Skip to main content
Log in

Partial to Complete Suppression of Unilateral Noise-Induced Tinnitus in Rats after Cyclobenzaprine Treatment

  • Research Article
  • Published:
Journal of the Association for Research in Otolaryngology Aims and scope Submit manuscript

Abstract

Some forms of tinnitus are believed to arise from abnormal central nervous system activity following a single or repeated noise exposure, for which there are no widely accepted pharmacological treatments. One central site that could be related to tinnitus awareness or modulation is the locus coeruleus, a brainstem structure associated with stress, arousal, and attention. In the present study, we evaluated the effects of cyclobenzaprine, a drug known to act on the rat locus coeruleus, on noise-induced tinnitus using Gap Prepulse Inhibition of the Acoustic Startle (GPIAS). In untreated rats, brief silent gaps presented prior to a 5–10-kHz bandpass startling stimulus produced robust GPIAS. Treatment with cyclobenzaprine alone had no effect on the ability of gaps to suppress the startle response. When animals were exposed to intense narrow-band (126 dB SPL, 16 kHz, 100 Hz BW) unilateral noise, GPIAS was significantly reduced, suggesting the presence of tinnitus. Following the noise exposure, a subset of rats that maintained a robust startle response continued to show GPIAS impairment at 6–20 kHz, 40 days post-noise, suggesting chronic tinnitus. When this subset of animals was treated with cyclobenzaprine, at a dose that had no significant effects on the startle response (0.5 mg/kg), GPIAS recovered partially or to near baseline levels at the affected frequencies. These results were consistent with the absence of tinnitus. By 48 h post-treatment, evidence of tinnitus re-emerged. Our results suggest that cyclobenzaprine was effective in transiently suppressing noise-induced tinnitus in rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

FIG. 1
FIG. 2
FIG. 3

Similar content being viewed by others

References

  • Aston-Jones G, Chiang C, Alexinsky T (1991) Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Prog Brain Res 88:501–520

    Article  CAS  PubMed  Google Scholar 

  • Basmajian JV (1978) Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies. Arch Phys Med Rehabil 59:58–63

    CAS  PubMed  Google Scholar 

  • Bauer CA, Brozoski TJ (2001) Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model. J Assoc Res Otolaryngol 2:54–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bauer CA, Brozoski TJ (2006) Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 116:675–681

    Article  CAS  PubMed  Google Scholar 

  • Bauer CA, Brozoski TJ, Rojas R, Boley J, Wyder M (1999) Behavioral model of chronic tinnitus in rats. Otolaryngol Head Neck Surg 121:457–462

    Article  CAS  PubMed  Google Scholar 

  • Bauer CA, Turner JG, Caspary DM, Myers KS, Brozoski TJ (2008) Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J Neurosci Res 86:2564–2578

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brozoski TJ, Bauer CA, Caspary DM (2002) Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus. J Neurosci 22:2383–2390

    CAS  PubMed  Google Scholar 

  • Brozoski TJ, Spires TJ, Bauer CA (2007a) Vigabatrin, a GABA transaminase inhibitor, reversibly eliminates tinnitus in an animal model. J Assoc Res Otolaryngol 8:105–118

    Article  PubMed Central  PubMed  Google Scholar 

  • Brozoski TJ, Ciobanu L, Bauer CA (2007b) Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI). Hear Res 228:168–179

    Article  PubMed  Google Scholar 

  • Cave KM, Cornish EM, Chandler DW (2007) Blast injury of the ear: clinical update from the global war on terror. Mil Med 172:726–730

    PubMed  Google Scholar 

  • Coelho C, Figueiredo R, Frank E, Burger J, Schecklmann M, Landgrebe M, Langguth B, Elgoyhen AB (2012) Reduction of tinnitus severity by the centrally acting muscle relaxant cyclobenzaprine: an open-label pilot study. Audiol Neuro-otol 17:179–188

    Article  CAS  Google Scholar 

  • Commissiong JW, Karoum F, Reiffenstein RJ, Neff NH (1981) Cyclobenzaprine: a possible mechanism of action for its muscle relaxant effect. Can J Physiol Pharmacol 59:37–44

