animals in the quinine group showed GPIAS changes at a higher pitch (20 kHz); however, changes were more variable among animals, and the mean data were not statistically significant. Hearing function varied across treatments. In the salicylate group, high-level DPOAEs were slightly affected; most changes occurred 2 hours posttreatment. Low-level DPOAEs were affected at all frequencies with a progressive dose-dependent effect. In the quinine group, only high-level DPOAEs were affected, mainly at 16 kHz.. The present study highlights the similarities and differences in the frequency and the time course of tinnitus and hypoacusis induced by salicylate and quinine. Transient tinnitus was reliably induced pharmacologically with salicylate, whereas hearing loss remained subclinical with only minor changes in DPOAEs.

Topics: Animals; Behavior, Animal; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Male; Noise; Otoacoustic Emissions, Spontaneous; Quinine; Rats; Rats, Sprague-Dawley; Reflex, Startle; Salicylates; Time Factors; Tinnitus

A sudden hearing loss in a woman on aspirin has uncovered a frequently neglected toxicological parameter.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Disease Progression; Female; Hearing Loss; Humans; Lupus Erythematosus, Systemic; Proteinuria; Salicylates; Tinnitus

This study aims to investigate corticofugal modulation on spontaneous activities of the external nucleus of the inferior colliculus (ICx) in a salicylate acid (SA) induced tinnitus rat model by the stimulation of the primary auditory cortex (AI). Extracellular recording techniques and stereotaxic method were used. The spontaneous activities of a single unit were recorded from the left ICx after electrical stimulation was given to the left AI of the rats duplicated as acute SA models. The average rate of spontaneous discharge and the interspike interval histogram of spontaneous activities were used as indices. The single unit spontaneous discharges of the same unit of ICx before and after AI stimulation were observed. There was an inhibitory effect of AI stimulation on the activities of the high discharge unit [(8.75+/-2.70) Hz vs (5.06+/-2.01) Hz] and a facilitatory effect on the low discharge unit [(1.41+/-0.45) Hz vs (2.46+/-0.79) Hz]. In the normal group, there was a restraining effect on the average rate of spontaneous discharge of the ICx after AI stimulation. The average rate of spontaneous discharge changed from (3.66+/-0.84) Hz to (2.47+/-0.43) Hz in the first hour after AI stimulation and then recovered within 2-4 h. And the discharge rate of the spike interval within 0-20 ms decreased (17% vs 7.3%, 11.2%) in the first 2 h and recovered 3-4 h after AI stimulation. The discharge rate of the spike interval within 0-6 ms (short interval) recovered 2 h after AI stimulation. In the acute SA model group, the average rate of spontaneous discharge recorded from the ICx decreased from (7.48+/-0.85) Hz to (3.38+/-0.39) Hz in the first hour after AI stimulation and the suppression effect remained 4 h (P<0.05). There was no difference in the average rate of spontaneous discharge between the acute SA model group and the normal group at 2-4 h after AI stimulation. The suppression effect after AI stimulation on the 0-20 ms interval spikes in the ICx lasted 4 h, while that on the shorter interval (0-6 ms) spikes recovered in the 3rd hour after AI stimulation in acute SA model group. It is concluded that the high average spontaneous discharge rate of ICx in acute SA model decreases significantly by AI stimulation, and the suppression effects on the shorter interval spikes recovers in the 3rd hour after AI stimulation. It might be inferred that stimulation of AI, through exciting the auditory descending projections, could remit the increased spontaneous discharge

Topics: Animals; Auditory Cortex; Disease Models, Animal; Electric Stimulation; Inferior Colliculi; Rats; Salicylates; Tinnitus

Tinnitus is a phantom auditory perception, which can be induced via application of concentrated sodium salicylate, and is known to be associated with hearing loss and altered neuronal excitability in peripheral and central auditory neurons. The molecular features of this excitability, however, has been poorly characterized to date. Brain-derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1, also known as Arc), and c-Fos are known to be affected by changes in excitability and plasticity. Using reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, the expression of these genes was monitored in the rat auditory system after local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioral model. Regardless of the mode of salicylate application, a common pattern became evident: 1) BDNF mRNA expression was increased in the spiral ganglion neurons of the cochlea; and 2) Arg3.1 expression was significantly reduced in the auditory cortex. Local application of the GABA(A) receptor modulator midazolam resulted in the reversal not only of salicylate-induced changes in cochlear BDNF expression, but also in cortical Arg3.1 expression, indicating that the tinnitus-associated changes in cochlear BDNF expression trigger the decline of cortical Arg3.1 expression. Furthermore, local midazolam application reduced tinnitus perception in the animal model. These findings support Arg3.1 and BDNF as markers for activity changes in the auditory system and suggest a role of GABAergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.

Topics: Animals; Auditory Cortex; Auditory Pathways; Auditory Perception; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cochlea; Cytoskeletal Proteins; Female; Gene Expression Regulation; Hearing Loss; Midazolam; Models, Biological; Nerve Tissue Proteins; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, GABA; RNA, Messenger; Salicylates; Tinnitus

Salicylate (aspirin) can reversibly eliminate outer hair cell (OHC) electromotility to induce hearing loss. Prestin is the OHC electromotility motor protein. Here we report that, consistency with increase in distortion product otoacoustic emission, long-term administration of salicylate can increase prestin expression and OHC electromotility. The prestin expression at the mRNA and protein levels was increased by three- to four-fold. In contrast to the acute inhibition, the OHC electromotility associated charge density was also increased by 18%. This incremental increase was reversible. After cessation of salicylate administration, the prestin expression returned to normal. We also found that long-term administration of salicylate did not alter cyclooxygenase (Cox) II expression but down-regulated NF-kappaB and increased nuclear transcription factors c-fos and egr-1. The data suggest that prestin expression in vivo is dynamically up-regulated to increase OHC electromotility in long-term administration of salicylate via the Cox-II-independent pathways.

