Sunderland G R, Southey B R, Villamil M B, Rodriguez-Zas S L
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA.
Mol Cell Neurosci. 2025 May 30;134:104014. doi: 10.1016/j.mcn.2025.104014.
Synaptic plasticity is a recognized neuroadaptation of the brain in response to environmental cues. In addition, differences between females and males in neuronal plasticity in response to opioids have been reported. However, the response to opioids in the hypothalamus, a structure that encompasses sexually dimorphic nuclei, is partially characterized. Furthering the characterization of the sex-dependent dysregulation of gene networks, the hypothalamus transcriptome was profiled in female and male pigs that were exposed to morphine relative to controls. Among the 923 genes that were differentially expressed (FDR-adjusted p-value <0.05) across treatments and sexes, 179 genes were identified between saline and morphine-treated females, and 129 genes were identified between saline-treated females and males. The under-expression of genes in the morphine-exposed relative to the saline groups in both sexes characterized the enrichment of the peroxisome pathway and neuropeptide signaling process whereas the opposite pattern characterized the enrichment of the glutamatergic synapse pathway in females. The neuropeptide pathway included differentially expressed neuropeptide and corresponding receptor genes, including Npy and its family receptors, Penk, Pomc, and Tac1, and the peroxisome pathway included Mvk and Dao and the Hmgc family of genes. The effect of morphine treatment in males was detected in the enrichment of the interleukin-17 and T cell receptor signaling pathways. These results offer further evidence that chronic morphine exposure evokes distinct molecular mechanism disruption in females and males, highlighting the need for sex-dependent molecular target therapies.
突触可塑性是大脑对环境线索的一种公认的神经适应性变化。此外，已有报道称，在对阿片类药物的反应中，雌性和雄性在神经元可塑性方面存在差异。然而，下丘脑（一个包含性二态核的结构）对阿片类药物的反应仅得到部分表征。为了进一步表征基因网络的性别依赖性失调，我们对暴露于吗啡的雌性和雄性猪以及对照组猪的下丘脑转录组进行了分析。在跨处理和性别的923个差异表达基因（FDR校正p值<0.05）中，在生理盐水处理的雌性和吗啡处理的雌性之间鉴定出179个基因，在生理盐水处理的雌性和雄性之间鉴定出129个基因。与生理盐水组相比，暴露于吗啡的两性中基因的低表达特征为过氧化物酶体途径和神经肽信号传导过程的富集，而相反的模式则特征为雌性中谷氨酸能突触途径的富集。神经肽途径包括差异表达的神经肽和相应的受体基因，包括Npy及其家族受体、Penk、Pomc和Tac1，过氧化物酶体途径包括Mvk、Dao和Hmgc家族基因。在雄性中，吗啡处理的影响在白细胞介素-17和T细胞受体信号通路的富集中被检测到。这些结果提供了进一步的证据，表明慢性吗啡暴露在雌性和雄性中引发了不同的分子机制破坏，突出了性别依赖性分子靶向治疗的必要性。
