Purpose
We assessed the effect of ovariectomy and estrogen replacement on nociceptive responses to bladder distention in a rat model.
Materials and Methods
Female Sprague-Dawley rats (Harlan™) underwent ovariectomy or sham surgery. Visceromotor responses (abdominal contractions) to bladder distention were determined 3 to 4 weeks later under isoflurane anesthesia. In rat subsets estrogen was chronically replaced with a subcutaneous estrogen pellet vs a placebo pellet or acutely replaced by subcutaneous injection 24 hours before testing. Effects of estrogen withdrawal were examined in another group of rats by implanting a pellet and explanting the pellet 24 hours before testing. Uterine weight was measured to assess the estrogen dose.
Results
Visceromotor responses to bladder distention were significantly less vigorous in ovariectomized rats vs controls. Acute estrogen replacement increased visceromotor responses in these rats but chronic estrogen replacement did not. Sudden chronic estrogen withdrawal resulted in increased visceromotor responses. Uterine weight was consistent with the physiological estrogen dose.
Conclusions
Estrogen alone was not sufficient to produce increased nociceptive responses but an acute decrease in estrogen resulted in increased visceromotor responses. These data suggest that the pronociceptive effects of estrogen may be due to a mismatch between peripheral vs central and/or genomic vs nongenomic effects of the hormone, which occur during rapidly decreasing estrogen levels.
The present studies examined the involvement of the rostral ventral medulla (RVM) in modulating the visceromotor response (VMR) evoked by urinary bladder distension (UBD) in adult female rats. The VMR was indexed by electromyographic (EMG) responses of the abdominal external oblique muscle to UBD. Experiment 1 showed that the predominant effect of electrical stimulation of the RVM in normal rats was to produce intensity-dependent inhibition of the VMR (54% of sites sampled). Facilitatory, biphasic, or no effects were obtained at the remaining sites. Experiment 2 showed that RVM-induced inhibition of the VMR was significantly attenuated by intraperitoneal (i.p.) administration of naloxone, but not saline vehicle. In Experiment 3, we examined the effect of lesions of the RVM in rats with inflamed bladders since previous research has shown that an endogenous opioid inhibitory system is engaged by bladder inflammation. Electrolytic lesions of the RVM, but not sham-lesions of the RVM, significantly increased the VMR to graded UBD in rats with augmented VMRs induced by prior inflammation of the bladder. The present data suggest that the RVM can inhibit the VMR to UBD acting in part via an opioid inhibitory system and that bladder inflammation can recruit the RVM to produce a net inhibitory effect on the VMR to UBD. Keywords bladder; rostral ventromedial medulla; visceromotor reflex; pain; inhibition
PerspectiveStimulation of the RVM resulted in inhibitory, facilitatory, and biphasic modulation of the visceromotor reflex to urinary bladder distension. Inhibitory effects of stimulation were attenuated by naloxone and lesions of the RVM enhanced the VMR in rats with inflamed bladders. These data indicate an important role of the RVM in modulating bladder pain.
Cystic fibrosis transmembrane conductance regulator (CFTR) functions as both a chloride channel and an epithelial transport regulator, interacting with Na ؉ (epithelial sodium channel), Cl ؊ , renal outer medullary potassium channel ؉ , and H 2 O channels and some exchangers (i.e. Na ؉ /H ؉ ) and co-transporters (Na ؉ -HCO 3. Acid-sensitive ion channels (ASICs), members of the epithelial sodium channel/degenerin superfamily, were originally cloned from neuronal tissue, and recently localized in epithelia. Because CFTR has been immunocytochemically and functionally identified in rat, murine, and human brain, the regulation of ASICs by CFTR was tested in oocytes. Our observations show that the proton-gated Na ؉ current formed by the heteromultimeric ASIC1a/2a channel was up-regulated by wild type but not by ⌬F508-CFTR. In contrast, the acid-gated Na ؉ current associated with either the homomultimeric ASIC1a or ASIC2a channel was not influenced by wild type CFTR. The apparent equilibrium dissociation constant for extracellular Na ؉ for ASIC1a/2a was increased by CFTR, but CFTR had no effect on the gating behavior or acid sensitivity of ASIC1a/2a. CFTR had no effect on the pH activation of ASIC1a/2a. We conclude that wild type CFTR elevates the acid-gated Na ؉ current of ASIC1a/2a in part by altering the kinetics of extracellular Na ؉ interaction.
Current results parallel those in a recent study showing that most patients with painful bladder syndrome/interstitial cystitis experience pain when undergoing ice water testing after previous urodynamic testing. These findings suggest that this animal model may be useful for understanding the etiology of and treatment for painful bladder syndrome/interstitial cystitis.
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