Ness Timothy John, McNaught Jamie, Clodfelder-Miller Buffie, Nelson Dwight E, Su Xin
Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Reg Anesth Pain Med. 2019 Sep 4. doi: 10.1136/rapm-2018-100353.
Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models and anecdotally reduces pain in humans with pelvic pain of urologic origin. Concomitant opioids are known to alter responses to neuromodulation in some systems. So prior to the development of a clinical trial for purposes of regulatory approval, the preclinical interaction between opioids and stimulation effectiveness was examined.
Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Morphine was administered acutely (1-4 mg/kg intraperitoneal) or chronically (5 mg/kg subcutaneously daily for 2 weeks prior to the terminal experiment). bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMR; abdominal muscle contractile responses to urinary bladder distension (UBD)) were used as nociceptive endpoints.
Morphine produced a dose-dependent inhibition of VMRs to UBD that was naloxone reversible. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received acute or chronic subcutaneous morphine injections.
This study suggests that inhibitory effects of bPNS can still be evoked in subjects who are receiving opioid therapy, thus giving guidance to potential clinical trials seeking regulatory approval for the treatment of chronic bladder pain.
双侧阴部神经电刺激（bPNS）可降低大鼠模型中的膀胱超敏反应，且据传闻可减轻源于泌尿系统的盆腔疼痛患者的疼痛。已知阿片类药物会改变某些系统对神经调节的反应。因此，在开展旨在获得监管批准的临床试验之前，研究了阿片类药物与刺激效果之间的临床前相互作用。
通过新生大鼠膀胱炎症并在成年时给予第二次炎症刺激来诱导膀胱超敏反应。急性给予吗啡（腹腔注射1 - 4毫克/千克）或慢性给予吗啡（在末次实验前2周皮下注射5毫克/千克，每日一次）。bPNS包括对阴部神经的运动/感觉混合成分进行双侧双相电刺激。将内脏运动反应（VMR；腹部肌肉对膀胱扩张（UBD）的收缩反应）用作伤害性感受终点。
吗啡对UBD的VMR产生剂量依赖性抑制，且这种抑制可被纳洛酮逆转。在接受急性或慢性皮下注射吗啡的超敏大鼠中，bPNS对UBD的VMR产生了统计学上显著的抑制作用。
本研究表明，在接受阿片类药物治疗的受试者中仍可诱发bPNS的抑制作用，从而为寻求监管批准用于治疗慢性膀胱疼痛的潜在临床试验提供指导。
