Increased functional coupling of the mu opioid receptor in the anterior insula of depressed individuals.
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
04
10
2020
accepted:
14
01
2021
pubmed:
4
2
2021
medline:
24
6
2021
entrez:
3
2
2021
Statut:
ppublish
Résumé
The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N = 95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.
Identifiants
pubmed: 33531622
doi: 10.1038/s41386-021-00974-y
pii: 10.1038/s41386-021-00974-y
pmc: PMC8115105
doi:
Substances chimiques
Analgesics, Opioid
0
OPRM1 protein, human
0
Receptors, Opioid, mu
0
GNAI2 protein, human
EC 3.6.5.1
GTP-Binding Protein alpha Subunit, Gi2
EC 3.6.5.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
920-927Subventions
Organisme : CIHR
ID : 201311MFE-320636-218885
Pays : Canada
Références
Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36:195–206.
doi: 10.1016/j.tins.2012.11.002
pubmed: 23219016
Nummenmaa L, Karjalainen T, Isojärvi J, Kantonen T, Tuisku J, Kaasinen V, et al. Lowered endogenous mu-opioid receptor availability in subclinical depression and anxiety. Neuropsychopharmacology. 2020. https://doi.org/10.1038/s41386-020-0725-9 .
Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–5.
pubmed: 11452128
doi: 10.1126/science.1060952
Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA, et al. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry. 2003;60:1145–53.
doi: 10.1001/archpsyc.60.11.1145
pubmed: 14609890
Kennedy SE, Koeppe RA, Young EA, Zubieta JK. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63:1199–208.
doi: 10.1001/archpsyc.63.11.1199
pubmed: 17088500
Namkung H, Kim S-H, Sawa A. The insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci. 2017;40:200–7.
pubmed: 28314446
pmcid: 5538352
doi: 10.1016/j.tins.2017.02.002
Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Wang H, et al. Response of the mu-opioid system to social rejection and acceptance. Mol Psychiatry. 2013;18:1211–7.
pubmed: 23958960
pmcid: 3814222
doi: 10.1038/mp.2013.96
Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Walker SJ, et al. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry. 2015;20:193–200.
pubmed: 25600108
pmcid: 4469367
doi: 10.1038/mp.2014.185
Spagnolo PA, Kimes A, Schwandt ML, Shokri-Kojori E, Thada S, Phillips KA, et al. Striatal dopamine release in response to morphine: a [11C]Raclopride positron emission tomography study in healthy men. Biol Psychiatry. 2019;86:356–64.
pubmed: 31097294
pmcid: 6699765
doi: 10.1016/j.biopsych.2019.03.965
Zalsman G, Molcho A, Huang Y, Dwork A, Li S, Mann JJ. Postmortem mu-opioid receptor binding in suicide victims and controls. J Neural Transm. 2005;112:949–54.
pubmed: 15937639
doi: 10.1007/s00702-004-0239-3
Meana JJ, Gonzalez-Maeso J, Garcia-Sevilla JA, Guimon J. mu-opioid receptor and alpha2-adrenoceptor agonist stimulation of [35S]GTPgammaS binding to G-proteins in postmortem brains of opioid addicts. Mol Psychiatry. 2000;5:308–15.
pubmed: 10889534
doi: 10.1038/sj.mp.4000727
Gross-Isseroff R, Dillon KA, Israeli M, Biegon A. Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res. 1990;530:312–6.
pubmed: 2176118
doi: 10.1016/0006-8993(90)91301-V
Gabilondo AM, Meana JJ, Garcia-Sevilla JA. Increased density of mu-opioid receptors in the postmortem brain of suicide victims. Brain Res. 1995;682:245–50.
pubmed: 7552322
doi: 10.1016/0006-8993(95)00333-L
Scarr E, Money TT, Pavey G, Neo J, Dean B. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study. BMC Psychiatry. 2012;12:126.
pubmed: 22925223
pmcid: 3479023
doi: 10.1186/1471-244X-12-126
Dumais A, Lesage AD, Alda M, Rouleau G, Dumont M, Chawky N, et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry. 2005;162:2116–24.
pubmed: 16263852
doi: 10.1176/appi.ajp.162.11.2116
Brent DA, Perper JA, Moritz G, Allman CJ, Roth C, Schweers J, et al. The validity of diagnoses obtained through the psychological autopsy procedure in adolescent suicide victims: use of family history. Acta Psychiatr Scand. 1993;87:118–22.
pubmed: 8447238
doi: 10.1111/j.1600-0447.1993.tb03341.x
Conner KR, Conwell Y, Duberstein PR. The validity of proxy-based data in suicide research: a study of patients 50 years of age and older who attempted suicide. II. Life events, social support and suicidal behavior. Acta Psychiatr Scand. 2001;104:452–7.
pubmed: 11782238
doi: 10.1034/j.1600-0447.2001.00091.x
Kelly TM, Mann JJ. Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr Scand. 1996;94:337–43.
pubmed: 9124080
doi: 10.1111/j.1600-0447.1996.tb09869.x
Mai JK, Paxinos G, Voss T. Atlas of the human brain. Academic Press Inc, 3rd ed. Elsevier Science. 2007.
