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.
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.
|Pennock, Reagan L; Hentges, Shane T (2016) Desensitization-resistant and -sensitive GPCR-mediated inhibition of GABA release occurs by Ca2+-dependent and -independent mechanisms at a hypothalamic synapse. J Neurophysiol 115:2376-88|
|Pennock, Reagan L; Hentges, Shane T (2014) Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the Î¼-opioid receptor. J Physiol 592:4247-56|
|Matsui, Aya; Jarvie, Brooke C; Robinson, Brooks G et al. (2014) Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron 82:1346-56|
|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|
|Dicken, Matthew S; Tooker, Ryan E; Hentges, Shane T (2012) Regulation of GABA and glutamate release from proopiomelanocortin neuron terminals in intact hypothalamic networks. J Neurosci 32:4042-8|
|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|