Tony L. Sahley, School of Health Sciences, Cleveland State University
Subjective tinnitus is a clinical disorder, defined traditionally as a perception of sound (a tone, a hum or a hiss) that is experienced in the absence of an externally evoking auditory stimulus. For this reason, subjective tinnitus is often referred to as a phantom auditory perception. Approximately 25.3% of the general population (or 50 million adults) in the United States experiences the disorder.
The relationship between stressfully loud sounds (acoustic over-stimulation) and subjective, neural-generated tinnitus is well known and is well documented. Both acute (short-lasting or temporary) and chronic (long-term) tinnitus often begins with or follows an episode of stressful acoustic over-stimulation. Acoustic over-stimulation is at times followed by an acute or a chronic reduction in hearing sensitivity that may or may not be accompanied by an acute or chronic tinnitus. Over-exposure to loud, intense environmental sounds often results in tinnitus when the auditory stimuli last for prolonged periods of time. Moreover, chronic subjective tinnitus is subsequently made worse or amplified (made louder or exacerbated) by physical fatigue and/or by numerous forms of emotional stress. Acoustic over-exposure to loud sounds is often stressful to the nervous system in general, and often traumatizes the inner ear, in particular. Current opinion holds that neural events that give rise to the perception or exacerbation of tinnitus are likely to begin with anomalous or altered neural activity that originates from within the inner ear (cochlea), beginning with a preliminary lesion or insult to the peripheral sensory neural machinery (Type-I neurons) innervating the cochlear end-organ. The insult may be acute or chronic. In the chronic form, altered peripheral input from the cochlea, resulting from insult, injury, or peripheral Type-I neural damage, is the most common event that activates central neural plasticity changes that many believe, lead to an eventual neural reorganization of parts of the central auditory pathways. Central neural plasticity changes only then, generate and perpetuate the actual phantom auditory perception, known as (chronic) subjective tinnitus.
The auditory trauma that follows acoustic over-exposure is indeed well documented, and frequently consists of an acute or chronic inflammation of the primary (Type-I) auditory neurons within the cochlea. The Type-I auditory neurons are responsible for all or most of the auditory input that initially and ultimately reaches the auditory cortex. Therefore, they are responsible for processing essentially all that we hear. In the cochlea, glutamate (GLU) is the excitatory neurotransmitter that activates the Type-I auditory neurons. Acoustic over-exposure and the subsequent Type I auditory-neural trauma that follows, is the result of an excessive, excitotoxic accumulation of GLU. GLU is well known for its selective neurotoxicity and exacerbation of injury when present in excessive amounts in the nervous system. The GLU-mediated Type-I auditory neural (dendritic) swelling and inflammation that often follows from acoustic over-stimulation is symptomatically associated with tinnitus. To be sure, a sizable amount of evidence indicates that subjective, neural-generated tinnitus arises from factors that increase GLU availability in the cochlea, and/or from factors that potentiate the excitatory, and potentially excitotoxic receptor-mediated actions of GLU at the postsynaptic, inner hair cell (IHC)-Type-I auditory synapse.
In the mammalian nervous system, naturally occurring (endogenous) neuroactive opioid (peptide) substances called dynorphins (DYNs) are profoundly involved in the regulation of biological responses to all forms of stress, and correspondingly play a significant negative role in neural inflammatory disorders, edema, cytotoxicity, hyperalgesia and neural pathology. DYNs can interfere with the rate of extracellular GLU uptake by glial cells, and hence, can significantly increase the extracellular availability of GLU. DYNs also potentiate the excitatory properties of GLU at postsynaptic GLU-sensitive neural receptors. Indeed, the excitatory, neurotoxic GLU-receptor mediated actions of low concentrations of DYNs are well documented. More notably, DYNs are well known to exist within important anatomical microstructures within the cochlea. Specifically, DYNs are localized within the organized bundle of descending lateral (efferent) olivocochlear (LOC) axon terminals that directly innervate the dendrites of Type-I auditory neurons. Type-I auditory dendrites in turn, directly innervate the cochlear IHCs. In response to auditory stimuli, Type I auditory neurons are normally excited by the release, from the base of the IHCs, of the neurotransmitter GLU. Type I neural excitation is initiated at the dendrites, via postsynaptic GLU-sensitive receptors. Hence, the presynaptic DYN-bearing LOC axon terminals that innervate Type I auditory dendrites are in very close physical (and synaptic) proximity to the (postsynaptic) GLU-sensitive receptors located within the same dendrites. This close proximity between GLU-sensitive receptors and the DYN-bearing LOC axon terminals greatly increases the likelihood of a DYN-GLU-receptor interaction within the cochlea. Such an interaction would conceivably occur in the event that conditions favored a presynaptic release of DYNs from the LOC axon terminals. Under carefully controlled experimental conditions, we have repeatedly observed that auditory sensitivity to very soft sounds is enhanced when drugs that mimic the effects of DYNs are administered either systemically, or placed directly into the cochlea. That is, following the administration of such drugs, the excitatory, receptor-mediated actions of GLU are potentiated in the cochlea. Such evidence strongly suggests that endogenous DYNs may function within the cochlea to increase GLU availability and/or to potentiate the excitatory, and quite possibly, even the excitotoxic receptor-mediated actions, of GLU.