Topics: Animals; Guinea Pigs; Hair Cells, Auditory, Outer; Mice; Molecular Motor Proteins; Otoacoustic Emissions, Spontaneous; RNA, Messenger; Salicylates; Signal Transduction; Time Factors; Tinnitus; Transcription Factors; Up-Regulation

Topics: Aged; Aspirin; Diagnosis, Differential; Female; Hallucinations; Humans; Music; Salicylates; Tinnitus

Several physiological studies have linked experimentally induced tinnitus to increases in the spontaneous activity of auditory neurons. These results have led to the proposal of hyperactivity models of tinnitus in which elevated neural activity in the absence of auditory stimulation is perceived as phantom sound. Such models are appealing in their simplicity but remain controversial because a generalized elevation of spontaneous rates may not be observed after treatments that induce tinnitus in humans and experimental animals. Our study addressed these issues by characterizing the effects of common methods of tinnitus induction on spontaneous activity in the central nucleus of the inferior colliculus (ICC). The ICC is an interesting structure in tinnitus research because its diverse inputs include putative generator sites in the dorsal cochlear nucleus, as well as brainstem sources that appear to remain normal after tinnitus induction. Groups of CBA/J mice were subjected to one of three induction methods: bilateral or unilateral sound exposure, and acute salicylate intoxication. Relative to normal baselines, bilaterally exposed mice showed increases in the spontaneous rates of neurons with tuning near the exposure frequency. When the sample was separated into physiologically defined response classes, exposure effects were strongest among neurons with broad excitatory bandwidths. By contrast, salicylate decreased the spontaneous rates of low-frequency neurons with transient sound-evoked activity. Our results suggest that the disordered processes of hearing that give rise to tinnitus do not involve a pervasive elevation of spontaneous activity or a single mode of induction.

Topics: Animals; Auditory Cortex; Cochlear Nerve; Cochlear Nucleus; Cyclooxygenase Inhibitors; Disease Models, Animal; Electrophysiology; Evoked Potentials, Auditory, Brain Stem; Female; Inferior Colliculi; Male; Mice; Mice, Inbred CBA; Noise; Psychomotor Agitation; Random Allocation; Salicylates; Tinnitus

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Delirium; Drug Overdose; Emergency Service, Hospital; Fatigue; Female; Humans; Muscle Weakness; Neuropsychological Tests; Renal Dialysis; Salicylates; Tinnitus

High doses of salicylate induce a temporary hearing deficit and a temporary subjective tinnitus in humans and animals. In animals, salicylate suppresses activity in the ascending auditory system but generates activity and plasticity in the auditory cortex and central amygdala. In addition to changes in the auditory system evoked by hearing impairment, enhanced stress may be crucial for the salicylate-induced alterations in the auditory cortex. The central amygdala responds to stress, and may influence cortical excitability and plasticity through cholinergic mechanisms. We investigated whether salicylate-induced plasticity in the auditory cortex is prevented by blocking cortical cholinergic receptors with the muscarinic antagonist scopolamine. Scopolamine suppresses salicylate-induced plasticity in the auditory cortex and, therefore, may be effective in suppressing the tinnitus sensation.

Topics: Animals; Auditory Cortex; Cell Count; Dose-Response Relationship, Drug; Drug Combinations; Gerbillinae; Immunohistochemistry; Male; Muscarinic Antagonists; Nerve Tissue Proteins; Neuronal Plasticity; Proto-Oncogene Proteins c-fos; Salicylates; Scopolamine; Tinnitus

Although a number of studies suggest that the development of tinnitus is associated with hyperactive neuronal discharges in the brainstem cochlear nucleus (CN), there is relatively little evidence to indicate the neurochemical basis of this phenomenon. While some studies suggest that it may be partly due to a decrease in GABAergic inhibition, it is also possible that increased excitability is a contributing factor. In the current study, we investigated whether the salicylate animal model of tinnitus is associated with changes in the number of CN neurons expressing neuronal nitric oxide synthase (nNOS), one of the NOS isoforms that results in the production of the neurotransmitter, nitric oxide. We used a behavioral conditioning paradigm to confirm that animals receiving salicylate injections experienced tinnitus, and used immunohistochemistry with stereology to quantify the number of nNOS-expressing neurons in the dorsal and ventral CN (DCN and VCN, respectively) in salicylate- and vehicle control-treated animals. We also employed Western blotting to quantify the amount of nNOS protein expression in the total CN (i.e., the DCN and VCN together). We found a significant increase (of approximately 70%) in the number of nNOS-expressing principal neurons in the VCN of salicylate-treated animals compared to controls, with no significant differences in the DCN; nor did we find any significant difference in the overall level of nNOS protein in the total CN using Western blotting. These results suggest that changes in the number of neurons in the VCN expressing nNOS may be implicated in the mechanisms of tinnitus.