    Article  CAS  PubMed  Google Scholar 

  • Connor DE Jr, Nixon M, Nanda A, Guthikonda B (2012) Vagal nerve stimulation for the treatment of medically refractory epilepsy: a review of the current literature. Neurosurg Focus 32:E12

    Article  PubMed  Google Scholar 

  • Davis H, Morgan CT, Hawkins JE Jr, Galambos R, Smith FW (1950) Temporary deafness following exposure to loud tones and noise. Acta Otolaryngol Suppl 88:1–56

    CAS  PubMed  Google Scholar 

  • Dobie RA (1999) A review of randomized clinical trials in tinnitus. Laryngoscope 109:1202–1211

    Article  CAS  PubMed  Google Scholar 

  • VA DoVA (2011) Annual Benefits Report. In: http://www.vba.va.gov/reports/abr/2011_abr.pdf

  • Edeline JM, Manunta Y, Hennevin E (2011) Induction of selective plasticity in the frequency tuning of auditory cortex and auditory thalamus neurons by locus coeruleus stimulation. Hear Res 274:75–84

    Article  PubMed  Google Scholar 

  • Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, Borland MS, Kilgard MP (2011) Reversing pathological neural activity using targeted plasticity. Nature 470:101–104

    Article  PubMed Central  PubMed  Google Scholar 

  • Engineer ND, Moller AR, Kilgard MP (2013) Directing neural plasticity to understand and treat tinnitus. Hear Res 295:58–66

    Article  PubMed  Google Scholar 

  • Giorgi FS, Mauceli G, Blandini F, Ruggieri S, Paparelli A, Murri L, Fornai F (2006) Locus coeruleus and neuronal plasticity in a model of focal limbic epilepsy. Epilepsia 47(Suppl 5):21–25

    Article  CAS  PubMed  Google Scholar 

  • Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL (2003) Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 23:3944–3952

    CAS  PubMed  Google Scholar 

  • Hansen N, Manahan-Vaughan D (2014) Locus coeruleus stimulation facilitates long-term depression in the dentate gyrus that requires activation of beta-adrenergic receptors. Cereb Cortex. doi:10.1093/cercor/bht429

  • Hazell JW, Jastreboff PJ (1990) Tinnitus. I: auditory mechanisms: a model for tinnitus and hearing impairment. J Otolaryngol 19:1–5

    CAS  PubMed  Google Scholar 

  • Heffner HE (2011) A two-choice sound localization procedure for detecting lateralized tinnitus in animals. Behav Res Methods 43:577–589

    Article  PubMed  Google Scholar 

  • Heffner HE, Harrington IA (2002) Tinnitus in hamsters following exposure to intense sound. Hear Res 170:83–95

    Article  PubMed  Google Scholar 

  • Heffner HE, Koay G (2005) Tinnitus and hearing loss in hamsters (Mesocricetus auratus) exposed to loud sound. Behav Neurosci 119:734–742

    Article  PubMed  Google Scholar 

  • Heffner HE, Koay G, Heffner RS (2008) Comparison of behavioral and auditory brainstem response measures of threshold shift in rats exposed to loud sound. J Acoust Soc Am 124:1093–1104

    Article  PubMed Central  PubMed  Google Scholar 

  • Hucker HB, Stauffer SC, Balletto AJ, White SD, Zacchei AG, Arison BH (1978) Physiological disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab Dispos: Biol Fate Chem 6:659–672

    CAS  Google Scholar 

  • Ison JR (1982) Temporal acuity in auditory function in the rat: reflex inhibition by brief gaps in noise. J Comp Physiol Psychol 96:945–954

    Article  CAS  PubMed  Google Scholar 

  • Ison JR, O’Connor K, Bowen GP, Bocirnea A (1991) Temporal resolution of gaps in noise by the rat is lost with functional decortication. Behav Neurosci 105:33–40

    Article  CAS  PubMed  Google Scholar 

  • Jastreboff PJ (1990) Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci Res 8:221–254

    Article  CAS  PubMed  Google Scholar 

  • Jastreboff PJ, Brennan JF, Sasaki CT (1988a) An animal model for tinnitus. Laryngoscope 98:280–286

