Pharmacologic evaluation of pressor and visceromotor reflex responses to bladder distension.
OBJECTIVE
Several mechanisms that are involved in acute rat bladder nociception were examined. The nociceptive response was measured by analyzing both cardiovascular and visceromotor reflex responses to urinary bladder distension. The contributions of micro-opioid receptor, kappa-opioid receptor, sodium channels, muscarinic receptors, and cyclooxygenase, were explored with morphine, U50,488, mexiletine, oxybutynin, and naproxen, respectively.


METHODS
Female Sprague-Dawley rats were acutely instrumented with jugular venous, carotid arterial, and bladder cannulas. Needle electrodes were placed directly into the abdominal musculature to measure myoelectrical activity subsequent to repeated phasic urinary bladder distension (60 mmHg for 20 sec in 3 min intervals) under 1% isoflurane. Drugs were administered by i.v. bolus injection 2 min prior to distension.


RESULTS
The analgesics morphine (ID50 0.69 mg/kg), U50,488 (1.34 mg/kg), and mexiletine (2.60 mg/kg) significantly inhibited the visceromotor reflex response to noxious urinary bladder distension. Oxybutynin also attenuated reflex responses to noxious urinary bladder distension to 41% of the maximal pressor response and 32% of the control visceromotor reflex response (3.01 and 5.05 mg/kg), respectively, indicating a role of muscarinic receptors in bladder nociception. Naproxen did not attenuate the pressor response, but moderately inhibited visceromotor reflex to 45% of control at 30 mg/kg (P < 0.05).


CONCLUSIONS
Current results using the rat urinary bladder distension model are consistent with previous research demonstrating a role of the analgesics (morphine, U50,488, and mexiletine) in the inhibition of visceral nociceptive transmission. The utility of the reflex responses to urinary bladder distension may provide a method useful to examine mechanisms which target the bladder sensory pathway.
Su
Xin
X
Department of Urology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. xin.2.su@gsk.com
Riedel
Erin S
ES
Leon
Lisa A
LA
Laping
Nicholas J
NJ
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects* / Q000294:innervation; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008333:Mandelic Acids / Q000494:pharmacology; D008801:Mexiletine / Q000494:pharmacology; D023421:Models, Animal; D009020:Morphine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000294:innervation; D009288:Naproxen / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D011312:Pressure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012018:Reflex / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000294:innervation / Q000378:metabolism
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D016861:Cyclooxygenase Inhibitors; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine; D009288:Naproxen; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D011451:Prostaglandin-Endoperoxide Synthases; C005419:oxybutynin