Topics: Animals; Cochlear Nucleus; Extinction, Psychological; Immunohistochemistry; Male; Neurons; Nitric Oxide Synthase Type I; Rats; Rats, Wistar; Salicylates; Tinnitus

The serotonin receptor 5-HT2c agonist m-chlorophenylpiperazine (mCPP) has been widely used to induce anxiety-like states in animals and anxiety in humans. We here addressed the effect of an intraperitoneal injection of mCPP on the perception of tinnitus in a behavioural protocol based on an active avoidance paradigm. In control saline-treated animals, mCPP did not change compound action potential audiograms or measurable tinnitus. In contrast, mCPP to animals demonstrating salicylate-induced tinnitus exacerbated tinnitus perception by nearly twofold. We went on to test whether manipulation of the peripheral generator of tinnitus (i.e. the cochlea) could extinguish this exacerbated perception by applying the N-methyl-d-aspartate (NMDA) antagonist 7-chlorokynurenate (7-CK) into cochlear fluids using a 7-CK-soaked Gelfoam ball placed on the round window of each of the animals' two ears. In addition to blocking the tinnitus induced by salicylate alone, 50 microm of 7-CK clearly abolished tinnitus in animals receiving salicylate and an injection of mCPP. The demonstration that cochlear NMDA receptor blockade abolishes the exacerbated perception of tinnitus is highly relevant in terms of treatment. In addition to psychotherapeutic treatment that may help to attenuate an individual's perception of tinnitus, targeting cochlear NMDA receptors represents a promising therapeutic strategy, even in depressed or chronically anxious patients.

Topics: Animals; Anxiety; Avoidance Learning; Female; Injections, Intraperitoneal; Piperazines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Salicylates; Serotonin Receptor Agonists; Tinnitus

A behavioral technique was developed that allowed the onset and recovery of tinnitus to be measured in individual rats treated with different doses of salicylate. Food-restricted rats were self-trained to lick for water during the time between scheduled delivery of food pellets, i.e., schedule-induced polydipsia (SIP). SIP-induced licking was placed under stimulus control by administering foot shock if licks occurred when sound (one of six stimuli, 40 dB SPL) was present; rats were allowed to lick during quiet. After the number of licks-in-quiet (correct response) exceeded 90% of total licks, rats were treated with saline and four different doses of salicylate (50, 100, 150 and 350 mg/kg, intraperitoneally (i.p.); 2 days). Performance was assessed before, during and after treatment. Licks-in-sound remained extremely low with saline and all four salicylate doses indicating that the sounds were audible under all treatment conditions. Licks-in-quiet remained high during the saline control and 50 mg/kg dose of salicylate, behavior consistent with the absence of tinnitus. However, licks-in-quiet showed a statistically significant decline with the 150 and 350 mg/kg dose, behavior consistent with the presence of tinnitus. Licks-in-quiet gradually recovered to baseline level 2-3 days following high-dose salicylate treatments, behavior consistent with the gradual disappearance of tinnitus. The salicylate dose needed to induce tinnitus and the length of recovery are consistent with previous reports, providing support for the method. The ability to obtain sequential estimates of tinnitus-like behavior in an animal after administering a tinnitus-inducing agent could aid in understanding the underlying neural mechanisms and assessing potential treatments.

Topics: Animals; Avoidance Learning; Behavior, Animal; Conditioning, Operant; Cyclooxygenase Inhibitors; Drinking Behavior; Drug Administration Schedule; Male; Rats; Rats, Sprague-Dawley; Salicylates; Tinnitus; Treatment Outcome

Acetylic acid, such as aspirin, is one of the most commonly used medication in Western societies. Aspirin overdosage causes ototoxic side effects in some patients, such as bilateral mild to moderate sensorineural hearing loss and tinnitus. Recent literature describes, that salicylates act as competitive inhibitors of Cl- anions at the anion-binding site of prestin, the motor protein of the outer hair cell. This molecular mechanism correlates well with the clinical audiological mainstays of aspirin-induced hearing loss, dose dependency, cochlear site of hearing loss and reversibility. We report about a young man with an acute moderate aspirin intoxication resulting in asymmetric hearing loss of 50 dB HL and tinnitus for five days. Otoacoustic emissions were absent on the first day of intoxication but could be measured again on the fifth day after the intoxication. As the ototoxic side effects resolve with in two or three days, no specific treatment is necessary for ototoxicity. Medical treatment of acute or chronic aspirin intoxications aims to decrease further drug absorption by gastrointestinal decontamination and to accelerate elimination by alkaline diuresis. Only in severe intoxications hemodialysis may be considered to treat neurologic, pulmonal, renal or cardial complications.

Topics: Adaptation, Physiological; Adult; Aspirin; Drug Overdose; Hearing Loss; Humans; Male; Otoacoustic Emissions, Spontaneous; Salicylates; Tinnitus

Recent advances in molecular pharmacology of the cochlea have lead to a much better understanding of the physiology, and especially the pathophysiology, of the sensorineural structures of the organ of Corti. Knowledge of the intimate molecular mechanisms of cellular dysfunction is of considerable use in the development of new therapeutic strategies. Herein, we summarize the mechanisms of sensory hair cell death after various injuries. Based on these molecular mechanisms, we propose novel therapeutic strategies to restore hearing. In addition to permanent hearing loss, exposure to noise or ototoxic drugs also induces tinnitus. We thus review recent findings obtained from a behavioral model of tinnitus in rats. In addition to providing evidence for the site and mechanism of generation of tinnitus induced by salicylate, these results support the idea that targeting cochlear N-methyl-D-aspartate receptors may represent a promising therapeutic strategy for treating tinnitus.

