Research Article: Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids

Date Published: April 5, 2017

Publisher: Public Library of Science

Author(s): Joshua Hakimian, Ani Minasyan, Lily Zhe-Ying, Mariana Loureiro, Austin Beltrand, Camille Johnston, Alexander Vorperian, Nicole Romaneschi, Waleed Atallah, Fernando Gomez-Pinilla, Wendy Walwyn, Manabu Sakakibara.


Opiates, one of the oldest known drugs, are the benchmark for treating pain. Regular opioid exposure also induces euphoria making these compounds addictive and often misused, as shown by the current epidemic of opioid abuse and overdose mortalities. In addition to the effect of opioids on their cognate receptors and signaling cascades, these compounds also induce multiple adaptations at cellular and behavioral levels. As omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a ubiquitous role in behavioral and cellular processes, we proposed that supplemental n-3 PUFAs, enriched in docosahexanoic acid (DHA), could offset these adaptations following chronic opioid exposure. We used an 8 week regimen of n-3 PUFA supplementation followed by 8 days of morphine in the presence of this diet. We first assessed the effect of morphine in different behavioral measures and found that morphine increased anxiety and reduced wheel-running behavior. These effects were reduced by dietary n-3 PUFAs without affecting morphine-induced analgesia or hyperlocomotion, known effects of this opiate acting at mu opioid receptors. At the cellular level we found that morphine reduced striatal DHA content and that this was reversed by supplemental n-3 PUFAs. Chronic morphine also increased glutamatergic plasticity and the proportion of Grin2B-NMDARs in striatal projection neurons. This effect was similarly reversed by supplemental n-3 PUFAs. Gene analysis showed that supplemental PUFAs offset the effect of morphine on genes found in neurons of the dopamine receptor 2 (D2)-enriched indirect pathway but not of genes found in dopamine receptor 1(D1)-enriched direct-pathway neurons. Analysis of the D2 striatal connectome by a retrogradely transported pseudorabies virus showed that n-3 PUFA supplementation reversed the effect of chronic morphine on the innervation of D2 neurons by the dorsomedial prefontal and piriform cortices. Together these changes outline specific behavioral and cellular effects of morphine that can be reduced or reversed by dietary n-3 PUFAs.

Partial Text

Opioids are prescribed for pain relief but are also used to induce euphoria contributing to the increasing diversion of these readily available pharmaceutical compounds for non-medical use [1, 2]. In the last decade there has been an exponential rise in the abuse of prescription opioids which have become a gateway to heroin and fentanyl abuse [3]. Together these, and other synthetic opioids have led to a meteoric rise in overdose mortalities [2–8] making the development and use of suitable interventions to address this epidemic a priority of state and federal regulators [9, 10].

This preclinical study shows that specific behavioral and cellular effects of chronic morphine can be reduced by a diet supplemented with n-3 PUFAs. The 8 week n-3 PUFA dietary intervention used in this study reduced the increased anxiety following chronic morphine and reversed the effect of repeated morphine exposure on striatal DHA content. This dietary intervention also normalized morphine-induced glutamatergic plasticity and increased Grin2B expression and the proportion of Grin2B-NMDAR currents in the striatum. Furthermore the effect of morphine on the expression of genes enriched in D2-MSNs and on the D2-striatal connectome was offset by this DHA-enriched diet. These data show how this intervention offset allostatic adaptations known to be induced by chronic opioid exposure [38] without altering the proto-typical effects of activating the mu opioid receptor, the predominant target of morphine and other opioids.




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