Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

Joel I Berger,Ben Coomber,Samantha Hill,Steve P.H Alexander,William Owen,Alan R Palmer,Mark N Wallace

doi:10.1016/j.heares.2017.10.012

Abstract

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6–10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Highlights

Cannabis has been used for centuries, both recreationally and for medicinal purposes (Kuddus et al, 2013)
We previously demonstrated that salicylate administration significantly reduced wave I auditory brainstem responses (ABRs) amplitudes, increased cortical evoked potentials (EPs) and decreased oscillatory alpha band activity in auditory cortex (Berger et al, 2017)
Contrasting with the results of Berger et al (2017), when ACEA was co-administered with salicylate, there was no significant effect of treatment on ABR amplitudes for either the left ear (F(1,10) 1⁄4 2.83, p 1⁄4 0.12) or the right ear (F(1,15) 1⁄4 3.88, p 1⁄4 0.07), a small reduction in wave I amplitudes was evident at 20 kHz for both ears (Fig. 2A and B), albeit not to a statistically significant extent

Summary

Introduction

Cannabis has been used for centuries, both recreationally and for medicinal purposes (Kuddus et al, 2013). CB1 receptors are present in the spiral ganglion (Stincic and Hyson, 2011), dorsal and ventral cochlear nucleus (Mailleux and Vanderhaeghen, 1992; Zheng et al, 2007; Zhao et al, 2009), medial nucleus of the trapezoid body (Kushmerick et al, 2004), the inferior colliculus (Moldrich and Wenger, 2000) and the auditory cortex (Eggan and Lewis, 2007) Their presence throughout the auditory system suggests that they play a major role in synaptic regulation (Gerdeman and Lovinger, 2001; Medeiros et al, 2016). We sought to examine whether a highly-selective CB1 agonist could be a potential candidate target for attenuating auditory effects caused by sodium salicylate

Methods

Results

Conclusion