Topics: Animals; Apoptosis; Disease Models, Animal; Hair Cells, Auditory; Hearing Loss; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Neuroprotective Agents; Peptides; Riluzole; Salicylates; Signal Transduction; Tinnitus

Distributions of arg3.1 and c-fos immunoreactive neurons (IRN) in gerbil auditory cortex (AC) and amygdala showed characteristic differences when comparing systemic application of the tinnitus-eliciting drug salicylate with acoustic stimulation or saline injections. In AC, arg3.1 IRN induced by stimulation focused in regions corresponding to the frequency content of the stimulus. Injections of salicylate (350 mg/kg body weight) led to accumulation of arg3.1 IRN in the high frequency domain, while saline injections produced a diffuse distribution. After all treatments, c-fos IRN outnumbered arg3.1 IRN in AC and showed a broad distribution. In subcortical auditory structures arg3.1 IRN were absent in all but one brain. In ventral cochlear nucleus, c-fos IRN were always found after stimulation and often also after saline injections, whereas none were present when injecting salicylate. Similarly, in inferior colliculus, numbers of c-fos IRN were lowest after salicylate injections. In the amygdala, c-fos and arg3.1 IRN were increased substantially after salicylate injections compared to auditory stimulation or saline injections. In particular in its central nucleus, c-fos and arg3.1 IRN were found exclusively after the tinnitus-inducing treatment, suggesting that coactivation of the AC and the amygdala may by an essential feature of tinnitus-related activation.

Topics: Acoustic Stimulation; Amygdala; Animals; Auditory Cortex; Auditory Pathways; Cell Count; Cochlear Nucleus; Cytoskeletal Proteins; Female; Gerbillinae; Immunohistochemistry; Inferior Colliculi; Injections; Male; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Proto-Oncogene Proteins c-fos; Salicylates; Sodium Chloride; Tinnitus

Salicylate is a well-known substance to produce reversible tinnitus in humans and animals. It has been shown that systemic application of salicylate changes the neuronal spontaneous activity in several parts of the auditory pathway. Salicylate has also a direct influence on cochlear outer hair cell electromotility. The effects observed in the central auditory structures in vivo could therefore be based upon the change in afferent cochlear input to the auditory system and in addition by a direct action of salicylate on neurons within the auditory pathway. The present study investigated the direct effect of salicylate application on the spontaneous activity of mouse inferior colliculus neurons in brain slices. Out of 92 neurons, 87% responded statistically significantly to the superfusate by changing their firing rates. 70% increased and 17% decreased their firing rates, respectively. Salicylate superfusion induced a general increase of electrophysiological activity within the inferior colliculus brain slice preparation which was similar to those obtained during systemic application of salicylate. The results suggest that the salicylate sensitivity of inferior colliculus neurons can modulate to a great extent the salicylate-induced generation of tinnitus.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Inferior Colliculi; Male; Mice; Neurons; Organ Culture Techniques; Salicylates; Tinnitus

In vivo microdialysis offers a unique approach to monitor biochemical events related to brain function and metabolism, and has been used extensively in many systems to measure the release of endogenous transmitters and other neuroactive substances during normal and pathological conditions. The characterization of neurotransmitters' changes induced by salicylate in the inferior colliculus (IC) and the auditory cortex (AC) may provide insight into the action of salicylate on the auditory system and, through this, provide a better understanding of neurological mechanism of salicylate-induced tinnitus. In the present study, the effect of salicylate on 5-HT system in IC and AC has been monitored by microdialysis in salicylate-induced tinnitus animal models. Glucose and lactate levels in IC and AC were significantly increased after application of salicylate (350 mg/kg, i.p.), indicating a salicylate-related increase in regional neuronal activity. The 5-HT level increased to a maximum of 268+/-27% basal level in IC 2 h after application and of 277+/-24% basal level in AC around 3 h after application. These data suggest that the increases of 5-HT levels in IC and AC may be involved in the tinnitus generation.

Topics: Animals; Auditory Cortex; Dialysis Solutions; Glucose; Inferior Colliculi; Lactic Acid; Microdialysis; Rats; Rats, Wistar; Salicylates; Serotonin; Tinnitus

Salicylate, the active component of aspirin, is known to induce tinnitus. However, the site and the mechanism of generation of tinnitus induced by salicylate remains unclear. Here, we developed a behavioral procedure to measure tinnitus in rats. The behavioral model was based on an active avoidance paradigm in which rats had to display a motor task (i.e., to jump on a climbing pole when hearing a sound). Giving salicylate led to a decrease in the percentage of correct responses (score) and a drastic increase in the number of false positive responses (i.e., animals execute the motor task during a silent period). Presentation of the sound at a constant perceptive level prevents decrease of the score, leading to the proposal that score is related to hearing performance. In contrast, the increase of false positive responses remained unchanged. In fact, animals behaved as if they hear a sound, indicating that they are experiencing tinnitus. Mefenamate in place of salicylate also increased the number of false positive responses, suggesting that salicylate-induced tinnitus is related to an inhibition of cyclooxygenase. One physiological basis of salicylate ototoxicity is likely to originate from altered arachidonic acid metabolism. Because arachidonic acid potentiates NMDA receptor currents, we tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Application of NMDA antagonists into the perilymphatic fluids of the cochlea blocked the increase in pole-jumping behavior induced by salicylate, suggesting that salicylate induces tinnitus through activation of cochlear NMDA receptors.

