Epigenetic therapies and morphine addiction 1
Christopher Paton
With annual spending by the US government on illicit drug control, prevention and treatment rising rapidly in the past decade, costing $40.4 billion in 2021 alone, and deaths due to opioid overdose steadily increasing since 1999, it is indisputable that the US, and indeed the rest of the developed world, are in desperate need of more effective methods of recovery from drug addiction (Office of National Drug Control Policy, 2021; Hedegaard, Miniño and Warner, 1999). At present, approved pharmaceutical treatments for attenuating morphine addiction can vary in efficacy from 90% to as low as 49%, and often the best efficacy is only observed when patients remain in a rehabilitation centre throughout recovery (American Addiction Centers, 2021). Yet in many patients, even after prolonged periods of morphine abstinence, underlying addictive behaviours still frequently return, presenting a clear and immediate need for more sustained physiological treatments (Robinson and Kolb, 2004). Several large-scale studies have previously illustrated the role of genetics in heritable predisposition to addictive behaviour (Kendler et al., 2000; Kendler, Karkowski and Prescott, 2007); most notably, it has been demonstrated through ‘large, carefully characterized cohorts of twins’ that the heritability of opiate addictions (e.g., to morphine) rank amongst the most transmissible (from parent to child) of drug addictions (Goldman, Oroszi and Ducci, 2005). However, despite the clear evidence provided by these studies of the heritability of addictive behaviour, previous attempts to identify the exact genes involved in addiction have proven challenging, suggesting that there is more to the condition’s heredity than once believed. Indeed, there is now increasing evidence that it is the way in which the expression of different genes is modified by our cells, a mechanism known as epigenetics, that underpins both the development and long-term persistence of drug addictions (Hamilton et al., 2018). In this essay, I will explore several mechanisms by which epigenetic modifications in the brain produce alterations in neuroplasticity that contribute to morphine addiction, whilst analysing the suitability of theoretical treatments that target these modifications to assess their ability to provide more effective rehabilitation options for patients.
Some of the earliest evidence for the role of epigenetics in addictive behaviours came from studying the effects of inhibiting histone deacetylases (HDACs), a class of enzymes responsible for downregulating gene expression (see Figure 1), in mice addicted to cocaine (Kumar et al., 2005). Since then, researchers have found that morphine irrefutably alters gene expression in the brain by ‘ significantly [upregulating] HDAC4 ’ (Doke, Pendyala and Samikkannu, 2021), a specific type of HDAC which is known toe important in ‘learning and memory and
Figure 1 – Diagram to show the effects of histone acetylation (left) and deacetylation (right) on gene expression. When an acetyl group is present it causes DNA packing to loosen, increasing expression of the nearby gene or genes. The ‘HDAC’ shown is a class of epigenetic enzyme which modulates gene expression via the removal of acetyl groups from histones.
1 All images in this essay are original material created by me using an online program: www.biorender.com.
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