Opioid receptor agonists are highly effective at producing analgesia, but their clinical use is hindered by the development of tolerance and high abuse liability resulting from activation of the neural reward circuitry. Therefore, understanding how opioids regulate reward circuits and how opioid receptor signaling changes with opioid exposure are key steps towards overcoming current clinical limitations of opioid therapy. One important reward pathway that releases and responds to opioids includes the hypothalamic proopiomelanocortin (POMC) neurons. Recent data show that POMC neurons are regulated by opioids acting on POMC neurons and also by opioids acting on terminals presynaptic to POMC neurons. Interestingly, while postsynaptic mu opioid receptors on POMC neurons undergo desensitization within minutes, presynaptic mu opioid receptors that mediate the inhibition of transmitter release do not readily desensitize. The goals of the present proposal are to 1) determine the mechanisms underlying the presynaptic resistance to desensitization and 2) to determine the consequence of differential pre- and postsynaptic opioid receptor regulation. These goals will be achieved using electrophysiologic, optogenetic and imaging approaches in brain slices. The results may provide insight into ways to prevent postsynaptic receptor desensitization and will thoroughly define how opioids affect neuron activity in a reward circuit via pre- and postsynaptic receptors during acute and chronic exposure to opioids.

Public Health Relevance

In order to better treat chronic pain and to prevent opioid abuse, it is essential to understand how opioids affect the brain's reward pathways and to determine why opioids become less effective with repeated use. These are the overall goals of the proposed research.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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Colorado State University-Fort Collins
Veterinary Sciences
Schools of Veterinary Medicine
Fort Collins
United States
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Rau, Andrew R; Hughes, Alexander R; Hentges, Shane T (2018) Various transgenic mouse lines to study proopiomelanocortin cells in the brain stem label disparate populations of GABAergic and glutamatergic neurons. Am J Physiol Regul Integr Comp Physiol 315:R144-R152
Fox, Philip D; Hentges, Shane T (2017) Differential Desensitization Observed at Multiple Effectors of Somatic ?-Opioid Receptors Underlies Sustained Agonist-Mediated Inhibition of Proopiomelanocortin Neuron Activity. J Neurosci 37:8667-8677
Rau, Andrew R; Hentges, Shane T (2017) The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release. J Neurosci 37:7362-7372
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Pennock, Reagan L; Dicken, Matthew S; Hentges, Shane T (2012) Multiple inhibitory G-protein-coupled receptors resist acute desensitization in the presynaptic but not postsynaptic compartments of neurons. J Neurosci 32:10192-200
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Pennock, Reagan L; Hentges, Shane T (2011) Differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating hypothalamic proopiomelanocortin neurons. J Neurosci 31:281-8