Abstract
The rise in opioid prescribing in recent years has accompanied an increase in the number of individuals at risk of the adverse effects of opioids – most notably opioid used disorder (OUD). Exposure to adverse childhood experiences (ACEs), such as abuse and neglect, results in toxic stress and are associated with maladaptive changes in the brain and poor health outcomes in adulthood. ACEs, which are most prevalent in areas of highest deprivation, are associated with increased vulnerability to chronic pain and OUD. Preclinical models of early life stress (ELS) have been developed to mimic characteristics of ACEs to better understand these associations and the mechanisms involved, in the absence of confounding factors. For example, the limited bedding and nesting material (LBN) paradigm has been developed to study the impact of resource scarcity induced maternal neglect on subsequent adult behaviours.Therefore, the overarching goal of my PhD research was to test the hypothesis that ELS affects rodent behaviours related to OUD and to examine the mechanisms underlying the impact of ELS. This was tested by:
1) Conducting a systematic review of the literature and meta-analyses to examine the evidence for maternal neglect affecting adult rodent behaviours related to OUD.
2) Using the mouse LBN model to establish whether fragmented maternal care (a model of neglect) affects morphine conditioned place preference and if this is influenced by persistent potentially painful inflammation.
3) Exploring mechanisms including DNA methylation and altered gene expression that might mediate the effects of ELS on pain vulnerability, effectiveness of opioids as analgesics and OUD.
Overall, the systematic review and meta-analyses demonstrated an impact of ELS across multiple behaviours related to OUD and highlighted areas of improvement for reporting preclinical studies. Additionally, the fragmented maternal care (FC) model altered basal locomotor activity in female mice, and enhanced morphine-primed reinstatement, effects that are consistent with changes in the nigrostriatal and mesocorticolimbic pathways. DNA methylation and gene expressive analysis revealed an impact of FC and repeated morphine exposure on genes involved in pain and/or reward signalling. In the spinal cord, FC was also associated with increased DNA methylation and gene expression of fibroblast growth factor binding protein 3, which targets fibroblast growth factor 2 (FGF2), implicated in pain sensitisation and drug reward. FC also altered the expression of modulators of dopamine signalling (preproenkephalin, proopiomelanocortin and FGF2) in the striatum in a sex specific manner. Additionally, repeated morphine exposure led to widespread changes in the striatum and the prefrontal cortex, including consistent upregulation of the κ-opioid receptors which has been implicated in the depressive state associated with opioid withdrawal.
The findings highlight that early life adversity has a major impact, altering behaviours and mechanisms that predict vulnerability to OUD and pain.
| Date of Award | 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | Medical Research Council |
| Supervisor | Tim Hales (Supervisor) & Stephen Martin (Supervisor) |
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