Sahid Arshman S, Bebbington Melissa J, Marcus Abigail, Baracz Sarah J, Zimmermann Kelsey S, Oei JuLee, Ward Meredith C, Clemens Kelly J
School of Psychology, University of New South Wales, Sydney, Australia.
School of Women's and Children's Health, University of New South Wales, Kensington, NSW, Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Mar 20;137:111255. doi: 10.1016/j.pnpbp.2025.111255. Epub 2025 Jan 19.
The opioid crisis continues to escalate, disproportionately affecting women of reproductive age. Traditionally the first line of treatment for pregnant women with opioid use disorder is the mu-opioid receptor agonist methadone. However, in recent years, the use of buprenorphine as a replacement therapy has increased as it has fewer side-effects and longer duration of action. Either drug significantly improves outcomes for the mother, but their impact on the developing infant is less certain. To this end, we directly compared the effects of perinatal methadone (MET; 9 mg/kg/day starting dose) versus buprenorphine (BUP; 1 mg/kg/day starting dose) delivered via mini osmotic pump on the long-term behavior of offspring and associated molecular changes in the brain. Opioid exposure across pregnancy resulted in reduced weight gain and smaller litters compared to sham controls, and female pups in particular gained weight at a slower rate across development. Opioid treatment delayed neuromuscular reflex development, with subtle differences observed between MET and BUP. As juveniles, pups with prenatal MET exposure showed poor object recognition, although both MET and BUP have led to deficits in place recognition task. Immunofluorescence studies found corresponding decreases in astrocytes and myelin-positive cells in the hippocampus in both MET and BUP pups. Overall, both MET and BUP were associated with significant developmental and cognitive delays and changes in markers of neuronal development and inflammation, particularly in the hippocampus. The majority of changes were similar between MET and BUP-treated pups, suggesting that gestational exposure to either drug has a similar long-term negative impact on offspring.
阿片类药物危机持续升级，对育龄女性的影响尤为严重。传统上，患有阿片类药物使用障碍的孕妇的一线治疗方法是使用μ-阿片受体激动剂美沙酮。然而，近年来，丁丙诺啡作为替代疗法的使用有所增加，因为它的副作用较少且作用持续时间更长。这两种药物都能显著改善母亲的治疗效果，但它们对发育中的婴儿的影响尚不确定。为此，我们直接比较了通过微型渗透泵给予围产期美沙酮（MET；起始剂量为9毫克/千克/天）与丁丙诺啡（BUP；起始剂量为1毫克/千克/天）对后代长期行为及大脑相关分子变化的影响。与假手术对照组相比，孕期暴露于阿片类药物导致体重增加减少和窝仔数减少，尤其是雌性幼崽在整个发育过程中体重增加速度较慢。阿片类药物治疗延迟了神经肌肉反射发育，MET和BUP之间观察到细微差异。作为幼崽，产前暴露于MET的幼崽表现出较差的物体识别能力，尽管MET和BUP都导致了位置识别任务的缺陷。免疫荧光研究发现，MET和BUP幼崽海马体中的星形胶质细胞和髓磷脂阳性细胞相应减少。总体而言，MET和BUP都与显著的发育和认知延迟以及神经元发育和炎症标志物的变化有关，尤其是在海马体中。MET和BUP处理的幼崽之间的大多数变化相似，这表明孕期接触这两种药物中的任何一种对后代都有类似的长期负面影响。