Topics: Action Potentials; Animals; Behavior, Animal; Cochlea; Cochlear Nerve; Conditioning, Classical; Cyclooxygenase Inhibitors; Disease Models, Animal; Electrodes, Implanted; Electroshock; False Positive Reactions; Female; Mefenamic Acid; Otoacoustic Emissions, Spontaneous; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Salicylates; Tinnitus

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Child; Cochlear Nerve; Hearing Loss; Humans; Salicylates; Tinnitus

Topics: Animals; Drugs, Chinese Herbal; Evoked Potentials, Auditory, Brain Stem; Male; Rats; Salicylates; Tinnitus

Topics: Adult; Cochlea; Drug Overdose; Female; Humans; Otoacoustic Emissions, Spontaneous; Salicylates; Severity of Illness Index; Tinnitus

This study presents firing rates for simultaneously recorded spontaneous and stimulus driven multi-unit activity in primary auditory cortex (AI), anterior auditory field (AAF) and secondary auditory cortex (AII) in cats before and after application of salicylate or quinine. From 21 cats, in three cortical areas simultaneously, a total of 1533 multi-unit files were obtained. The data suggest (1) that both salicylate and quinine significantly increase spontaneous firing rates in AII, whereas in AI and AAF both quinine and salicylate reduced the spontaneous rate; (2) the effect of both drugs was to increase spontaneous rates for recording sites with high characteristic frequency (CF) and a tendency to decrease them for low CF sites; (3) the mean stimulus driven firing rates were not affected by either drug except for a decrease produced by quinine in AI; (4) changes in driven firing rate were positively correlated with changes in spontaneous firing rates. This suggests that tinnitus inducing agents selectively increase spontaneous firing rates in the extralemniscal pathway.

Topics: Acoustic Stimulation; Analgesics, Non-Narcotic; Animals; Auditory Cortex; Auditory Threshold; Cats; Disease Models, Animal; Electrodes, Implanted; Enzyme Inhibitors; Inferior Colliculi; Neurons; Quinine; Salicylates; Salicylic Acid; Tinnitus

The effects of lidocaine (a local anesthetic known to relieve tinnitus) in a guinea pig animal model of tinnitus in which spontaneous discharge of inferior colliculus (IC) neurons was augmented by intravenous application of salicylate (200 mg/kg) were studied by extracellular recording. The salicylate induced discharge was inhibited by intravenous injection of lidocaine at a concentration (lmg/kg) used clinically for treating tinnitus. IC neurons could be divided into two groups according to the difference in sensitivity to lidocaine, weakly sensitive neurons and highly sensitive neurons. In weakly sensitive neurons, the lidocaine effect lasted for less than five min, and the inhibiton of the discharge of neurons was increased as the latency of response to the sound stimulus became longer. It was considered that lidocaine inhibited the propagation of action potentials by blocking Na+ channels. In highly sensitive neurons, on the other hand, the activity of neurons was almost completely inhibited for longer than 30 min and it might involved different mechanisms. Furthermore, the inhibitory action of lidocaine was stronger in IC neurons discharging at higher frequencies, suggesting a use dependent blocking action of Na+ channels, by lidocaine.

Topics: Action Potentials; Anesthetics, Local; Animals; Dose-Response Relationship, Drug; Guinea Pigs; Inferior Colliculi; Lidocaine; Neurons, Afferent; Salicylates; Sodium Channels; Tinnitus

Salicylate, one of the most widely used drugs, produces at repetitive high doses reversible tinnitus and hearing loss. Neural correlates of hearing loss have long been established, whereas they remain elusive for tinnitus. The average spectrum of electrophysiological cochleoneural activity (ASECA), a measure of spontaneous auditory nerve activity, was monitored in guinea pigs over weeks of salicylate administration. Auditory nerve compound action potential (CAP) was also recorded to monitor acoustic sensitivity. In the first days of treatment, ASECA decreased acutely during hours after salicylate administration; after several days this decrease could be reduced. Over weeks of treatment the level of ASECA increased progressively. No change in CAP threshold was observed. The ASECA decrease induced by a contralateral broadband noise remained unchanged. At the end of treatment, acoustic tuning of ASECA showed a partially decreased sensitivity. After cessation of treatment the ASECA level returned progressively to initial values. In control animals delivery of an ipsilateral acoustic noise could reproduce the ASECA increase observed in long-term salicylate-treated animals. This white noise was of moderate sound pressure level and it elevated slightly CAP thresholds at high frequencies. These data provide evidence for salicylate-induced ASECA alterations without changes in CAP thresholds, in accord with clinical reports of tinnitus being the first subjective sign of salicylate ototoxicity. The similarities in occurrence, development, reversibility, frequency content, and acoustic level support the idea that ASECA changes, which indicates alterations of spontaneous eighth nerve activity and reflects the presence of salicylate-induced high-pitch tinnitus.

Topics: Acoustic Stimulation; Action Potentials; Animals; Cochlear Nerve; Electrophysiology; Guinea Pigs; Lidocaine; Salicylates; Time Factors; Tinnitus

Using the extracellular recording method, the effects of lidocaine (a local anesthetic known to relieve tinnitus) on discharge of inferior colliculus (IC) neurons of the guinea pig were studied before and after salicylate (200 mg/kg) administration. The salicylate-induced discharge was inhibited by intravenous injection of lidocaine at a concentration (1 mg/kg) clinically used for treating tinnitus. IC neurons could be classified into two groups according to the difference in sensitivity to lidocaine: (1) weakly-sensitive neurons and (2) highly-sensitive neurons. In weakly-sensitive neurons, the duration of the lidocaine effect lasted for less than 5 min, and the inhibitory action on the discharge of neurons was greater when the latency to sound stimulus became longer. In highly-sensitive neurons, on the other hand, the activity of neurons was almost completely inhibited for longer than 30 min, irrespective of the latency to sound stimulus. The clinical relevance of these types of neurons is discussed.

