{"id":4122,"date":"2019-09-23T18:50:43","date_gmt":"2019-09-23T09:50:43","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4122"},"modified":"2019-09-23T18:50:43","modified_gmt":"2019-09-23T09:50:43","slug":"countering-opioid-side-effects","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4122","title":{"rendered":"Countering opioid side effects"},"content":{"rendered":"

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The toll from opioid overdose in the United States now exceeds 45,000 deaths per year. Shockingly, more Americans die from opioid overdose than from motor vehicle collisions (1<\/em><\/a>), and opioid overdose has become the number one cause of accidental death. Worldwide, two-thirds of drug-related deaths were a result of opioids, as reported by the United Nations 2019 drug report. As well as searching for opioid replacements, scientists are developing therapeutics to block the detrimental side effects of opioids, particularly addiction and fatal opioid-induced respiratory depression (OIRD) (2<\/em><\/a>). Addiction and OIRD are a direct result of opioid activation of receptors that regulate neural circuits that control reward and breathing\u2014circuits distinct from those that regulate pain (3<\/em><\/a>). On page 1267 of this issue, Wang\u00a0et al.<\/em>\u00a0(4<\/em><\/a>) identify the orphan G protein\u2013coupled receptor (GPCR) GPR139 as a regulator of opioid receptors and provide evidence that this receptor could be a useful therapeutic target to reduce opioid side effects.<\/p>\n

Wang\u00a0et al.<\/em>\u00a0turned to a model organism with a simpler nervous system than that in mammals, the nematode worm\u00a0Caenorhabditis elegans<\/em>\u00a0(5<\/em><\/a>). They developed an ingenious forward genetic screen to identify mutations that affect opioid receptor function. Fentanyl, morphine, and other abused opioids primarily act on the \u00b5-type opioid receptor (MOR). MOR is a GPCR present on the cell surface. Deletion of\u00a0Oprm1<\/em>, the gene that encodes MOR, in mice demonstrated that MOR is responsible for the analgesic effects of opioids as well as the harmful addiction and OIRD (6<\/em><\/a>,\u00a07<\/em><\/a>). In rodents and humans, opioids have motor effects, altering locomotion and muscle tension (8<\/em><\/a>,\u00a09<\/em><\/a>).\u00a0C. elegans<\/em>\u00a0does not express MOR and is unresponsive to opioids. However, the authors found that following introduction of a transgene to express mammalian MOR (tgMOR), fentanyl and morphine decreased locomotion in tgMOR\u00a0C. elegans<\/em>\u00a0mutants. Wang\u00a0et al.<\/em>\u00a0then induced random mutations in the tgMOR\u00a0C. elegans<\/em>\u00a0population to identify worms resistant to fentanyl. They found \u223c900 mutations and chose to examine one of the affected genes,\u00a0frpr-13<\/em>, which encodes a GPCR.<\/p>\n

The mammalian ortholog of FRPR-13 is GPR139. Wang\u00a0et al.<\/em>\u00a0validated the functional interaction of MOR and GPR139 by showing that MOR-induced membrane hyperpolarization, a known effect of opioids, was inhibited by GPR139 expression in cultured human kidney cells that do not usually express the GPCR. They next explored three possible molecular mechanisms by which GPR139 negatively regulates MOR function (see the figure). First, they explored whether GPR139 and MOR dimerization could explain this finding. They showed that GPR139 and MOR can be coimmunoprecipitated. However, both receptors were artificially overexpressed in a non-native cellular context; whether these interactions occur in vivo between endogenous receptors expressed at physiological concentrations and in the neurons that mediate opioid side effects remains to be determined. Second, when GPR139 is expressed at high amounts, they found that MOR is present at the cell surface in lower densities, suggesting that GPR139 may modulate\u00a0Oprm1<\/em>\u00a0expression and\/or MOR trafficking inside the cell, either its transport to the cell surface or its internalization. At stoichiometric amounts, GPR139 has no effect on surface localization of MOR, suggesting that this mechanism may only take place when GPR139 expression is upregulated, potentially in the setting of chronic drug exposure and disease. Third, the authors provided evidence that GPR139 negatively regulates MOR by facilitating \u03b2-arrestin 2 recruitment. \u03b2-Arrestins are cytosolic proteins that interact with GPCRs and promote receptor desensitization, internalization, trafficking, and signaling (10<\/em><\/a>). \u03b2-Arrestin 2 is thought to contribute differentially to the multiple side effects of opioids (e.g., promoting OIRD, reducing reward without affecting withdrawal) (11<\/em><\/a>,\u00a012<\/em><\/a>) and may do so in an opioid ligand\u2013dependent manner (13<\/em><\/a>). Consequently, the exact opioid drugs and detrimental effects for which GPR139 modulation might prove useful will need to be established.<\/p>\n

To investigate GPR139 function in neural circuits, the authors examined the medial habenula (MHb) and locus coeruleus (LC) of mice, two regions of the brain with neurons that express MOR, for electrophysiological evidence of MOR and GPR139 functional interactions. They found\u00a0Oprm1<\/em>\u00a0and\u00a0Gpr139<\/em>\u00a0mRNA colocalized in neurons in the MHb and LC. Using cultured brain slices, they found that the loss of\u00a0Gpr139<\/em>\u00a0reduced the basal firing rate of MHb neurons and increased the opioid sensitivity of LC neurons. The authors conclude that GPR139 modulates MOR control of neuronal excitability by a cell-autonomous mechanism. However it seems that these effects could also result from an action of GPR139 in non\u2013MOR-expressing neurons within the slice. Future studies should determine which ion channels are involved in the reduced neuronal firing; they should also establish whether GPR139 modulates MOR-induced inhibition of neurotransmitter release and probe GPR139 function in other brain nuclei of critical importance for opioid addiction, including the nucleus accumbens and the ventral tegmental area (14<\/em><\/a>), and implicated in OIRD, such as the pre-B\u00f6tzinger complex (15<\/em><\/a>).<\/p>\n

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