Morphine-responsive neurons of the medial habenula : a role in aversive states of morphine withdrawal ?

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Abstract Opioids target the mu opioid receptor (MOR). Opioid use is essentially motivated by pain relief and/or reward-seeking, however opioid abuse is strongly driven by other factors that include aversive emotional aspects of opioid withdrawal, which are at the center of this proposal. Here, we hypothesize that MOR- expressing neurons of the medial habenula (hereafter called MHb-MOR neurons) play a key role in the development of negative emotional responses characterizing opioid withdrawal. The proposal is based on four premises: (i) the MHb has become a recognized aversion center in addiction research, (ii) MOR-expressing neurons are highly abundant in the MHb, (iii) MOR-expressing neurons of the MHb modulate aversive states (our recent publication) and (iv) MOR-MHb neurons project to the raphe nucleus (RN), a major center for mood control (our unpublished data). Overall, we speculate that stimulating MHb-MOR neurons enhances the negative emotional experience of opioid withdrawal, whereas silencing these neurons alleviates the negative affect of withdrawal. Manipulating MOR-neurons has now become possible, as we have created a new transgenic MOR-Cre mouse line (unpublished). These mice will be used to manipulate MHb-MOR neurons in two behavioral models of short- (Aim 1) and long- (Aim 2) term withdrawal well established in our laboratory, and behavioral hallmarks of negative affect and their associated brain connectivity patterns will be studied. Aim 1 will use optogenetics to interrogate the contribution of MHb-MOR neurons in conditioned place aversion to low dose naloxone, and fMRI to characterize whole brain functional connectivity (WBFC) of the naloxone-evoked aversive state. Aim 2 will use chemogenetics to interrogate the contribution of MHb-MOR neurons in depressive-like behavior and social interaction deficits that develop upon prolonged withdrawal, and fMRI to identify the causal role of MHb-MOR in WBFC patterns alterations. Innovative aspects of this proposal are: (i) the focus on the function of MOR-expressing neurons for the first time; (ii) the notion that MOR neurons modulates activity of an aversion brain center (the MHb), providing a yet unexplored mechanistic angle on aversive states of opioid withdrawal; (iii) the study of a poorly known neural pathway (MHb/IPN/DRN microcircuitry), which has strong relevance to both addiction and depression research, (iv) the analysis of brain wide adaptations to chronic morphine using animal fMRI and (v) the translational potential for human research in growing efforts to fight the opioid crisis. We anticipate discovering novel neural mechanisms contributing to the negative affect of opioid withdrawal, and relevant to opioid use disorders. In the long-term, fMRI signatures may be translatable to human research. This proposal has strong basic and clinical implications, and can uniquely be developed by our team at the Douglas Research Center, McGill University Montréal. 1