Topics: Action Potentials; Anesthetics, Local; Animals; Auditory Pathways; Disease Models, Animal; Electrophysiology; Female; Guinea Pigs; Humans; Inferior Colliculi; Lidocaine; Neurons; Salicylates; Salicylic Acid; Tinnitus

The effect of salicylate and quinine on the spontaneous firing rate in the cat primary auditory cortex was investigated in 13 healthy cats. Spontaneous firing rates were calculated for each single unit. A dose of 200 mg of sodium salicylate per kg was administered intraperitoneally to six cats, and the findings from the same single unit were recorded prior to application and continuously up to, on average, 6 hours after application. A dose of 100 or 200 mg of quinine hydrochloride per kg was administered intramuscularly to seven cats, and the findings from the same single unit were recorded in the same manner as for the cats treated with sodium salicylate. Twenty one single units in salicylate-treated cats and 29 single units in quinine-treated cats were evaluated. All animals treated with salicylate showed a 20-30 dB threshold shift about 2 hours after application and showed no recovery during the course of the investigation. All animals treated with quinine showed a 10-40 dB threshold shift about 1 hour after application and recovered during the course of the investigation. There was no consistent difference in overall spontaneous firing rate before and after application in either salicylate-treated cats or quinine treated cats. In order to investigate a potential different effect on units with different spontaneous firing rates, we divided the cats into two groups, a high-firing rate group (pre-application firing rate > 1 spike/s) and a low firing rate group (pre-application firing rate < 1 spike/s). A significant decrease in the high-firing rate group (p < 0.05) and a significant increase in the low firing rate (p < 0.01) were observed in salicylate-treated cats. The same tendencies were observed in quinine-treated cats, but only the difference in the low firing rate group was significant (p < 0.05). The difference in the high-firing rate group was close to the significant level (p = 0.055). These changes in spontaneous firing rates in cat primary auditory cortex may be related to the generation of tinnitus.

Topics: Animals; Auditory Cortex; Cats; Quinine; Salicylates; Salicylic Acid; Tinnitus

The effect of systemically applied quinine on single-unit firing activity in primary auditory cortex was investigated in seven cats. A dose of 100 or 200 mg/kg of quinine hydrochloride was administered intramuscularly and recordings from the same units were performed prior to application and continuously up to on average 5.5 h after administration. All animals showed 10-40 dB of threshold shift about 30 min after administration and some animals showed recovery during the course of the investigation. Significant increases were found in spontaneous firing rates for low-firing-rate units (initial firing rate < 1 spike/s). For high-firing-rate units (initial firing rate > 1 spike/s) no significant changes were observed. There were no significant changes in modal and mean interspike interval. The time-to-rebound peak in the autocorrelation function for spontaneous firings was not altered significantly. The rate of burst occurrence showed no significant change. The best modulation frequency in response to stimulation with periodic click trains decreased after administration, but the limiting rate did not change. Peak cross-correlation coefficients for the spontaneous firings of simultaneously recorded cells showed a significant increase and the correlogram's central peak was significantly narrower after quinine application. Dose effects were only present for cross-correlation results and temporal modulation transfer functions. The results for both spontaneous firing rate, peak width in the cross-correlogram and click stimulation were similar to those observed in salicylate-treated cats (Ochi and Eggermont, 1996). The other findings were different from those observed after salicylate. It is obvious that the effects of quinine on the auditory system are not the same as those of salicylate. The increased synchronization of the spontaneous firings across different neurons observed after application of both drugs may be related to tinnitus.

Topics: Acoustic Stimulation; Animals; Auditory Cortex; Auditory Threshold; Cats; Cortical Synchronization; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Evoked Potentials, Auditory, Brain Stem; Injections, Intramuscular; Muscle Relaxants, Central; Nerve Fibers; Neurons; Quinine; Salicylates; Salicylic Acid; Tinnitus; Vestibulocochlear Nerve

Whereas cochlear impairment after intravenous ingestions of salicylates is well known, reports of cochlear symptoms after topical application are quite rare. The extent of the ototoxic salicylate impact is increased by diabetes, renal insufficiency, and alcoholism.. This study presents a case report of a female patient who suffered a repeated, symmetric, pancochlear, reversible inner ear impairment after two treatments with salicylate containing ointment for psoriasis. The correlation of the salicylate therapy with the observed inner ear lesions is obvious due to the close interval between these incidences and to the audiologic criteria typical for salicylate intoxication.. Audiologic controls should be carried out during extended local application of salicylate containing ointment.

Topics: Adult; Audiometry, Pure-Tone; Auditory Threshold; Female; Hearing Loss, Sensorineural; Humans; Keratolytic Agents; Nystagmus, Physiologic; Ointments; Otoacoustic Emissions, Spontaneous; Psoriasis; Salicylates; Salicylic Acid; Tinnitus

Because salicylate is known to produce tinnitus in humans and animals, the effect of salicylate on the auditory system of gerbils was investigated using [14C]2-deoxyglucose (2-DG). Salicylate treatment reduced activity in the inferior colliculus (IC), particularly in the high frequency part, whereas activation along some isofrequency contours was observed in auditory cortex. In contrast, in saline-treated controls the IC but not the auditory cortex was active. These results suggest that the sensation of subjective tinnitus may be generated within auditory brain structures. The 2-DG method may be used to measure tinnitus objectively in animals and also to evaluate tinnitus treatments.

Topics: Animals; Auditory Cortex; Deoxyglucose; Disease Models, Animal; Female; Gerbillinae; Male; Salicylates; Tinnitus

The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10-16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.

Topics: Acoustic Stimulation; Animals; Calcium; Dose-Response Relationship, Drug; Free Radical Scavengers; Inferior Colliculi; Microelectrodes; Neurons; Rats; Salicylates; Salicylic Acid; Tinnitus

Growing rats were exposed to noise and/or tinnitus-producing drugs (sodium salicylate, quinine, gentamycin). Growth inhibition or weight loss was absent or significantly lower in the noise-only and salicylate-only/quinine-only groups than in the groups exposed to both noise and drugs. In the gentamycin groups, initially the same trend was found, but general toxicity soon prevailed, leading to heavy weight losses in both groups. The findings clearly favor the hypothesis that tinnitus-induced stress may be the cause for this effect. The experimental set-up thus could serve as an animal model for tinnitus research. In humans, high doses of salicylate or quinine should be avoided in persons exposed to elevated noise levels.

