Neonatal Bladder Inflammation Induces Long-term Visceral pain and Altered Responses of Spinal Neurons in Adult Rats

Painful events early in life have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. However, the intrinsic mechanism is not well studied. We previously reported that neonatal bladder inflammation causes chronic visceral hypersensitivity along with molecular disruption of spinal GABAergic system in rats. The present study investigates whether these molecular changes affect the integrative function and responses of bladder-sensitive primary afferent and spinal neurons. Neonatal bladder inflammation was induced by intravesicular injection of zymosan during postnatal (P) days 14 to 16. In adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was significantly inhibited by intrathecal (i.t) HZ166 (GABAAα-2 agonist) only in neonatally saline-treated, but not in neonatally zymosan-treated rats. HZ166 significantly inhibited the responses of bladder responsive lumbosacral (LS) spinal neurons to urinary bladder distension (UBD) and slow infusion (SI) in neonatally saline-treated rats. Similar results were also observed in naïve adult rats where HZ166 produced significant inhibition of bladder responsive spinal neurons. However, HZ166 did not inhibit responses of UBD-responsive spinal neurons from neonatally zymosan-treated rats. The drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD and SI in either group of rats tested. Immunohistochemical studies showed a significantly lower level of GABAAα-2 receptor expression in the LS spinal cord of neonatally zymosan treated rats compared to saline treated rats. These findings indicate that neonatal bladder inflammation leads to functional and molecular alteration of spinal GABAAα-2 receptor subtypes, which may result in chronic visceral hyperalgesia in adulthood.

Neuroscience. 2017 Jan 23 [Epub ahead of print]

Pradeep Kannampalli, Reji Babygirija, Jiang Zhang, Michael M Poe, Guanguan Li, James M Cook, Reza Shaker, Banani Banerjee, Jyoti N Sengupta

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin., Department of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin., Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin., Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: .