# Gender dependent modulation of opioid dependance genes and signaling pathways in HIV-1 Transgenic rats at morphine tolerance

## TL;DR

This study explores how HIV and morphine affect opioid dependence genes and brain pathways differently in male and female rats.

## Contribution

The study identifies gender-specific changes in opioid dependence gene expression and signaling pathways in HIV-1 transgenic rats at morphine tolerance.

## Key findings

- CREB signaling in neurons and neuroinflammation pathways were activated in the striatum of both male and female HIV-1Tg rats.
- Gαq and S100 family signaling were activated in female HIV-1Tg rats given morphine.
- Gender differences were observed in pathway activation in the prefrontal cortex related to IP3 synthesis and CREB signaling.

## Abstract

Misuse of opioids is a major comorbidity in people with HIV (PWH). Neurological abnormalities and opioid addiction seen in PWH involve the interplay among signaling pathways. However, the impact of HIV proteins on morphine dependence is understudied. We aimed to understand the modulation of the opioid dependence genes and signaling pathways in the striatum (Str) and prefrontal cortex (PFC) of PWH. HIV-1 transgenic (HIV-1Tg) rats and F344 control animals were given 2 and 4 pellets of morphine (75-mg/pellet)/placebo on Days 1 and 2, respectively, via subcutaneous implantation. On Day 5, at morphine tolerance the rats were sacrificed, Str and PFC were collected for RNA isolation and cDNA preparation. A PCR-array was used to examine the expression of the 65 opioid dependance genes. Varying numbers of genes were significantly upregulated in the Str and PFC of morphine treated rats. Fold change values were uploaded to QIAGEN Ingenuity Pathway Analysis, to study the signaling pathways associated with the treatment conditions. CREB signaling in neurons and Neuroinflammation signaling pathway were highly activated in the Str of both male and female HIV-1Tg rats given morphine. Gαq signaling and S100 family signaling were activated in female HIV-1Tg rats received morphine. Similarly, in the PFC, synthesis of IP3, CREB Signaling in neurons, Gαq signaling in males and CREB Signaling in neuron, and Gαq signaling in females were activated. Using bioinformatic analysis, we identified key signaling pathways and gender dependent changes in the opioid dependent gene expression and pathway enrichment of HIV-1Tg rats at morphine tolerance.

The online version contains supplementary material available at 10.1007/s13365-025-01257-8.