Establishment of a mouse model of pain in mild inflamed bladder and the involvement of NGF in bladder pain

Abstract

   Bladder pain is a most prominent feature of interstitial cystitis ⁄ painful bladder syndrome (IC ⁄ PBS), but unfortunately the efficacy of current analgesic­s was thought to be insufficient in many patients with IC. Despite the clinical significance of bladder pain, there have been only a few research efforts to elucidate the mechanisms of this chronic pain and its patho­physiology remains poorly understood. One of the reasons is the lack of well–characterized experimental animal models of bladder pain. Hence, the present study was conducted to establish a novel bladder pain model in mice and examined whether nerve growth factor (NGF), a major pain mediator, was involved in bladder pain. Repeated injections of cyclophosphamide (150 mg/kg) for 4 days induced persisting mechanical hypersensitivity in mouse abdomen, decreased the threshold gradually from day 1, peaked at day 4 and persisted for at least day 7 after the first injection. The treatments also altered the levels of bladder impairment markers such as heparin binding–epidermal growth factor–like growth factor and glycosaminoglycan without apparent inflammatory signs on day 4. Peroral administrations of amitriptyline (2.5 – 10 mg/kg) and gabapentin (10 and 30 mg/kg) suppressed the mechanical hypersensitivity on day 4 in these cystitis mice, but indometha­cin (10 and 30 mg/kg) did not affect it. Bladder NGF levels were significantly increased in these cystitis mice and an intravenous injection of anti–NGF serum reversed mechanical hypersensitivity. These results show that this chronic cystitis model induced by repeated cyclophosphamide treatments has less inflammatory elements and NGF–sensitive pain mechanism, which are similar to some features observed in IC patients. Recently, anti–NGF antibody tanezumab has been reported to show the signifi­cant efficacy in relieving bladder pain of IC patients and is now working on clinical stage. This model may be useful for not only the mechanism study of chronic bladder pain but also the development of novel therapies for IC patients.