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Pain and the fetus
1.  What is the clinical significance of fetal sentience?
2.  Can anesthesia in-utero affect later behavioral responses?

1.  胎儿感觉有何临床意义？
2.  子宫内的麻醉是否影响日后的行为反应？

参考答案： 

1.胎儿感觉有何临床意义？

最近在关于胎儿感觉的生理和周期方面取得一些进展，但宫内矫治术期间对胎儿的关注主要集中于减少子宫的移动，而不是对疼痛的反应。有文献建议，神经肌肉阻滞剂可用于替代麻醉剂[1]。必须认识到胎儿对刺激的反应是一种可能的感觉，同时需要明确的是，这种感知并非必然导致可察觉的反应，例如麻醉下的术中知晓。

2.子宫内的麻醉是否影响日后的行为反应？

当研究胎儿感知的周期和程度时，应该考虑到镇痛/麻醉存在与否的潜在影响，在一个评价宫内麻醉对新生儿行为反应的影响的研究中，Mickley等[2]假设，在宫内存在胎儿行为，并受母体麻醉药物的影响。他们通过对大鼠进行胎儿研究，并对在给与甘甜物质（Sac，糖精）后鼠胎是否有味觉发生变化进行研究，与注射LiCl产生的不适进行对照。

通过下列一种或多种药物对孕鼠进行麻醉：（1）戊巴比妥钠；（2）盐酸氯胺酮和甲苯噻嗪；（3）戊巴比妥钠和盐酸氯胺酮。在这些麻醉剂的麻醉下，孕鼠同时接受Sac+LiCl注射，或口服/全身注射下列中的任何一种：Sac+Saline，H₂O+LiCl；H₂O+Saline。在出生15天，观察新生鼠选择分别涂上Sac或水的奶嘴进行味觉选择性测试。断奶之后，再次对大鼠行味觉选择性测试，这次使其品尝装在瓶中的0.30%Sac或水。那些接受Sac+LiCl宫内注射的新生大鼠不愿选择Sac涂抹的奶嘴，而接受对照注射的新生大鼠则更愿意选择Sac涂抹的奶嘴。因此，作者认为，可以在宫内对味觉进行改变。

此外，相对于注射戊巴比妥钠的Dams，氯胺酮影响下发生味觉改变的大鼠在味觉选择性测试中表现出显著的条件味觉厌恶。因为ketamine阻断了NMDA-谷氨酸受体，而这些受体可能在神经可塑性的形成中发挥一定作用，因此作者认为，NMDA阻滞剂可用于胎儿感觉的研究，同时作者得出结论认为，宫内可发生认知行为，并且这种现象在条件反射形成前通过给与孕鼠不同的麻醉剂而得到明显调控。

因此，很明显，胎儿感觉和认知是存在的，并可对以后的成人产生可测量的行为作用。

What is the anesthetic significance of fetal sentience?

Despite the recent progress in understanding the physiology and timing of fetal sentience, fetal considerations during corrective in-utero surgeries has focused more on reducing movement than modulating response to painful stimuli; one reference went so far as to suggest that neuromuscular blocking agents could be used in lieu of narcotics (1). Fetal responses to stimuli must be recognized as possible sensation, bearing in mind that sensation does not result necessarily in an observable response For example, consider awareness under anesthesia.

Can anesthesia in-utero affect later behavioral responses?

While investigation into timing and extent of fetal sentience continues, an understanding of the potential impact of the provision or absence of analgesia/anesthesia should be considered. In an interesting study evaluating the impact of in-utero anesthesia on neonatal behavioral responses, Mickley et al.(2) postulated that fetal behavioral learning could occur in-utero and be influenced by the drugs utilized for maternal anesthesia. As their model for fetal learning, the authors evaluated whether rat fetuses could learn taste aversion in utero if given a sweet flavor (saccharin = Sac) followed by a malaise-producing injection of lithium chloride (LiCl).

Dams were anesthetized with one of the following drugs or drug combinations: (1) sodium pentobarbital; (2) ketamine hydrochloride and xylazine; or (3) sodium pentobarbital and ketamine hydrochloride. While under the influence of these anesthetics, rat fetuses received paired administration of Sac + LiCl or one of the following sets of oral and systemic control injections: Sac + Saline, H₂O + LiCl; H₂O + Saline. At 15 days of age, neonatal rats were given a taste preference test by allowing them to select nipples painted with either saccharin or water. After weaning, rats were given an additional taste preference test where they were allowed to drink from bottles filled with either 0.30% saccharin or water. Neonates that received Sac + LiCl injections in utero avoided saccharin-painted nipples while neonates that received control injections preferred saccharin-painted nipples. Thus the authors concluded that taste aversion could be learned in-utero.

In addition, the rats that acquired the taste aversion under the influence of ketamine showed a significantly stronger conditioned taste aversion on the nipple preference test than did those from dams injected with sodium pentobarbital. Since ketamine blocks N-methyl-D-aspartate (NMDA)-glutamate receptors, and these receptors have been implicated in neural plasticity during development, the authors suggested that NMDA antagonism could potentiate fetal learning. The authors concluded that learned behavior could occur in-utero, and this phenomenon could be significantly modulated by the type of anesthesia administered to the pregnant dam before the conditioning procedure.

It appears, therefore, that fetal sentience and learning may occur and produce measurable behavioral effects subsequently in the adult.

References:

1.  Fan SZ, Susetio L, Tsai MC. Neuromuscular blockade of the fetus with pancuronium or pipecuronium for intra-uterine procedures. Anaesthesia 1994;49:284-6.
2.  Mickley GA, Lovelace JD, Farrell ST, Chang KS The intensity of a fetal taste aversion is modulated by the anesthesia used during conditioning. Brain Res Dev Brain Res 1995 Mar 16;85(1):119-27.


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