Abstract
Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence–a critical period of frontal lobe development–influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.
Highlights
The use of opioids is a widespread public health crisis
The impact of adolescent social stress on morphine sensitization varied by strain
Adult C57BL/6J mice exposed to adolescent social stress had blunted morphine sensitization, but BALB/cJ mice did not (Figures 1A–D vs. E–H)
Summary
The use of opioids is a widespread public health crisis. Between 1999 and 2018 opioid overdoses accounted for 440,000 deaths in the United States (Wilson et al, 2020). Research with inbred panels of mice have confirmed a genetic influence for individual opioids, including morphine, with heritability estimates of morphine behavioral responses ranging from 0.26 to 0.44 (Bergeson et al, 2001; Kest et al, 2002; Liang et al, 2006). These findings support genetic influences on opioid use and responses, environmental factors impact opioid use
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