The capsaicin analogue SDZ249-665 attenuates the hyper-reflexia and referred hyperalgesia associated with inflammation of the rat urinary bladder

Abstract

This study assessed the effects of the systemically administered capsaicin analogue SDZ249-665 in an animal model of visceral pain and hyper-reflexia. The effects of prophylactic administration of SDZ249-665 (in the dose range 0.05–1 mg/kg) on the viscero-visceral hyper-reflexia (VVH) and the referred viscero-somatic hyperalgesia to mechanical stimuli (VSH) associated with turpentine inflammation of the rat urinary bladder were evaluated. SDZ249-665 attenuated both the VVH and the VSH in a dose related fashion. In the VVH model, following solvent control administration, intra-vesical turpentine administration was associated with a significant reduction in micturition threshold to 43.7% (SEM 6.3) of baseline, indicating the presence of a VVH. This effect was not observed when animals were prophylactically treated with SDZ249-665 alone. At a dose of 0.1 mg/kg the micturition threshold was 90.7% (SEM 10.2) of baseline at 1 h after intra-vesical instillation of turpentine. In the VSH model, curves were plotted of the difference in fore and hind limb withdrawal latencies from a mechanical stimulus and the area under these curves (AUCs) were compared between different treatment protocols. Intra-vesical turpentine was associated with a negative deflection of the curve (AUC −5.2×10 3 SEM 1.7) in comparison with naı̈ve animals (AUC −0.02×10 3 SEM 0.6), indicative of a referred hyperalgesia. This was prevented, in a dose-related manner, by prophylactic administration of SDZ249-665. For example, at a dose of 0.5 mg/kg the AUC was +0.4×10 3 (SEM 0.8). These findings support previous work indicating that capsaicin sensitive neurones participate in patho-physiological events occurring following inflammation of the bladder, and provides evidence that systemically active capsaicin based compounds may be developed for use in the clinical setting.