This study uncovers the sex-specific effect of prolonged morphine exposure on the hypothalamus pathways.

Key neurotransmission and signaling pathways are differentially disrupted by morphine in females and males.

The profiles indicate a complex interplay between immune response and substance exposure.

The transcriptomic analysis revealed that sex and morphine exposure impact the critical peroxisome and ribosome pathways.

Evidence from this research pinpoints specific gene networks influenced by morphine and highlight potential targets for sex-specific intervention strategies.

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.

RNA-seq

Hypothalamus

Morphine

Sex- differences

Gene networks

Transcription factors

© 2025 The Authors. Published by Elsevier Inc.