An excitatory role for peripheral EP₃ receptors in bladder afferent function

Abstract

The excitatory roles of EP3 receptors at the peripheral afferent nerve innervating the rat urinary bladder have been evaluated by using the selective EP3 antagonist (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041). The bladder rhythmic contraction model and a bladder pain model measuring the visceromotor reflex (VMR) to urinary bladder distension (UBD) have been used to evaluate DG-041 in female rats. In addition, male rats [spontaneously hypertensive rat (SHR), WistarKyoto (WKY), and Sprague-Dawley (SD)] were anesthetized with pentobarbital sodium, and primary afferent fibers in the L 6 dorsal root were isolated for recording the inhibitory response to UBD following intravenous injection of DG-041. Intravenous injection of DG-041 (10 mg/kg), a peripherally restricted EP 3 receptor antagonist, significantly reduced the frequency of bladder rhythmic contraction and inhibited the VMR response to bladder distension. The magnitude of reduction of the VMR response was not different in the different strains of rats (SD, SHR, and WKY). Furthermore, quantitative characterization of the mechanosensitive properties of bladder afferent nerves in SHR, WKY, and SD rats did not show the SHR to be supersensitive to bladder distension. DG-041 selectively attenuated responses of mechanosensitive afferent nerves to UBD, with strong suppression on the slow-conducting, high-threshold afferent fibers, with equivalent activity in the three strains. We conclude that sensitization of afferent nerve activity was not one of the mechanisms of bladder hypersensitivity in SHR. EP 3 receptors are involved in the regulation of bladder micturition and bladder nociception at the peripheral level.EP3; viscermotor reflex; bladder rhythmic contraction; bladder distension; afferent nerve SENSATION ASSOCIATED WITH the urinary bladder is conveyed primarily by pelvic and hypogastric nerves, by which the signal is relayed to the central nervous system (CNS). Most afferent fibers innervating the musculature of the bladder body pass through the pelvic nerve, whereas the majority of afferent endings in the bladder submucosa are derived from the hypogastric nerve (41), suggesting that the afferent fibers in the pelvic and hypogastric nerves have different roles, signaling mechanical stimulation (e.g., bladder distension) and chemical stimulation (e.g., inflammation), respectively (20,22,30,34). Bladder distension is a natural mechanical stimulus to evoke sensations such as fullness, urgency, and pain while the literature suggests a complex regulatory role of prostaglandins (PGs) in multiple aspects of urinary bladder physiology/pathophysiology. PGE 2 , one of the principal PGs, is synthesized in urothelium and detrusor smooth muscle (19,24,25,27) as well as in neurons and glial cells (18,23) and is released in response to various physiological (e.g., bladder distension) and pathological (e.g., mediators of inflammation) stimulation. PGE 2 interacts with four EP receptor subt...

Enhanced Sensitivity to Afferent Stimulation and Impact of Overactive Bladder Therapies in the Conscious, Spontaneously Hypertensive Rat

“…This suggests that the SHR does present with a hypersensitive afferent innervation that may also contribute to its basal bladder overactivity. Although we have clearly detected an enhanced sensitivity to chemical irritants in the conscious SHR, sensitivity to bladder distention (pressure) seems to be unaffected based on visceromotor reflex and afferent nerve recording studies performed under urethane anesthesia Su et al, 2008). Taken together, this suggests that SHR afferent hypersensitivity is observed only in response to chemical and not mechanical stimuli, or alternatively that anesthesia may have interfered with detecting the SHR afferent hypersensitivity in early studies in which the effect of pressure was evaluated.…”

“…Functional analyses of afferent mechanosensitivity in the anesthetized SHR did not detect any alteration in responses to increased bladder pressure Su et al, 2008). It has been shown previously that hyperactivity induced by intravesicular bladder infusion of acetic acid (AA) or prostaglandin E 2 (PGE 2 ) is capsaicin-sensitive and dependent on sensory afferent nerves in the rat (Maggi et al, 1988;Mitsui et al, 2001).…”

“…Therefore, there has been interest around the SHR as a model of bladder dysfunction, as reflected by attempts to identify novel targets (Yono et al, 2010), and its use in urodynamic validation studies with novel pharmacological modulators Su et al, 2008). Functional analyses of afferent mechanosensitivity in the anesthetized SHR did not detect any alteration in responses to increased bladder pressure Su et al, 2008).…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…However, a peripherally acting EP 3 receptor antagonist reduced the increased discharge activity of urinary bladder afferents evoked by bladder distension (681). A TP receptor antagonist reduced ischemia-induced activation of cardiac spinal afferents in anesthetized cats and TP receptor expression was revealed in thoracic DRGs, suggesting that TXA 2 from activated thrombocytes may contribute to excitation of cardiac afferents during myocardial ischemia (212).…”

Prostaglandin E2 and Pain-An Update

“…55) There is also evidence for involvement of peripheral EP 3 receptors in the regulation of bladder micturition and bladder nociception. 56) Thus, selective antagonists of EP 1 receptors and, perhaps, EP 3 receptors may be useful for treatment of visceral pain including esophageal and/or bladder pain.…”