Dynorphins: Their Likely Role in Neural Excitotoxicity and Inflammation within the Cochlea

by Tony L. Sahley, Ph.D., CCC-A

Acoustic overstimulation (AOS) is defined as an over-exposure to stressfully loud sounds. AOS often results in symptoms that include a chronic reduction in hearing sensitivity, referred to as a sensorineural hearing loss (SNHL). AOS is the principal cause of acquired SNHL and is second only to SNHL that is age-related. AOS also appears to be the most common military service-related origin of SNHL.

AOS often traumatizes structures within the cochlea of the inner ear. Indeed, the auditory-related consequences of AOS are well known experimentally and often include pervasive forms of degenerative damage to structures within the cochlea. Specifically, the SNHL that follows AOS is often accompanied by swelling and destruction of structural components within the cochlea, such as the stereocilia, the pillar cells, the blood vessels and capillaries of the lateral wall/stria vascularis, the Type-II/Type-IV spiral ligament fibrocytes, and most prominently, the outer hair cells. AOS and the associated SNHL that follows, is also frequently accompanied by an acute or chronic inner ear inflammation that often includes neural trauma consisting of dendritic swelling and the rupturing of primary Type-I auditory neurons. The Type-I auditory neurons are responsible for all or most of the auditory input that initially and ultimately reaches the auditory cortex. Therefore, the Type-I auditory neurons are responsible for processing essentially all that we hear.

The dendritic swelling and Type-I auditory-neural trauma, neuropathy and SNHL associated with AOS are frequently the result of necrotic cell death caused by elevated (excitotoxic) and prolonged accumulations of the peripheral auditory neurotransmitter glutamate (GLU), subsequent to its release from the inner hair cells (IHCs). Indeed, in the cochlea, GLU is the excitatory neurotransmitter that activates the Type-I auditory neurons in response to auditory stimuli. GLU is also well known for its selective neurotoxicity and exacerbation of injury when present in excessive amounts within the nervous system. Oxidative stress and the production of free radicals/superoxides are also major factors within the cochlea that often follow AOS, and additionally contribute to the SNHL, inner ear inflammation and the inner ear cellular damage that are often observed. In general, the overproduction of oxygen-based free radical substances is well known to be biologically toxic to cells. Finally, the inner ear has the cellular machinery to become immunologically active in response to AOS. AOS leads to an upregulation (increased production) within the cochlea of certain pro-inflammatory signalling proteins (cytokines) of the immune/inflammatory system, resulting in Type-I auditory inflammation/neural degeneration and SNHL. Indeed, these very same pro-inflammatory signalling components of the immune system are well known to promote and/or to mediate cellular damage and inflammation in a number of systemic inflammatory disorders. Hence, AOS has been shown to result in 1) a GLU-induced Type-I auditory neural excitotoxicity within the cochlea, 2) oxidative stress and free radical/superoxide production within the cochlea, and finally, 3) an upregulated inner ear immune/inflammatory response, all of which, either singularly and/or in combination, lead to cochlear pathology and SNHL.

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 role in promoting neural inflammation, edema, cytotoxicity, hyperalgesia and neural pathology. Specifically, DYNs are a class of neuroactive opioids that can interfere with the rate of extracellular GLU uptake by glial cells and hence, significantly increase the excitotoxic and neuro-inflammatory availability of GLU, as well as potentiate the postsynaptic receptor-mediated excitotoxic properties of GLU. To be sure, the participation and actions of low concentrations of DYNs in pathologies involving GLU-receptor mediated neurotoxicity and inflammation are well documented. DYNs have also been found to play a significant role in the regulation of the immune/inflammatory signal transduction pathways that lead to free radical/superoxide production, and to the upregulated production of pro-inflammatory cytokines. DYN-mediated effects on the immune/inflammatory system can lead to a reduced state of immunocompetence, an increase in inflammation, cytotoxicity, cell destruction, and to a greater susceptibility to viral and bacterial infection.

