Michael Gulledge

Determining the Behavioral and Neurobiological Effects of Oxycodone Withdrawal on Sleep

Harvard University

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Clinical Implications

During withdrawal, rats suffer from many opioid related sleep deficits. Oxycodone decreased REM sleep and increased wake during lights on (the rat’s sleep period). Rats also woke up more frequently as seen by the lower inter-wake interval. Activity was reduced during the night (the rat’s wake period) because they had more NREM and REM sleep which suggests that their sleep pattern was disturbed. Additionally, EEG power was decreased across many different frequencies during withdrawal which suggests that brain activity was abnormal. We plan to manipulate activity of the Lateral Hypothalamus to Paraventricular Thalamus circuit in order to see what effects this has on the sleep deficits during withdrawal from oxycodone. We expect that if we decrease activity of this circuit both pharmacologically and chemogenetically, we will normalize all of the above sleep effects.

Research Narrative

It is known that opioid dependence and withdrawal can cause sleep deficits in humans; in fact, according to the NIH 75% of people suffering from opioid use disorder (OUD) also suffer from sleep disturbances (1). Despite this fact, sleep in OUD patients has been overlooked. One of the most effective therapies for OUD is methadone maintenance therapy; in which patients take a controlled dosage of the less abusable opioid methadone (slower onset of action). However, given that methadone acts on the same receptor (mu opioid receptor) as other abusable opioids (such as heroin and oxycodone), methadone itself contributes to poor sleep (2).

More typical sleep medicines like benzodiazepines are problematic, especially with regards to people suffering from OUD. Benzodiazepines are highly addictive on their own and are frequently abused together with opioids. For all of these reasons, there has been a recent push towards finding alternative drug classes that can better treat opioid-induced sleep deficits.

The field has been gravitating towards a certain class of drug; orexin antagonists. Orexin is an excitatory peptide, well known for modulating wake, and animal studies have shown that orexin and the Lateral Hypothalamus (where most of the orexinergic neurons reside in the brain) is involved in facilitating somatic withdrawal behaviors during opioid withdrawal. Therefore, my aims are focused on fully understanding the neurobiological mechanisms by which opioid withdrawal disrupts sleep; specifically focusing on the role of a particular Lateral Hypothalamic circuit (LH -> Paraventricular Nucleus of the Thalamus (PVT) -> Nucleus Accumbens (NAc)) to see how sleep changes when we manipulate activity of this circuit (via orexin antagonists or through chemogenetics) during opioid withdrawal.

1: https://heal.nih.gov/research/new-strategies/sleep-dysfunction
2: Baldassarri, S.R., Beitel, M., Zinchuk, A. et al. Correlates of sleep quality and excessive daytime sleepiness in people with opioid use disorder receiving methadone treatment. Sleep Breath (2020). https://doi-org.ezp-prod1.hul.harvard.edu/10.1007/s11325-020-02123-z