Aside from the possibility that endogenous cochlear DYNs are likely to contribute to the excitotoxic, Type-I auditory neural dendritic swelling and inflammation that typically follows acoustic over-stimulation, how else might the receptor properties of DYNs be connected to the symptomology of tinnitus? DYNs exhibit pharmacological actions that closely resemble those of the excitatory, and sometimes cytotoxic drug, sodium salicylate (aspirin). Sodium salicylate is well known and is well-studied for its capacity to produce a transient, dose-dependent neural-generated tinnitus when administered systemically. For this reason, salicylate-induced tinnitus has historically served as a reliable, highly controlled pharmacological model for naturally occurring, neural-generated tinnitus. Sodium salicylate has been shown, in repeated investigations, to potentiate the Type-I neural excitatory properties of the auditory neurotransmitter, GLU. The salicylate-induced potentiation of GLU, and resulting well-known neural-generated tinnitus, is mediated by the same class of GLU-sensitive receptors that are known to interact with DYNs. Moreover, in the cochlea, the Type-I auditory dendrites that bear this class of GLU-sensitive receptor are situated in such a way that places them in very close proximity to high concentrations of presynaptic, DYN-bearing axon terminals.
In summary, following acoustic over-stimulation, an endogenous cochlear mechanism is likely to exist whereby a DYN-mediated increase in receptor sensitivity to GLU could selectively enhance Type-I auditory neural activity, and thereby contribute significantly to the production of an acute (reversible) tinnitus, and temporary inflammation, in a manner that is reminiscent of the reported mechanism of action of sodium salicylate. During periods of psychological (non-auditory) stress, the same mechanism could selectively enhance Type-I auditory neural activity at low or possibly negligible levels of an auditory stimulus. Normally, such an increase in auditory sensitivity during periods of vigilance would be considered appropriate and adaptive. However, in a neurologically compromised inner ear, a psychological stress-induced DYN-mediated increase in receptor sensitivity to GLU could result in, or contribute to an exacerbation of a pre-existing (chronic) condition of tinnitus and neural inflammation, perhaps resulting as well in the generation of hyperacusis. Hyperacusis, which is often associated with tinnitus, is usually defined as increased sensitivity, intolerance, and an abnormally strong reaction to ordinary, low intensity-level environmental sounds, that are neither threatening nor uncomfortably loud. Hyperacusis, like tinnitus, is often associated with or is worsened by physical fatigue or emotional stress. Given that DYNs are involved in the regulation of biological responses to all forms of stress, what possible connection might exist between environmental or psychological stressors, and the release of DYNs from the LOC axon terminals within the cochlea?
The LOC dendrites and cell bodies (LOC nuclei) of the DYN-bearing axon terminals that directly innervate cochlear Type-I auditory dendrites, are located in the brainstem. These nuclei receive abundant axonal projections from norepinephrine (NE)-rich axons of another brainstem nucleus, the locus coeruleus (LC). The LC exhibits high activity levels during periods of emotional stress, increased behavioral vigilance, anxiety, and generally in response to autonomic (sympathetic) arousal. In awake animals, acoustic over-stimulation produces vigorous activity in LC neurons, and results in very intense metabolic and/or functional activity within cochlear LOC axon terminals. Application of NE to LOC brainstem nuclei produces Type-I neural activity changes in response to sound that closely resemble those that follow systemic or cochlear administrations of drugs that mimic DYNs. Hence, LOC-induced alterations in Type-I auditory responses to sound may well be regulated by sympathetic input from the LC, and possibly mediated in the cochlea by a presynaptic release of DYNs.
In conclusion, establishing a link between cochlear DYNs and tinnitus is a promising first step in elucidating an effective, pharmacological strategy for the possible management and/or prevention of tinnitus. FDA-approved drugs are available that can safely be used to antagonize the properties of DYNs. It may be possible in the future to protect the cochlea from not only acoustic over-exposure, but from the added worsening of tinnitus symptoms caused by physical and/or emotional stress.
https://www.pluralpublishing.com/author_Tony_Sahley.htm
Tony L. Sahley, PhD, CCC-A, is currently an associate professor in the School of Health Sciences at Cleveland State University. Dr. Sahley also holds an adjunct appointment in the Department of Biological, Geological, and Environmental Sciences (BGES).
Key References
Elgoyhen, A.B., Fuchs, P.A. (2010). Efferent innervation and function. In: Fuchs, P.A. (Ed.), The Oxford Handbook of Auditory Science: The Ear, vol. 1, New York, N.Y.: Oxford University Press, pp. 283-306.
Sahley, T.L., Hammonds, M.D., Musiek, F.E. (2013). Endogenous dynorphins, glutamate and N-methyl-D-aspartate receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus. Brain Research, 1499, 80-108.
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Guitton, M.J. (2012). Tinnitus: pathology of synaptic plasticity at the cellular and system levels. Frontiers in Systems Neuroscience, DOI 10.3389/fnsys
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