Pain Management Research Institute, Kolling Institute of Medical Research, University of Sydney at Royal North Shore Hospital, St Leonards NSW 2065, Australia.
BMC Neurosci. 2009 Dec 28;10:156. doi: 10.1186/1471-2202-10-156.
Interstitial cystitis is a chronic condition associated with bladder inflammation and, like a number of other chronic pain states, symptoms associated with interstitial cystitis are more common in females and fluctuate during the menstrual cycle. The aim of this study was to determine if estrogens could directly modulate signalling pathways within bladder sensory neurons, such as extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. These signalling pathways have been implicated in neuronal plasticity underlying development of inflammatory somatic pain but have not been as extensively investigated in visceral nociceptors. We have focused on lumbosacral dorsal root ganglion (DRG) neurons projecting to pelvic viscera (L1, L2, L6, S1) of adult female Sprague-Dawley rats and performed both in vitro and in vivo manipulations to compare the effects of short- and long-term changes in estrogen levels on MAPK expression and activation. We have also investigated if prolonged estrogen deprivation influences the effects of lower urinary tract inflammation on MAPK signalling.
In studies of isolated DRG neurons in short-term (overnight) culture, we found that estradiol and estrogen receptor (ER) agonists rapidly stimulated ER-dependent p38 phosphorylation relative to total p38. Examination of DRGs following chronic estrogen deprivation in vivo (ovariectomy) showed a parallel increase in total and phosphorylated p38 (relative to beta-tubulin). We also observed an increase in ERK1 phosphorylation (relative to total ERK1), but no change in ERK1 expression (relative to beta-tubulin). We observed no change in ERK2 expression or phosphorylation. Although ovariectomy increased the level of phosphorylated ERK1 (vs. total ERK1), cyclophosphamide-induced lower urinary tract inflammation did not cause a net increase of either ERK1 or ERK2, or their phosphorylation. Inflammation did, however, cause an increase in p38 protein levels, relative to beta-tubulin. Prior ovariectomy did not alter the response to inflammation.
These results provide new insights into the complex effects of estrogens on bladder nociceptor signalling. The diversity of estrogen actions in these ganglia raises the possibility of developing new ways to modulate their function in pelvic hyperactivity or pain states.
间质性膀胱炎是一种与膀胱炎症相关的慢性疾病，与许多其他慢性疼痛状态一样，与间质性膀胱炎相关的症状在女性中更为常见，并在月经周期中波动。本研究的目的是确定雌激素是否可以直接调节膀胱感觉神经元中的信号通路，如细胞外信号相关激酶（ERK）和 p38 丝裂原活化蛋白（MAP）激酶。这些信号通路已被牵涉到炎症性躯体疼痛发展中的神经元可塑性中，但在内脏伤害感受器中尚未得到广泛研究。我们专注于投射到成年雌性 Sprague-Dawley 大鼠骨盆内脏（L1、L2、L6、S1）的腰骶部背根神经节（DRG）神经元，并进行了体外和体内操作，以比较短期和长期雌激素水平变化对 MAPK 表达和激活的影响。我们还研究了长期雌激素剥夺是否会影响下尿路炎症对 MAPK 信号的影响。
在短期（过夜）培养的分离 DRG 神经元研究中，我们发现雌二醇和雌激素受体（ER）激动剂相对于总 p38 快速刺激 ER 依赖性 p38 磷酸化。体内（卵巢切除术）慢性雌激素剥夺后对 DRG 的检查显示总 p38 和磷酸化 p38（相对于β-微管蛋白）平行增加。我们还观察到 ERK1 磷酸化（相对于总 ERK1）增加，但 ERK1 表达（相对于β-微管蛋白）没有变化。我们观察到 ERK2 表达或磷酸化没有变化。尽管卵巢切除术增加了磷酸化 ERK1（相对于总 ERK1）的水平，但环磷酰胺诱导的下尿路炎症并没有导致 ERK1 或 ERK2 或其磷酸化的净增加。然而，炎症确实导致 p38 蛋白水平相对于β-微管蛋白增加。预先卵巢切除术并未改变对炎症的反应。
这些结果为雌激素对膀胱伤害感受器信号的复杂影响提供了新的见解。这些神经节中雌激素作用的多样性提出了开发新方法来调节其在骨盆过度活跃或疼痛状态下功能的可能性。