Topics: Animals; Disease Models, Animal; Female; Gentamicins; Growth Disorders; Noise; Pilot Projects; Quinine; Rats; Rats, Inbred Strains; Salicylates; Stress, Physiological; Tinnitus; Weight Loss

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Nimodipine; Quinine; Rats; Salicylates; Tinnitus

A three phase study was designed to define further the sensitivity and specificity of symptomatic salicylate ototoxicity (primarily tinnitus) for serum salicylate concentrations. In phase one 260 patients with osteoarthritis and 112 with rheumatoid arthritis, none taking salicylates, were interviewed about their ear symptoms. Their responses were not significantly different from those of 134 salicylate treated patients with rheumatoid arthritis previously reported. In the second phase 56 patients who were taking salicylates, and who volunteered the complaint of tinnitus, had serum salicylate concentrations measured while symptomatic, and 30 (54%) had concentrations less than 1.3 mmol/l. Few tolerated an upward salicylate dose adjustment. For phase three, 94 patients were found to have a salicylate concentration above 2.2 mmol/l on one or more occasion, and these subjects were interviewed. Fifty two patients (55%) had no tinnitus, and tinnitus correlated with the blood salicylate concentration in only 28 (30%). Audiological evaluation of most of the symptomatic patients was carried out, and results were abnormal in the majority, even in those patients not reporting tinnitus. Symptomatic salicylate ototoxicity is too nonspecific and too insensitive to be a useful indicator of serum salicylate concentration.

Topics: Adult; Aged; Arthritis, Rheumatoid; Hearing Disorders; Humans; Middle Aged; Osteoarthritis; Salicylates; Sensitivity and Specificity; Tinnitus

The ototoxic effects of salicylates, reversible hearing loss and tinnitus, are well documented. However, the pharmacological mechanisms underlying these changes in cochlear function are not well understood. The studies reported here were an investigation of the site and mechanism of salicylate ototoxicity through an examination of its effects on ionic, neural and mechanical aspects of cochlear transduction. Salicylate administration produced an intensity dependent reduction of the AP and SP, with the predominant effects occurring at low stimulus levels. In direct contrast, a significant increase was observed for corresponding CM responses, independent of stimulus intensity. Salicylates also reduced the magnitude of efferent induced shifts in the AP, CM and EP. Cochlear mechanics were altered as evidenced by the reduction in two-tone distortion products, electrically evoked emissions, and electrophonic APs. These changes in cochlear function are attributed to a salicylate mediated increase in the membrane conductance of the outer hair cells. This change in membrane permeability interferes with the reverse transduction process, effectively reducing the gain of the cochlear amplifier. Results of single unit recordings suggest parallels between salicylate intoxication and noise trauma, which are discussed with regard to potential mechanisms of tinnitus generation.

Topics: Acoustic Stimulation; Action Potentials; Animals; Cats; Cochlea; Ear, Inner; Electric Stimulation; Hearing; Nerve Fibers; Reaction Time; Salicylates; Tinnitus

Using the American Rheumatism Association Medical Information System, we studied the effect of age upon salicylate toxicity in elderly patients with rheumatoid arthritis. Data were gathered from 545 patients by self-reported questionnaires for the 6 months and also the 7 days before the visit of interest. With one week data and weight adjusted doses in 253 patients in whom data were available, age related differences in lower gastrointestinal symptoms (p = 0.05) and tinnitus (p = 0.01) were found, despite the fact that elderly patients (E) took less salicylate than younger ones (y)--E [39.1 +/- 2.4 (SD) mg/kg/day] vs Y [49.8 +/- 3.89 mg/kg/day] (p = 0.02). Our data indicate a difference in salicylate dynamics among the elderly (i.e., increased toxicity in the face of decreased salicylate doses).

Topics: Adult; Age Factors; Aged; Arthritis, Rheumatoid; Aspirin; Central Nervous System Diseases; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Salicylates; Tinnitus

After intraperitoneal administration of salicylate in anesthetized rats and guinea pigs, we found that salicylate levels in perilymph (PL) are closely related to both drug levels in cerebrospinal fluid (CSF) and in serum, with higher levels systematically observed in PL than in CSF. Further analysis suggests that salicylate is not passively transported into PL across CSF but, rather, is transported from blood directly to PL. The time course of salicylate uptake in rats reveals maximum levels at 1 1/2 hours (serum) and two to four hours (CSF and PL). On the other hand, salicylate uptake into serum and CSF of guinea pigs exhibits a longer time course, with maximum levels reached at four hours (serum) and five hours (CSF). These data, not previously available, are basic to our understanding of salicylate-related auditory effects.

Topics: Animals; Biological Transport; Guinea Pigs; Labyrinthine Fluids; Perilymph; Rats; Salicylates; Species Specificity; Time Factors; Tinnitus

A high unit dose (15 grain/975 mg) enteric coated aspirin preparation was studied in normal individuals and patients with arthritis to determine how readily well tolerated, therapeutic (150-300 micrograms/ml) salicylate (SA) levels could be achieved using a twice daily dosing regimen. Of 36 participants enrolled, 33 (92%) achieved this goal (mean SA = 224 micrograms/ml), while in the remaining 3 an initially toxic level fell below the therapeutic range after reducing the dose by one tablet/day. Although the relationship between dose (mg/kg) and steady state SA levels was roughly linear (r = 0.74), in some subjects there was a striking incremental change in the SA level when the dose was adjusted. Over 90% of subjects taking a starting dose between 45-60 mg/kg/day achieved a therapeutic level. Thus, antiinflammatory therapy using 15 grain/975 mg enteric coated aspirin given twice daily appears to be feasible.

