title: The anti-inflammatory selective melanocortin receptor subtype 4 agonist, RO27-3225, fails to prevent acoustic trauma-induced tinnitus in rats.
abstract: In preliminary studies we have observed a massive microglial activation in the cochlear nucleus following acoustic trauma-induced tinnitus in rats, which suggests that inflammatory responses within the central auditory system may be involved in the development and maintenance of tinnitus. Recently, the anti-inflammatory properties of melanocortins (MCs), have gained increasing interest in pharmacology due to their promising therapeutic potential in the treatment of inflammatory-mediated diseases. Among the five subtypes of the MC receptor, MC3 and MC4 receptors are the predominant brain receptors and are thought to play an important role in brain inflammation and neuroprotection. Importantly, MC4 receptors have been found in the mouse and rat central auditory systems. In this study we investigated whether the MC4 receptor agonist, RO27-3225, injected s.c at a dose of 90 or 180µg/kg, 30min before acoustic trauma and then every 12h for 10 days, could prevent the development of acoustic trauma-induced tinnitus in rats, using a conditioned behavioural suppression model. Although evidence of tinnitus developed in the exposed-vehicle group compared to the sham-vehicle group (P≤0.03), in response to a 32kHz tone, there were no significant drug effects from treatment with RO27-3225, indicating that it did not confer any protection against the development of tinnitus in this animal model. This result suggests that the anti-inflammatory effects of MC4 receptor agonists may not be sufficient to prevent tinnitus.
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand. Electronic address: yiwen.zheng@otago.ac.nz.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Kate
authors.initials: K
authors.lastname: McPherson
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Peter
authors.initials: P
authors.lastname: Reid
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Smith
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001307:Auditory Perception / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D017626:Cochlear Nucleus / Q000187:drug effects* / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D009622:Noise / Q000009:adverse effects*; D010455:Peptides / Q000494:pharmacology*; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D014012:Tinnitus / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology
chemical_list: D000893:Anti-Inflammatory Agents; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; C560214:butir-His-Phe-Arg-Trp-Sar-NH2
keywords: Melanocortin receptors; Melanocortins; Rat; Tinnitus