Maladaptive pain-induced dysfunction in motivational circuits are the likely critical factors that lead to pathological alterations in natural and drug reward seeking behaviors, yet the neural circuit mechanisms for these effects are largely unknown. The mesolimbic system is a key network node that integrates pain and reward. Dopamine (DA) transmission in the mesolimbic system, via the VTA to NAc has long been recognized for its role in motivated behavior. Alterations in DA signaling within the mesolimbic pathway are associated with motivational deficits, and animals in pain show impaired motivated responses to natural and drug reward. Importantly, from a translational perspective, negative correlations between pain and mesolimbic DA activity in humans have been often reported. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant opioids used for alleviating clinical pain and recreational use/abuse. We recently found that persistent inflammatory pain downregulates function of MOPR in the VTA with a concomitant loss of opioid- induced DA release in the NAc in a dose-dependent manner leading to increase intake of higher doses of opioids which are known to contribute to abuse-associated phenotypes. In addition, our preliminary data suggest that persistent inflammation causes an increase in endogenous opioid tone which is likely leading to desensitization of MOPR in the VTA. Collectively, these findings suggest that pain suppresses VTA?NAc neural circuit activity through suppression of mesolimbic DA release. We predict that this effect is mediated by an increase in endogenous opioid tone and reduction of MOPR function in the VTA which negatively impact the animal's motivational state contributing to an opioid abuse-associated phenotype. In this application we propose cross disciplinary cutting-edge approaches to dissect the neuronal and cellular mechanisms underlying the downregulation of mu-opioid circuits in the presence of inflammatory pain. In three specific aims we will: i) determine the mechanisms for downregulation of mu-opioid-containing GABAergic circuits in inflammatory pain ii) determine whether increases in endogenous mu-opioid agonist tone changes mu-opioid function, and whether these processes are necessary and sufficient for the effects of inflammatory pain on motivated behavior. Finally, in a third aim we will directly visualize endogenous opioid-containing neuronal ensembles during the development of inflammatory pain and decreased motivational states. Here we will determine whether mu-opioid receptors, their endogenous agonists, within discrete mesolimbic neural circuits, are necessary and sufficient to mediate pain-induced alterations in opioid intake and motivated behavior.
Opioids are used widely in the clinic for the treatment of both acute and chronic pain, but surprisingly relatively few studies have examined the neural mechanisms and circuits underlying abuse liability of commonly prescribed opiate medications during pain conditions. Here we propose mechanistic studies to determine how the presence of pain alters the motivational properties of opioids that may predispose individuals to opioid abuse. These results could provide rationale for development of alternate opioid treatments.
|Wilson-Poe, Adrianne R; Morón, Jose A (2018) The dynamic interaction between pain and opioid misuse. Br J Pharmacol 175:2770-2777|
|Bavley, Charlotte C; Rice, Richard C; Fischer, Delaney K et al. (2018) Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase-mTORC1 Translational Pathway. J Neurosci 38:2780-2795|
|Massaly, Nicolas; Morón, Jose A; Al-Hasani, Ream (2016) A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System. Front Neurosci 10:480|
|Fakira, Amanda K; Massaly, Nicolas; Cohensedgh, Omid et al. (2016) Morphine-Associated Contextual Cues Induce Structural Plasticity in Hippocampal CA1 Pyramidal Neurons. Neuropsychopharmacology 41:2668-78|
|Cabañero, David; Irie, Takeshi; Celorrio, Marta et al. (2016) Identification of an epidermal keratinocyte AMPA glutamate receptor involved in dermatopathies associated with sensory abnormalities. Pain Rep 1:|