Bi-phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: Partial blockade by an N-Methyl-d-Aspartate (NMDA)-receptor antagonist

Abstract

Dynorphins, glutamate, and glutamate-sensitive N-Methyl-D-Aspartate (NMDA) receptors exist in the mammalian cochlea. Dynorphins produce neural excitation and excitotoxic effects in the spinal cord through a κ-opioid facilitation of NMDA receptor sensitivity to glutamate. The κ-opioid receptor drug agonists N-dimethylallyl-normetazocine [(-)-pentazocine (50 mmol)] and trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide [U-50488H (100 mmol)] were administered across the cochlear round window membrane in the chinchilla. Each drug produced significant post-baseline amplitude changes in the click-evoked auditory nerve compound action potential. Amplitude changes at threshold amounted to increases in sensitivity that ranged from 4-8 decibels, measured in sound pressure level (dB SPL). The large neural amplitude increases at threshold were accompanied by progressively smaller amplitude changes at 5 and 10 dB above threshold (dB SL). However, at stimulus intensities ≥ 20dB SL, post-baseline neural amplitudes were suppressed to levels below baseline and control values. These bi-phasic intensity-dependent neural amplitude changes have never before been observed following i.v. administered (-)-pentazocine in this species. Finally, the bi-phasic neural amplitude changes in U-50488H-treated (100 mmol) animals were partially blocked (except at 20dB SL), following a round window pretreatment with the NMDA receptor drug antagonist, dizocilpine hydrogen maleate [(+)-MK-801 (8 mmol)]. Our data suggests that endogenous dynorphins within lateral efferent olivocochlear neurons differentially modulate auditory neural excitation, possibly through cochlear NMDA receptors and glutamate. The role played by lateral efferent opioid neuromodulation at cochlear NMDA receptors, is discussed.

Dynorphin release by the lateral olivocochlear efferents may inhibit auditory nerve activity: A cochlear drug delivery study

“…In earlier studies reporting excitatory [34, 37] or biphasic [32, 39] changes in CAP amplitude, post-drug CAP amplitudes were normalized using a single pre-drug threshold as 0-dB SL. In a final analysis, we normalized post-drug CAP amplitude data using pre-drug baseline as in earlier reports (Figure 3I–3L).…”

“…“Biphasic” effects were replicated using 50-mM (−)pentazocine and 100-mM U50488 [32]; however, high drug concentrations may induce non-selective effects. Endogenous cochlear opioid release is suggested to achieve nanomolar , or perhaps micromolar, concentrations [28].…”

Molecular aspects of tinnitus

“…Together with its localization in the lateral olivocochlear complex and potential activity on NMDA receptors (for review see: Sahley and Nodar, 2001;Sahley et al, 2008), the finding justifies consideration of a more direct impact of stress responses on the pathophysiology of auditory nerve activity also during tinnitus.…”

“…Accordingly, i.v. administration of opioid receptor agonists in comparison to round window application exhibit entirely diverging effects (Sahley et al, 2008). Moreover, the application of NMDA antagonists at the round window membrane abolished tinnitus, even in animals receiving treatment with the anxiogenic serotonergic agent meta-chlorophenylpiperazine (mCPP) (Puel and Guitton, 2007).…”

Molecular Mechanism of Tinnitus

“…Stress-induced release of opioid peptides occurred, for example, in response to intense and presumably stressful wideband noise leading to enhanced levels of [Met5] enkephalin-like opioid peptides in guinea pig perilymph (Drescher et al, 1983 ;Drescher & Drescher, 1985 ) . Together with localization of opioid receptors in the lateral olivocochlear complex and potential activity on NMDA receptors (for review see Sahley & Nodar, 2001 ;Sahley et al, 2008 ) , the fi nding justi fi es the assumption of a more direct impact of stress responses on the physiology of auditory nerve activity of hearing impaired specimens with tinnitus, but perhaps also of hearing impaired animals without tinnitus.…”