dynorphins and Tinnitus

Tinnitus is the phantom perception of sounds occurring in the absence of an external auditory stimulus. Tinnitus: [1] effects 50 million individuals, [2] often results from acoustic trauma and, [3] is very often exacerbated under stressful conditions. Tinnitus may result from lesions occurring at any location in the auditory system, but its mechanisms are poorly understood. Evidence is provided supporting an endogenous dynorphin-mediated potentiation of glutamate excitotoxicity at cochlear Type-I auditory dendrites that may well exacerbate chronic subjective neural-generated tinnitus during periods of heightened stress. The proposed mechanism is based on the following: [1] lateral efferent olivocochlear (LEOC) axon terminals contain endogenous dynorphin neuromodulators and are presynaptic to cochlear Type-I auditory dendrites that bear both κ-opioid and N-methyl-d-aspartate (NMDA) receptors/binding sites; [2] the release of presynaptic LEOC dynorphins is likely to be triggered by sympathetic stress via the locus coeruleus; [3] sodium salicylate induces an acute excitotoxicity by potentiating glutamate neurotransmitter effects at cochlear NMDA receptors, resulting in a Type-I auditory neural-generated tinnitus; [4] dynorphins participate in central NMDA-receptor-mediated excitotoxic inflammation; and [5] κ-opioid receptor ligands also modulate Type-I auditory neural activity by potentiating glutamate at cochlear NMDA receptors. A stress-activated release of dynorphins into the cochlea could potentiate the already excitotoxic effects of glutamate, producing: [1] hyperacusis, together with an acute exacerbation of [2] chronic aberrant Type-I neural activity and [3] a worsening of the activity-dependent central auditory neural plasticity changes that must certainly generate the perception of tinnitus. Treatment options are discussed.

Topics: Dynorphins; Humans; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Stress, Psychological; Tinnitus

Subjective tinnitus may be defined as the perceptual correlate of altered spontaneous neural activity occurring in the absence of an externally evoking auditory stimulus. Tinnitus can be caused or exacerbated by one or more of five forms of stress. We propose and provide evidence supporting a model that explains, but is not limited to, peripheral (cochlear) tinnitus. In this model, naturally occurring opioid dynorphins are released from lateral efferent axons into the synaptic region beneath the cochlear inner hair cells during stressful episodes. In the presence of dynorphins, the excitatory neurotransmitter glutamate, released by inner hair cells in response to stimuli or (spontaneously) in silence, is enhanced at cochlear N-methyl-D-aspartate (NMDA) receptors. This results in altered neural excitability and/or an altered discharge spectrum in (modiolar-oriented) type I neurons normally characterized by low rates of spontaneous discharge and relatively poor thresholds. It is also possible that chronic exposure to dynorphins leads to auditory neural excitotoxicity via the same receptor mechanism. Finally, the proposed excitatory interactions of dynorphins and glutamate at NMDA receptors need not be restricted to the auditory periphery.

Topics: Animals; Dynorphins; Humans; Models, Biological; Stress, Physiological; Tinnitus

Tinnitus has been defined as the perceptual correlate of altered spontaneous neural activity occurring without an external auditory stimulus. Hyperacusis, defined as a collapse of tolerance to sound, is present in 40-86% of those who suffer from disabling forms of tinnitus. Both phenomena often are induced or exacerbated by physical or psychological stress. Biological systems known to regulate the body's overall response to stress use and release endogenous neuroactive opioid peptides. These stress-related neuromodulators consist of products derived from three genetically distinct precursor hormones. Two of these precursor hormones are proenkephalin and prodynorphin. Enkephalin and dynorphin-related peptides exist within the efferent olivocochlear systems (lateral and medial) of several mammalian species, including humans. Prodynorphin derivatives, however, may be restricted exclusively to lateral efferent neurons. Descending lateral efferent axons terminate solely on primary (type I) auditory dendrites innervating cochlear inner hair cells in most species. This action indicates that they play an important role in modulating auditory nerve sensitivity and spontaneous discharge. In a fashion similar to that exhibited by the observed excitatory mechanism of action of dynorphins in the spinal cord, sodium salicylate (aspirin) recently was shown to facilitate the excitatory effects of glutamate in the cochlea. This article provides support for a neurochemical model in which endogenous dynorphins may induce hyperacusis and can contribute to the induction, maintenance, or exacerbation of tinnitus in the auditory periphery by altering auditory type I neural excitability to glutamate.

Topics: Cochlea; Dynorphins; Endorphins; Enkephalins; Humans; Olivary Nucleus; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Tinnitus