In view of these considerations, it is significant to note that DYNs are well known to exist within important anatomical microstructures within the mammalian 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. Specifically, the DYN-bearing LOC axon terminals exhibit a more concentrated innervation with the Type-I neurons that bear the same class of GLU-sensitive receptors that have been strongly implicated in the neural excitotoxicity that follows AOS. This very same class of GLU-sensitive receptor is also well known to interact with DYNs, and the close proximity within the cochlea between these GLU-sensitive receptors and the DYN-bearing LOC axon terminals greatly increases the likelihood of a neurotoxic, DYN-GLU-receptor interaction within the cochlea. Such an interaction is highly likely to occur whenever conditions favor a significant release of DYNs from the presynaptic 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. Given that DYNs increase GLU availability, potentiate GLU excitotoxicity, induce free radical/superoxide production, increase the production of immune-system pro-inflammatory cytokines, and are involved in the regulation of biological responses to all forms of stress, what possible connection might exist between AOS 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 in response to overall autonomic (sympathetic) arousal. In awake animals, AOS also 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 and/or cochlear administrations of drugs that mimic DYNs.

In summary, the possibility exists that the GLU-mediated Type-I auditory neural dendritic swelling, inflammation, excitotoxicity and SNHL that follows AOS may be part of a brainstem activated, DYN-mediated cascade of inflammatory-excitotoxic events, subsequent to the LOC release of DYNs into the cochlea, and triggered by diffuse NE-regulated neural networks within the CNS that normally respond to environmental, physical and/or psychological stressors, such as AOS. That is, the enhanced Type-I auditory neural activity that leads to oxidative stress, excitotoxicity, inflammation and SNHL that follows AOS may well be regulated by sympathetic input from the LC, and possibly mediated in the cochlea by the presynaptic release of DYNs from the axon terminals of the LOC system.

In conclusion, establishing a link between cochlear DYNs and AOS is a promising first step in elucidating an effective, pharmacological strategy for the possible management and/or prevention of the SNHL resulting from excessive noise-exposure. The possibility would then exist that opioid-receptor antagonism could become a clinically useful strategy for offsetting the negative effects of excessive exposure to loud, stressful noise. FDA-approved drugs are available that could safely be used to antagonize the properties of DYNs with the aim of protecting the cochlea during periods of acoustic over-exposure. On theoretical grounds, this strategy may have promise for reducing and/or possibly eliminating the progression of SNHL, as well as for reducing and/or eliminating the many related and damaging sequelae associated with AOS.

 

Key References

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Tony L. Sahley, Ph.D., CCC-A is currently a Professor of Audiology and Auditory Neuroscience in the School of Health Sciences at Cleveland State University, where he teaches upper-level undergraduate courses in Hearing & Speech Science, Neuroscience, Medical Physiology, and Clinical Audiometry. Dr. Sahley also holds an adjunct appointment in the Department of Biological, Geological, and Environmental Sciences (BGES). His dissertation was conducted at Dartmouth Medical School, Hanover New Hampshire under the mentorship of Dr. Frank E. Musiek, and he received a doctorate in Hearing Science from the joint programs at the University of California, Santa Barbara, and at University of California, San Francisco Medical Center. Dr. Sahley also completed a clinical internship at the Cleveland Clinic Foundation, and authored the books: Efferent Auditory System: Structure & Function with co-authors Dr. R.H. Nodar and Dr. F.E. Musiek, and Basic Fundamentals in Hearing Science, with co-author Dr. F.E. Musiek. Dr. Sahley began publishing articles on behavioral neuropharmacology in 1976. In collaboration with his colleagues, Dr. Sahley is currently investigating the potential interactive role of dynorphins with specific chemical messengers of the immune system that have been associated with the inner ear immune/inflammatory response and the hearing loss that often follows from exposure to acoustic overstimulation.