Parkar Nabil, Spencer Nick J, Wiklendt Luke, Olson Trent, Young Wayne, Janssen Patrick, McNabb Warren C, Dalziel Julie E
AgResearch, Palmerston North, New Zealand.
Riddet Institute, Massey University, Palmerston North, New Zealand.
Front Neurosci. 2024 Aug 29;18:1424936. doi: 10.3389/fnins.2024.1424936. eCollection 2024.
It is well known that opiates slow gastrointestinal (GI) transit, via suppression of enteric cholinergic neurotransmission throughout the GI tract, particularly the large intestine where constipation is commonly induced. It is not clear whether there is uniform suppression of enteric neurotransmission and colonic motility across the full length of the colon. Here, we investigated whether regional changes in colonic motility occur using the peripherally-restricted mu opioid agonist, loperamide to inhibit colonic motor complexes (CMCs) in isolated mouse colon.
High-resolution video imaging was performed to monitor colonic wall diameter on isolated whole mouse colon. Regional changes in the effects of loperamide on the pattern generator underlying cyclical CMCs and their propagation across the full length of large intestine were determined.
The sensitivity of CMCs to loperamide across the length of colon varied significantly. Although there was a dose-dependent inhibition of CMCs with increasing concentrations of loperamide (10 nM - 1 μM), a major observation was that in the mid and distal colon, CMCs were abolished at low doses of loperamide (100 nM), while in the proximal colon, CMCs persisted at the same low concentration, albeit at a significantly slower frequency. Propagation velocity of CMCs was significantly reduced by 46%. The inhibitory effects of loperamide on CMCs were reversed by naloxone (1 μM). Naloxone alone did not change ongoing CMC characteristics.
The results show pronounced differences in the inhibitory action of loperamide across the length of large intestine. The most potent effect of loperamide to retard colonic transit occurred between the proximal colon and mid/distal regions of colon. One of the possibilities as to why this occurs is because the greatest density of mu opioid receptors are located on interneurons responsible for neuro-neuronal transmission underlying CMCs propagation between the proximal and mid/distal colon. The absence of effect of naloxone alone on CMC characteristics suggest that the mu opioid receptor has little ongoing constitutive activity under our recording conditions.
众所周知，阿片类药物通过抑制整个胃肠道，尤其是通常会引发便秘的大肠的肠胆碱能神经传递来减缓胃肠（GI）蠕动。目前尚不清楚在结肠全长范围内，肠神经传递和结肠动力是否受到统一抑制。在此，我们使用外周限制性μ阿片受体激动剂洛哌丁胺抑制分离的小鼠结肠中的结肠运动复合体（CMC），研究结肠动力是否存在区域变化。
采用高分辨率视频成像技术监测分离的整个小鼠结肠的结肠壁直径。确定了洛哌丁胺对周期性CMC潜在模式发生器及其在大肠全长范围内传播的影响的区域变化。
结肠全长范围内，CMC对洛哌丁胺的敏感性存在显著差异。尽管随着洛哌丁胺浓度增加（10 nM - 1 μM），CMC受到剂量依赖性抑制，但一个主要发现是，在结肠中、远端，低剂量洛哌丁胺（100 nM）即可消除CMC，而在结肠近端，相同低浓度下CMC仍会持续存在，尽管频率明显减慢。CMC的传播速度显著降低了46%。纳洛酮（1 μM）可逆转洛哌丁胺对CMC的抑制作用。单独使用纳洛酮不会改变正在进行的CMC特征。
结果显示洛哌丁胺在大肠全长范围内的抑制作用存在显著差异。洛哌丁胺延缓结肠转运的最有效作用发生在结肠近端与中/远端区域之间。出现这种情况的一种可能性是，μ阿片受体的最大密度位于负责近端与中/远端结肠之间CMC传播的神经神经元传递的中间神经元上。单独使用纳洛酮对CMC特征无影响，这表明在我们的记录条件下，μ阿片受体几乎没有持续的组成性活性。
