Abstract
Early life adversity has profound health implications in later life. Individuals that experience early life adversity as neonates in the form of preterm birth, or those that require surgical intervention later, exhibit altered pain sensitivity. Fragmented maternal care (FC) is potentially the most common form of early life adversity, but less is known about its effects on pain. Individuals are more likely to experience FC in regions of greater deprivation where poverty, divorce rates and drug abuse levels are highest. Populations that experience deprivation also exhibit vulnerability to chronic pain and high rates of opioid prescribing and misuse. It is possible that exposure to FC alters pain resilience and/or behavioural responses to opioids, perhaps contributing to the increased prescribing and misuse of opioids.Mu opioid receptors (MOP), delta opioid receptors (DOP), β-arrestin 2 (Barr2) and c-Src kinase are all components of the opioid signalling system, which to differing degrees have been implicated in pain sensitivity and the behavioural effects of opioids including analgesia, tolerance, hyperalgesia, locomotor function and reinforcement.
We generated FC in post-natal day (PD) 2-9 mice and investigated their nociception and morphine analgesia, tolerance, hyperalgesia, hyperlocomotion and reinforcement at adulthood. To do this we utilised a variety of different behavioural techniques such as the tail withdrawal assay, conditioned place preference (CPP), and locomotor analysis. We also investigated the influence of FC on the expression and methylation of key genes including those encoding opioid peptide precursors, MOP, DOP, Barr2 and c-Src in several brain regions, the spinal cord and dorsal root ganglia (DRG).
Wild type (WT) FC mice exhibited basal hypoalgesia that was not observed in the control cohort. By contrast, FC did not affect basal nociception in MOP+/- or Barr2-/- mice. Furthermore, WT and MOP+/- FC mice exhibited reduced morphine analgesic potencies when compared to their respective controls. Repeated daily subcutaneous morphine administration resulted in more rapid development of morphine analgesic tolerance in WT, but not MOP+/- FC mice when compared to the respective control mice. Neither the Barr2-/- control nor FC mice developed tolerance to morphine. The c-Src inhibitor, dasatinib, did not affect the development of tolerance in WT FC mice, nor did it completely reverse tolerance once developed in MOP+/- control mice. Increased morphine-associated hyperalgesia occurred in WT FC mice compared to controls. There was no effect of FC on morphine-associated hyperalgesia in either MOP+/- or Barr2-/- mice. Interestingly, despite neither the control nor FC Barr2-/- mice displaying morphine tolerance, both cohorts developed morphine-associated hyperalgesia.
FC did not affect morphine reinforcement in WT mice. However, WT FC mice exhibited increased morphine sensitisation, as measured by increased morphine induced hyperlocomotion, thought to be a drug-seeking-related behaviour. Gene expression and DNA methylation analysis in WT FC animals suggest that the behavioural effects observed may be due to altered opioid receptor expression and/or signalling. Despite altered gene expression in DRG neurones from mice exposed to FC, there were no differences in the ability of morphine to maximally inhibit voltage dependent calcium channel activity recorded from FC and control neurones.
The findings of this study emphasize the need to investigate both male and female mice as there are differences in the effects of FC on body weight and gene expression between the sexes. Importantly, FC results in altered pain perception, morphine analgesia, tolerance, hyperalgesia and sensitisation in mice. These potentially life-long effects of FC on pain perception and opioid behaviours are likely caused by epigenetic influences on the expression of key genes. This study establishes the possibility that exposure to early life adversity in human populations programmes altered vulnerability to pain and adverse responses to opioid analgesics.
| Date of Award | 2020 |
|---|---|
| Original language | English |
| Sponsors | Medical Research Council |
| Supervisor | Tim Hales (Supervisor) & Jeremy Lambert (Supervisor) |