Gintzler A R, Rothman T P, Gershon M D
Brain Res. 1980 May 5;189(1):31-48. doi: 10.1016/0006-8993(80)90005-0.
The development of opiate mechanisms in the guinea pig small intestine has been studied with reference to the development of transmitter mechanisms of neurons known to be components of the enteric nervous system. At 25 days' gestation neurons and a primitive neuropil could be found in the enteric mesenchyme. At this time, markers for two enteric neurotransmitters could be demonstrated; synthesis of [3H]acetylcholine ([3H]ACh) from [3H]choline, and specific axonal uptake of [3H]5-hydroxytryptamine ([3H]5-HT). This early gut also showed high affinity stereospecific binding of [3H]diprenorphine that was antagonized by levallorphan but not dextrophan. Thus, opiate receptors are detectable in the gut as soon as neurons can be identified. Neuronal precursors, however, are probably present prior to 25 days and putative serotonergic precursors were recognizable by their uptake of [3H]5-HT into cell bodies as early as day 20. Adrenergic innervation appeared gradually between days 32 and 48. Functional innervation of the longitudinal layer of smooth muscle was established much later in ontogeny. Spontaneous tone and a tetrodotoxin-sensitive 5-HT-induced relaxation of the muscle were detected at day 42 (neither norepinephrine nor ATP mediate this effect); contraction in response to ACh appeared at day 48; responses to electrical stimulation were elicited at days 50-56 and acute and chronic (tolerance-dependence) effects of opiates were apparent by day 56. The early appearance of opiate receptors is consistent with their being associated with either cholinergic or serotonergic neurons, or both. These early opiate receptors suggest that opiates or endogenous substances that act on opiate receptors might have effects not revealed by standard indices of opiate actions.
参照已知为肠神经系统组成部分的神经元递质机制的发育情况，对豚鼠小肠中阿片机制的发育进行了研究。在妊娠25天时，可在肠间充质中发现神经元和原始神经纤维网。此时，可证实两种肠神经递质的标志物：从[3H]胆碱合成[3H]乙酰胆碱（[3H]ACh），以及[3H]5-羟色胺（[3H]5-HT）的特异性轴突摄取。这个早期肠道还显示出[3H]二丙诺啡的高亲和力立体特异性结合，这种结合可被左洛啡烷拮抗，但不能被右洛啡烷拮抗。因此，一旦能够识别出神经元，肠道中就能检测到阿片受体。然而，神经元前体可能在25天之前就已存在，早在第20天，假定的5-羟色胺能前体就可通过其将[3H]5-HT摄取到细胞体中而被识别。肾上腺素能神经支配在第32天至48天之间逐渐出现。平滑肌纵层的功能性神经支配在个体发育后期才建立。在第42天检测到肌肉的自发张力和对河豚毒素敏感的5-羟色胺诱导的松弛（去甲肾上腺素和ATP均不介导这种效应）；对乙酰胆碱的收缩反应在第48天出现；对电刺激的反应在第50 - 56天引发，阿片类药物的急性和慢性（耐受性 - 依赖性）效应在第56天明显。阿片受体的早期出现与其与胆碱能或5-羟色胺能神经元或两者相关一致。这些早期阿片受体表明，作用于阿片受体的阿片类药物或内源性物质可能具有标准阿片作用指标未揭示的效应。