Topics: Adult; Aged; Arthritis, Rheumatoid; Aspirin; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Osteoarthritis; Salicylates; Salicylic Acid; Tablets, Enteric-Coated; Tinnitus

A crossover double-blind controlled trial was performed on 36 patients with rheumatoid arthritis to assess the necessity for serum salicylate monitoring in determining optimal dosage. There was no clinically or statistically significant increase in the clinical improvement of patients associated with serum monitoring but potentially toxic serum levels occurred without tinnitus when serum monitoring was not used.

Topics: Arthritis, Rheumatoid; Aspirin; Deafness; Double-Blind Method; Drug Administration Schedule; Evaluation Studies as Topic; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Salicylates; Tinnitus

A pilot study evaluated once-daily treatment of rheumatoid arthritis with choline magnesium trisalicylate (CMT) in patients diagnosed as having classical or definite rheumatoid arthritis, with morning stiffness as a major complaint. Twenty patients were selected who, in an earlier phase of the study, had found twice-daily treatment with CMT effective and tolerable. Efficacy was evaluated in 15 of these patients and safety was evaluated in all 20. Comparisons were made with the twice-daily regimen and with previous nonsteroidal anti-inflammatory drug (NSAID) therapy. Changes in clinical indicators (numbers of painful and swollen joints and the duration of morning stiffness) showed that once-daily treatment with CMT was as effective as twice-daily treatment with CMT or as treatment with other prior NSAIDs in controlling signs and symptoms of rheumatoid arthritis. Side effects in both the twice-daily and the once-daily treatment regimens were similar in incidence and nature.

Topics: Adult; Aged; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Choline; Female; Hearing Loss; Humans; Male; Middle Aged; Pilot Projects; Salicylates; Tinnitus

Topics: Animals; Auditory Pathways; Brain Mapping; Brain Stem; Cochlea; Cochlear Nerve; Deoxyglucose; Disease Models, Animal; Ear Ossicles; Guinea Pigs; Pons; Salicylates; Salicylic Acid; Tinnitus

Topics: Adult; Aged; Deafness; Female; Humans; Male; Middle Aged; Movement Disorders; Salicylates; Tinnitus

Thirty-one patients with rheumatoid arthritis in the Veterans General Hospital from July 1978 to June 1979 were treated with acetylsalicylic acid. The serum salicylate level was determined twice a week. The dose of acetylsalicylic acid was adjusted to keep the serum salicylate level around 15-30 mg%. All patients were started with an initial dose of 65 mg/kg/day. The serum salicylate levels at the 4th day varied greatly from 5.6 to 29.5 mg%. Tinnitus was noted in 24 patients. It occurred when the serum salicylate level reached 28.41 +/- 1.84 mg%. Abnormal liver function was noted in 19.35% (6/31) patients during treatment. It returned to normal after withdrawal of acetylsalicylic acid in 3 cases, after decrease of the dosage in 2 cases and on the same dosage in 1 case. Patients with positive FANA and RF were more prone to develop abnormal liver function during treatment. Monitoring of serum salicylate level may decrease the incidence of hepatic toxicity and maintain the dosage of acetylsalicylic acid in optimal range.

Topics: Adult; Arthritis, Rheumatoid; Aspirin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Rheumatoid Factor; Salicylates; Tinnitus

Intermittent and concomitant acetylsalicylic acid (ASA) therapy was superimposed onto a 21-day regimen with diflunisal 250 mg b.i.d. Low doses of ASA (600 mg single dose or 300 mg q.i.d.) did not influence signficantly diflunisal blood levels whereas a 600 mg q.i.d. dosing caused a small significant drop, especially at trough level. This drop is not expected to be clinically significant. No ototoxicity could be demonstrated with any treatment of diflunisal though four of fourteen subjects reported mild tinnitus during concomitant therapy at the higher doses of ASA. Diflunisal at 375 mg b.i.d. failed to alter the metabolism of a single dose of labelled ASA (600 mg) as judged by plasma levels, urinary excretion and plasma binding. Daily urinary excretion of prostaglandins E1 and E2 major metabolite was decreased by about 70% by diflunisal.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Drug Interactions; Hemostasis; Humans; Male; Prostaglandins E; Salicylates; Tinnitus

Topics: Adult; Aged; Anesthesia, Local; Body Weight; Boric Acids; Ear Diseases; Eustachian Tube; Female; Hearing Disorders; Humans; Middle Aged; Palate; Posture; Pressure; Salicylates; Sphenoid Bone; Tendons; Therapeutic Irrigation; Tinnitus

Topics: Acetanilides; Acetates; Arthritis, Rheumatoid; Deafness; Humans; Salicylates; Tinnitus

Topics: Acetanilides; Acetates; Humans; Salicylates; Tinnitus

Topics: Age Factors; Aged; Arthritis, Rheumatoid; Aspirin; Audiometry; Drug Tolerance; Humans; Indomethacin; Middle Aged; Salicylates; Spectrophotometry; Time Factors; Tinnitus

Topics: Arthritis; Arthritis, Rheumatoid; Aspirin; Audiometry; Blood; Cochlea; Drug Therapy; Enzyme Inhibitors; Geriatrics; Hearing Disorders; Hearing Tests; Humans; Oxidoreductases; Salicylates; Tinnitus; Toxicology