Kannampalli Pradeep, Babygirija Reji, Zhang Jiang, Poe Michael M, Li Guanguan, Cook James M, Shaker Reza, Banerjee Banani, Sengupta Jyoti N
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA.
Neuroscience. 2017 Mar 27;346:349-364. doi: 10.1016/j.neuroscience.2017.01.021. Epub 2017 Jan 23.
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 14-16. In adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was significantly inhibited by intrathecal (i.t) HZ166 (GABA 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 GABA 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 GABA receptor subtypes, which may result in chronic visceral hyperalgesia in adulthood.
早年的痛苦经历已被证明会增加成年后患间质性膀胱炎/膀胱疼痛综合征的几率。然而，其内在机制尚未得到充分研究。我们之前报道过，新生大鼠膀胱炎症会导致慢性内脏超敏反应，并伴有脊髓GABA能系统的分子破坏。本研究调查了这些分子变化是否会影响膀胱敏感的初级传入神经元和脊髓神经元的整合功能及反应。在出生后（P）14 - 16天，通过膀胱内注射酵母聚糖诱导新生大鼠膀胱炎症。在成年期（P60），鞘内注射（i.t）HZ166（GABA激动剂）仅在新生期用生理盐水处理的大鼠中显著抑制了对内脏刺激的内脏运动反应（VMR），而在新生期用酵母聚糖处理的大鼠中则没有。HZ166显著抑制了新生期用生理盐水处理的大鼠中膀胱反应性腰骶部（LS）脊髓神经元对膀胱扩张（UBD）和缓慢灌注（SI）的反应。在未处理的成年大鼠中也观察到了类似结果，其中HZ166对膀胱反应性脊髓神经元产生了显著抑制作用。然而，HZ166并未抑制新生期用酵母聚糖处理的大鼠中UBD反应性脊髓神经元的反应。在两组受试大鼠中，该药物均未减弱UBD敏感的盆神经传入（PNA）纤维对UBD和SI的反应。免疫组织化学研究表明，与生理盐水处理的大鼠相比，新生期用酵母聚糖处理的大鼠的LS脊髓中GABA受体表达水平显著降低。这些发现表明，新生大鼠膀胱炎症会导致脊髓GABA受体亚型的功能和分子改变，这可能会导致成年期慢性内脏痛觉过敏。