    Article  CAS  PubMed  Google Scholar 

  • Jastreboff PJ, Brennan JF, Coleman JK, Sasaki CT (1988b) Phantom auditory sensation in rats: an animal model for tinnitus. Behav Neurosci 102:811–822

    Article  CAS  PubMed  Google Scholar 

  • Justice A, Feldman SM, Brown LL (1989) The nucleus locus coeruleus modulates local cerebral glucose utilization during noise stress in rats. Brain Res 490:73–84

    Article  CAS  PubMed  Google Scholar 

  • Katz WA, Dube J (1988) Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience. Clin Ther 10:216–228

    CAS  PubMed  Google Scholar 

  • Kim DK, Park SN, Kim HM, Son HR, Kim NG, Park KH, Yeo SW (2011) Prevalence and significance of high-frequency hearing loss in subjectively normal-hearing patients with tinnitus. Ann Otol Rhinol Laryngol 120:523–528

    Article  PubMed  Google Scholar 

  • Kraus KS, Mitra S, Jimenez Z, Hinduja S, Ding D, Jiang H, Gray L, Lobarinas E, Sun W, Salvi RJ (2010) Noise trauma impairs neurogenesis in the rat hippocampus. Neuroscience 167:1216–1226

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lang IM, Barnes CD (1983) Cyclobenzaprine effects on locus coeruleus cells in tissue slice. Neuropharmacology 22:249–252

    Article  CAS  PubMed  Google Scholar 

  • Le Prell CG, Dell S, Hensley B, Hall JW 3rd, Campbell KC, Antonelli PJ, Green GE, Miller JM, Guire K (2012) Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects. Ear Hear 33:e44–e58

    Article  PubMed Central  PubMed  Google Scholar 

  • Lobarinas E, Sun W, Cushing R, Salvi R (2004) A novel behavioral paradigm for assessing tinnitus using schedule-induced polydipsia avoidance conditioning (SIP-AC). Hear Res 190:109–114

    Article  PubMed  Google Scholar 

  • Lobarinas E, Yang G, Sun W, Ding D, Mirza N, Dalby-Brown W, Hilczmayer E, Fitzgerald S, Zhang L, Salvi R (2006) Salicylate- and quinine-induced tinnitus and effects of memantine. Acta Otolaryngol Suppl 13–19

  • Lobarinas E, Dalby-Brown W, Stolzberg D, Mirza NR, Allman BL, Salvi R (2011) Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats. Physiol Behav 104:873–879

    Article  CAS  PubMed  Google Scholar 

  • Lobarinas E, Hayes SH, Allman BL (2013) The gap-startle paradigm for tinnitus screening in animal models: limitations and optimization. Hear Res 295:150–160

    Article  PubMed Central  PubMed  Google Scholar 

  • Lockwood AH, Salvi RJ, Burkard RF, Galantowicz PJ, Coad ML, Wack DS (1999) Neuroanatomy of tinnitus. Scand Audiol Suppl 51:47–52

    CAS  PubMed  Google Scholar 

  • Lofland JH, Szarlej D, Buttaro T, Shermock S, Jalali S (2001) Cyclobenzaprine hydrochloride is a commonly prescribed centrally acting muscle relaxant, which is structurally similar to tricyclic antidepressants (TCAs) and differs from amitriptyline by only one double bond. Clin J Pain 17:103–104

    Article  CAS  PubMed  Google Scholar 

  • Maurin Y, Enz A, Le Saux F, Besson MJ (1986) Supernumerary locus coeruleus neurons as a determinant of inherited epilepsy in the convulsive mutant mouse quaking. Brain Res 366:379–384

    Article  CAS  PubMed  Google Scholar 

  • McCombe A, Baguley D, Coles R, McKenna L, McKinney C, Windle-Taylor P (2001) Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999. Clin Otolaryngol Allied Sci 26:388–393

    Article  CAS  PubMed  Google Scholar 

  • Middleton JW, Tzounopoulos T (2012) Imaging the neural correlates of tinnitus: a comparison between animal models and human studies. Front Syst Neurosci 6:35

    Article  PubMed Central  PubMed  Google Scholar 

  • Moller AR, Moller MB, Yokota M (1992) Some forms of tinnitus may involve the extralemniscal auditory pathway. Laryngoscope 102:1165–1171

