Childhood lead (Pb²⁺) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb²⁺ intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system.

Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb²⁺ exposure (1500 ppm in the diet) on μ-opioid receptor (MOR) levels in the rat brain using [³H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([³H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats.

Our results indicate that chronic developmental Pb²⁺ exposure increases the levels of [³H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb²⁺-exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb²⁺-exposed adult male rats (PN120). Specifically, at PN14, Pb²⁺-exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb²⁺-exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb²⁺-exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb²⁺-exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb²⁺-exposed males in the medial thalamus.

Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb²⁺ exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans.

In summary, we show that chronic exposure to Pb²⁺, an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse.

儿童铅 (Pb ²⁺ ) 中毒是一个全球性的公共卫生问题，以造成学习障碍和学习成绩不佳而闻名。人类和临床前研究表明，儿童铅²⁺中毒与药物滥用倾向和违法行为之间存在关联。虽然环境因素与阿片类药物成瘾有关，但人们对暴露于环境污染物对大脑阿片类药物系统的作用知之甚少。

阿片受体参与阿片类药物和其他滥用药物的生物效应。在本研究中，我们使用 [ ³ H]- d -Ala2-MePhe4-Gly-ol5检查了慢性发育性 Pb ²⁺暴露（饮食中 1500 ppm）对大鼠大脑中 μ-阿片受体 (MOR) 水平的影响雄性和雌性大鼠不同发育阶段（青少年、青春期早期、青春期晚期和成年期）的脑啡肽 ([ ³ H]-DAMGO) 定量受体放射自显影。

我们的结果表明，长期发育性 Pb ²⁺暴露增加了 [ ³ H]-DAMGO 与 MOR 特异性结合的水平，在幼年和早期 Pb ²⁺暴露的雄性和雌性大鼠大脑中，青春期晚期 (PN50) 和暴露于 Pb ^{2+ 的}成年雄性大鼠 (PN120) 的微小变化。具体而言，在 PN14 时，暴露于 Pb ^{2+ 的}雄性在侧丘脑后核 (LPTN) 中的 MOR 结合增加，而暴露于Pb ^{2+ 的}雌性在 LPTN、内侧丘脑和下丘脑中增加了 MOR 结合。在 PN28 时，暴露于 Pb ^{2+ 的}雄性在纹状体、丘脑髓纹、LPTN、内侧丘脑和基底外侧杏仁核中的 MOR 水平增加，而 Pb²⁺暴露的女性表现出伏隔核核心、LPTN 和内侧丘脑的增加。在 PN50 时，雄性和雌性大鼠的任何脑区均未检测到变化，而在 PN120时，内侧丘脑中暴露于Pb ^{2+ 的}雄性的MOR 结合降低。

我们的研究结果表明，由于慢性发育性 Pb ²⁺暴露，MOR 水平在大鼠大脑中的年龄和性别特异性影响。这些结果表明，大脑 MOR 水平的主要变化发生在青春期前和青春期早期，在这个发育时期，人类更多地参与奖励和寻求药物的行为。

总之，我们表明，长期暴露于 Pb ²⁺是一种普遍存在且众所周知的环境污染物和神经毒物，会改变与青少年时期成瘾回路相关的大脑区域的 MOR 水平，这些发现对阿片类药物的使用和滥用具有重要意义.