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Authors Note: Earlier this week we established that fetal sentience, the ability of a fetus to appreciate pain, is a strong probability. This week, we'll discuss treatment of this pain by opioids.

1.  What is known regarding the developmental neurobiology of opioid systems?
2.  What is known regarding opioid modulation of spinal pain pathways?
3.  Are opioids systems (endogenous opioids and receptors) important for fetal development?

今天我们讨论胎儿疼痛的阿片剂治疗：
1.  请描述阿片系统的发育神经生物学进展。
2.  已知的脊髓疼痛通路的阿片调节作用。
3.  阿片系统（内源性阿片类物质和受体）对胎儿发育是否重要？

参考答案：

1. 请描述阿片系统的发育神经生物学进展（胎儿）。

最近关于胎儿和新生儿阿片镇痛机制的研究表明：出生前后有所不同[1]。然而，因为在人类研究数据有限，基础研究常集中于动物模型（主要为大鼠和小鼠）。大鼠与人类的神经学形成过程类似，新生大鼠CNS相当于人类胎儿24周左右[1]。通过大鼠的研究表明，阿片受体和内源性阿片肽在CNS形成过程中出现很早[2]。人类胎儿研究表明，阿片剂（类-脑腓肽）免疫反应纤维在10周左右即存在；而且，μ和κ受体在出生时占主导地位，δ受体则较少。这些受体主要集中于中脑、丘脑、下丘脑和脊髓[3]。有趣的是，这些阿片受体易受影响而处于动态变化之中。Korthank等[4]认为，暴露于子宫内羊水中的胎儿可促进κ阿片受体系统的活性。

2.已知的脊髓疼痛通路的阿片调节作用。

在成人，阿片剂可抑制脑干向脊髓的传递。然而，这种抑制作用似乎更多是在出生后出现。大鼠直到出生后10～20天方具有下行抑制控制功能，这可能是因为C和细的A纤维直到出生前几日才长入脊髓，出生后趋于成熟[1]。该理论表明，阿片剂在胎儿并不一定有效，直到出生后。

3.阿片系统（内源性阿片类物质和受体）对胎儿发育是否重要？

以上关于阿片受体较晚形成和抑制控制功能出生后方可形成的讨论，很容易得出这样的结论：阿片剂对胎儿影响很小。然而，除了神经传递作用，天然的类阿片活性肽包括[Met 5]脑啡肽（用于增强抑制生长因子的活性）、OGFs。OGFs与ζ阿片受体相互作用而影响细胞增殖和组织机化。

几个动物研究表明，阿片剂对胎儿神经形成很重要。其中部分研究显示OGFs在调节胎儿神经组织的DNA合成中有重要作用。其余研究表明，κ受体亚型在调解胎儿大脑的激素合成中有重要作用。

What is known regarding the developmental neurobiology of opioid systems?

Recent investigation into opioid analgesic mechanisms in the fetus and neonate suggest that there are differences before and after birth (1). However, as data in humans in limited, basic studies in laboratory animals (predominantly rats and mice) have been used as models. The neurological development sequence in the rat and human are similar, with the newborn rat CNS approximating that of the 24 week human fetus (1). Studies utilizing rats demonstrate that opioid receptors and endogenous opioid peptides appear very early in the CNS development (2). Studies in human fetuses note opioid (enkephalin-like) immunoreactive fibers as early as 10 weeks; moreover, mu and kappa receptors predominate at birth, with low densities of delta receptors. Most of these receptors are found in the midbrain, thalamus, hypothalamus, and spinal cord (3). Of interest, the levels of these opioids appears to be quite dynamic, with a number of influences. Korthank et al. (4) noted that exposure of the fetus to amniotic fluid in utero promoted the activity of the kappa opioid system.

What is known regarding opioid modulation of spinal pain pathways?

In the adult, opioids inhibit transmission from the brainstem to the spinal cord. However, it appears as much of this inhibitory ability develops only postnatally. In the rat, there is no "descending inhibitory control" until postnatal day 10-12, perhaps due to C and small diameter A fibers not growing into the spinal cord until a few days prior to birth and reaching maturation postnatally (1). This evidence suggests that opioids are not as effective, especially at a fetal spinal cord level, until the postnatal period.

Are opioids systems (endogenous opioids and receptors) important for fetal development?

