Salicylate toxicity model of tinnitus

Abstract

Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs, or aging, which affects ∼14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed.

Keywords: animal models; aspirin; auditory dysfunction; hearing loss; salicylate; tinnitus.

Figure 1

Effects of systemic or cochlear perfusion of salicylate on spontaneous (Spont.) or sound-evoked (Evoked) cochlear measures. OAE, otoacoustic emissions; SP, summating potential; CM, cochlear microphonic; CAP, compound action potential. 1. Fitzgerald et al. (1993); 2. Puel et al. (1990); 3. Stolzberg et al. (2011); 4. Ruel et al. (2008); 5. Ralli et al. (2010); 6. Guitton et al. (2003); 7. Wier et al. (1988); 8. Janssen et al. (2000); 9. McFadden and Plattsmier (1984); 10. Muller et al. (2003); 11. Didier et al. (1993); 12. Silverstein et al. (1967); 13. Guitton et al. (2005); 14. Chen et al. (2010); 15. Cazals et al. (1998) (^*spontaneous cochleoneural activity was decreased immediately after injection and increased on longer timescale; see text).

Figure 2

Summary of effects of salicylate on various auditory structures. Cytological studies include results from 2-DG and fos-IR imaging studies (see Section “Identifying Key Brain Regions”) and were performed at low (50 mg/kg i.p.) or high (350 mg/kg i.p.) acute doses of salicylate. Electrophysiology recordings were performed at various moderate to high salicylate doses. Results are from studies using in vivo extracellular recordings or in vitro extracellular or patch clamp recordings (see Section “Electrophysiology”). AN, auditory nerve; vCN, ventral cochlear nucleus; dCN, dorsal cochlear nucleus; cIC, central nucleus of the inferior colliculus; eIC, external nucleus of the inferior colliculus; dIC, dorsal nucleus of the inferior colliculus; vMGB, ventral portion of the medial geniculate body; dMGB, dorsal portion of the medial geniculate body; A1, primary auditory cortex; A2, secondary auditory cortex; AAF, anterior auditory field. Spont, single unit or multiunit spontaneous firing rates; Evoked, sound-evoked single unit or multiunit firing rates; ERP, sound-evoked response field potential; CAP, compound action potential of the cochlea; IC, inferior colliculus response potential; MGB, medial geniculate response potential; AC, auditory cortex response potential. ^*Represents acute effects of salicylate treatment (Wallhausser-Franke, ; Wallhausser-Franke et al., 2003). 2. Puel et al. (1990); 3. Stolzberg et al. (2011); 6. Guitton et al. (2003); 7. Wier et al. (1988); 8. Janssen et al. (2000); 9. McFadden and Plattsmier (1984); 10. Muller et al. (2003); 11. Didier et al. (1993); 12. Silverstein et al. (1967); 13. Guitton et al. (2005); 14. Chen et al. (2010); 15. Cazals et al. (1998); 16. Evans and Borerwe (1982); 17. Kumagai (1992); 18. Wei et al. (2010); 19. Basta et al. (2008); 20. Sun et al. (2009); 21. Ma et al. (2006); 22. Basta and Ernst (2004); 23. Jastreboff and Sasaki (1986); 24. Chen and Jastreboff (1995); 25. Lobarinas et al. (2006); 26. Norena et al. (2010); 27. Lu et al. (2011); 28. Lobarinas et al. (2006); 29. Paul et al. (2009); 30. Yang et al. (2007); 31. Eggermont and Kenmochi (1998); 32. Kenmochi and Eggermont (1997); 33. Zhang et al. (2011).

Figure 3

Frequency tuning of eight simultaneously recorded extracellularly recorded multunits from primary auditory cortex before (top panel) and after systemic salicylate injection (bottom panel; 250 mg/kg i.p.). Following systemic salicylate treatment, the frequency tunings of tracked multiunits shifted maximal frequency sensitivities toward the 10–20 kHz frequency region, near the estimated tinnitus pitch. Please see Stolzberg et al., for population statistics. [From Stolzberg et al. (2011) with permission].