    Article  CAS  PubMed  Google Scholar 

  • Muhlnickel W, Elbert T, Taub E, Flor H (1998) Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A 95:10340–10343

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • NCT01962558 (2014) A blinded randomized pilot study assessing vagus nerve stimulation (VNS) paired with tones for tinnitus vs. VNS with unpaired tones. http://clinicaltrials.gov/show/NCT01962558

  • Norena AJ (2011) An integrative model of tinnitus based on a central gain controlling neural sensitivity. Neurosci Biobehav Rev 35:1089–1109

    Article  PubMed  Google Scholar 

  • Puel JL (2007) Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus. B-Ent 3(Suppl 7):19–22

    PubMed  Google Scholar 

  • Roberts LE, Husain FT, Eggermont JJ (2013) Role of attention in the generation and modulation of tinnitus. Neurosci Biobehav Rev 37:1754–1773

    Article  PubMed  Google Scholar 

  • Ruttiger L, Ciuffani J, Zenner HP, Knipper M (2003) A behavioral paradigm to judge acute sodium salicylate-induced sound experience in rats: a new approach for an animal model on tinnitus. Hear Res 180:39–50

    Article  PubMed  Google Scholar 

  • Sahley TL, Hammonds MD, Musiek FE (2013) Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus. Brain Res 1499:80–108

    Article  CAS  PubMed  Google Scholar 

  • Salvi R, Lobarinas E, Sun W (2009) Pharmacological treatments for tinnitus: new and old. Drugs Future 34:381–400

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shargorodsky J, Curhan GC, Farwell WR (2010) Prevalence and characteristics of tinnitus among US adults. Am J Med 123:711–718

    Article  PubMed  Google Scholar 

  • Spankovich C, Griffiths SK, Lobarinas E, Morgenstein KE, De la Calle S, Ledon V, Guersio D, Le Prell CG (2013) Temporary threshold shift after impulse-noise during video game play: laboratory data. International J Audiol Accepted

  • Turner JG, Parrish J (2008) Gap detection methods for assessing salicylate-induced tinnitus and hyperacusis in rats. Am J Audiol 17:S185–S192

    Article  PubMed  Google Scholar 

  • Turner JG, Brozoski TJ, Bauer CA, Parrish JL, Myers K, Hughes LF, Caspary DM (2006) Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav Neurosci 120:188–195

    Article  PubMed  Google Scholar 

  • Van Hoey NM (2005) Effect of cyclobenzaprine on tricyclic antidepressant assays. Ann Pharmacother 39:1314–1317

    Article  PubMed  Google Scholar 

  • Vanneste S, Figueiredo R, De Ridder D (2012) Treatment of tinnitus with cyclobenzaprine: an open-label study. Int J Clin Pharmacol Ther 50:338–344

    Article  CAS  PubMed  Google Scholar 

  • Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S (2011) Homeostatic plasticity drives tinnitus perception in an animal model. Proc Natl Acad Sci U S A 108:14974–14979

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang J (2013) Auditory cortex stimulation to suppress tinnitus: mechanisms and strategies. Hear Res 295:38–57

    Article  PubMed  Google Scholar 

  • Zheng Y, Hooton K, Smith PF, Darlington CL (2008) Carbamazepine reduces the behavioural manifestations of tinnitus following salicylate treatment in rats. Acta Otolaryngol 128:48–52

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, McNamara E, Stiles L, Darlington CL, Smith PF (2012) Evidence that memantine reduces chronic tinnitus caused by acoustic trauma in rats. Front Neurol 3:127

    PubMed Central  PubMed  Google Scholar 

Download references

Conflict of Interest

The authors report no conflict of interest with the research presented in the manuscript.

All work was supported by the Tinnitus Research Initiative (TRI).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Edward Lobarinas.

Additional information

EL designed the experiments, EL and CB performed data collection and analysis, and all authors contributed to writing the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lobarinas, E., Blair, C., Spankovich, C. et al. Partial to Complete Suppression of Unilateral Noise-Induced Tinnitus in Rats after Cyclobenzaprine Treatment. JARO 16, 263–272 (2015). https://doi.org/10.1007/s10162-014-0500-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10162-014-0500-x

Keywords

Navigation