The capsaicin analogue SDZ249-665 attenuates the hyper-reflexia and referred hyperalgesia associated with inflammation of the rat urinary bladder.
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 -5.2x10(3) SEM 1.7) in comparison with naïve animals (AUC -0.02x10(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 +0.4x10(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.
Jaggar
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SI
Pain Research, Department of Anaesthetics, Imperial College School of Medicine, St. Mary's Hospital Campus, Praed Street, London W2 1NY, UK.
Scott
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HC
James
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Rice
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AS
D000465:Algorithms; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003556:Cystitis / Q000139:chemically induced / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects*; D013997:Time Factors; D014425:Turpentine; D014508:Urea / Q000031:analogs & derivatives; D014554:Urination / Q000187:drug effects
D000700:Analgesics; C425286:SDZ 249-665; D014508:Urea; D002211:Capsaicin; D014425:Turpentine