The above discussion on the relatively late proliferation of opioid receptors and the primarily postnatal development of inhibitory controls to spinal cord transmission, would lead most to conclude that opioids have little impact on the fetus. However, in addition to neurotransmission effects, native opioid peptides including [Met 5] enkephalin, serve as tonically active inhibitory growth molecules, termed opioid growth factors (OGFs). OGFs interact with the zeta opioid receptors to influence cell proliferation and tissue organization.

Several animal studies have demonstrated the importance of opioids to fetal neural development. Some have shown the importance of the OGFs to modulate DNA synthesis in fetal neural tissue. Others have demonstrated the importance of the kappa receptor subtype in modulating hormone synthesis in the fetal brain.

Importance of OGF's in neural development

Zagon et al (5) identified OGF and the zeta receptors in embryonic derivatives including ectoderm, mesoderm, and endoderm of the rat on the 20th gestational day. By detecting mRNA for preproenkephalin (PPE), the precursor of OGF, in the developing cells, an autocrine production of this peptide was suggested. The authors demonstrated that an acute exposure of pregnant females to OGF resulted in a direct, receptor-mediated decrease in DNA synthesis in cells of organs representing all three germ layers. In addition, the authors demonstrated that blockade of endogenous opioid interactions using naltrexone (NTX) produced an increase in DNA synthesis, indicating the constitutive and functional nature of opioid activity on prenatal growth. The authors concluded that endogenous opioid modulation of organ development is a fundamental principle of mammalian embryogenesis, and that OGF has a profound influence on ontogeny. Irregularities in the role of opioids as growth regulators may need to be evaluated with regard to newborns suffering from birth defects.

Importance of kappa receptor agonists vs. other opioid subtype agonists

Moreover, the role of receptor subtypes in opioid modulation of the hypothalamic-pituitary-adrenal (HPA) axis has recently been investigated in the developing fetus. Taylor et al.  evaluated the effects of highly selective mu, delta and kappa opioid agonists on plasma immunoreactive adrenocorticotropin (ir-ACTH) and immunoreactive cortisol (ir-cortisol) in the ovine fetus. Intravenous administration of the mu selective agonist [D-Ala2-N-Me-Phe4,Gly-ol]-enkephalin resulted in a 92% increase in ir-ACTH (P = .005) and ir-cortisol. The delta selective agonist, [D-Pen 2,D-Pen 5]-enkephalin, elicited a much smaller increase (52%) in ir-ACTH (P = .01). In contrast, there was a 7-fold increase in ir-ACTH (P < .001) and a significant increase in ir-cortisol (P = .02) with the kappa selective agonist U50,488H. When the same agonists were administered intracerebroventricularly, there was no change in ir-ACTH or ir-cortisol. The authors concluded that the kappa opioid receptor may be more important in the modulation of the fetal HPA axis than other opioids. As the fetal HPA axis plays an important role in the development of several vital organs and in the onset of parturition, an understanding of the role of opioid receptor subtypes on the fetal HPA axis is important in the design of new obstetrical analgesics.

References:

1.  Marsh DF, Hatch DJ, Fitzgerald M. Opioid systems and the newborn. Br J Anaesth 1997;79:787-95.
2.  Leslie FM, Tso S, Hurlbut DE. Differential appearance of opiate receptor subtypes in neonatal rat brain. Life Sciences 1982;31:1393-6.
3.  Park M, Tokunaga Y, Kimura H et al. Ontogeny of (D-Ala(2))-deltorphin I-like immunoreactive neurones in foetal rat brain. J Chem Neuroanat 2000;18(1-2):11-22.
4.  Korthank AJ, Robinson SR. Effects of amniotic fluid on opioid activity and fetal responses to chemosensory stimuli. Dev Psychobiol 1998;33(3):235-48.
5.  Zagon IS, Wu Y, McLaughlin PJ. Opioid growth factor and organ development in rat and human embryos. Brain Res 1999;839(2):313-22.
6.  Taylor CC, Wu D, Soong Y, Yee JS, Szeto HH. Opioid modulation of the fetal hypothalamic-pituitary-adrenal axis: the role of receptor subtypes and route of administration. J Pharmacol Exp Ther 1997;281(1):129-35.


编辑：西门吹血