Lutz PE, Gross JA, Dhir SK, Maussion G, Yang J, Bramoulle A, et al. Epigenetic regulation of the kappa opioid receptor by child abuse. Biol Psychiatry. 2018;84:751–61.
pubmed: 28886759
doi: 10.1016/j.biopsych.2017.07.012
Weckx S, Del-Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P, et al. novoSNP, a novel computational tool for sequence variation discovery. Genome Res. 2005;15:436–42.
pubmed: 15741513
pmcid: 551570
doi: 10.1101/gr.2754005
Gonzalez-Maeso J, Rodriguez-Puertas R, Meana JJ, Garcia-Sevilla JA, Guimon J. Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of alpha(2A)-adrenoceptors. Mol Psychiatry. 2002;7:755–67.
pubmed: 12192620
doi: 10.1038/sj.mp.4001067
Lutz PE, Tanti A, Gasecka A, Barnett-Burns S, Kim JJ, Zhou Y, et al. Association of a history of child abuse with impaired myelination in the anterior cingulate cortex: convergent epigenetic, transcriptional, and morphological evidence. Am J Psychiatry. 2017;174:1185–94.
pubmed: 28750583
doi: 10.1176/appi.ajp.2017.16111286
Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26:317–25.
pubmed: 18278033
doi: 10.1038/nbt1385
Oertel BG, Doehring A, Roskam B, Kettner M, Hackmann N, Ferreiros N, et al. Genetic-epigenetic interaction modulates mu-opioid receptor regulation. Hum Mol Genet. 2012;21:4751–60.
pubmed: 22875838
doi: 10.1093/hmg/dds314
Lutz PE, Kieffer BL. The multiple facets of opioid receptor function: implications for addiction. Curr Opin Neurobiol. 2013;23:473–9.
pubmed: 23453713
pmcid: 3702666
doi: 10.1016/j.conb.2013.02.005
Contet C, Kieffer BL, Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol. 2004;14:370–8.
pubmed: 15194118
doi: 10.1016/j.conb.2004.05.005
Xu J, Faskowitz AJ, Rossi GC, Xu M, Lu Z, Pan YX, et al. Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs. Proc Natl Acad Sci USA. 2015;112:279–84.
pubmed: 25535370
doi: 10.1073/pnas.1419183112
Verzillo V, Madia PA, Liu N-J, Chakrabarti S, Gintzler AR. Mu-opioid receptor splice variants: sex-dependent regulation by chronic morphine. J Neurochem. 2014;130:790–6.
pubmed: 24848866
pmcid: 4156545
doi: 10.1111/jnc.12768
Castelli MP, Melis M, Mameli M, Fadda P, Diaz G, Gessa GL. Chronic morphine and naltrexone fail to modify mu-opioid receptor mRNA levels in the rat brain. Brain Res Mol Brain Res. 1997;45:149–53.
pubmed: 9105683
doi: 10.1016/S0169-328X(96)00305-1
Bilbao A, Robinson JE, Heilig M, Malanga CJ, Spanagel R, Sommer WH, et al. A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol Psychiatry. 2015;77:850–8.
pubmed: 25442002
doi: 10.1016/j.biopsych.2014.08.021
Belzeaux R, Gorgievski V, Fiori LM, Lopez JP, Grenier J, Lin R, et al. GPR56/ADGRG1 is associated with response to antidepressant treatment. Nat Commun. 2020;11:1635.
pubmed: 32242018
pmcid: 7118175
doi: 10.1038/s41467-020-15423-5
Mague SD, Blendy JA. OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend. 2010;108:172–82.
pubmed: 20074870
pmcid: 2887703
doi: 10.1016/j.drugalcdep.2009.12.016
Cimino S, Carola V, Cerniglia L, Bussone S, Bevilacqua A, Tambelli R. The μ-opioid receptor gene A118G polymorphism is associated with insecure attachment in children with disruptive mood regulation disorder and their mothers. Brain Behav. 2020;10:e01659.
pubmed: 32424914
pmcid: 7375094
doi: 10.1002/brb3.1659
Troisi A, Frazzetto G, Carola V, Di Lorenzo G, Coviello M, Siracusano A, et al. Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of early maternal care on fearful attachment. Soc Cogn Affect Neurosci. 2012;7:542–7.
pubmed: 21742765
doi: 10.1093/scan/nsr037
Hancock DB, Levy JL, Gaddis NC, Glasheen C, Saccone NL, Page GP, et al. Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1. Biol Psychiatry. 2015. https://doi.org/10.1016/j.biopsych.2015.01.003 .
Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18:22–29.
pubmed: 7535487
doi: 10.1016/0166-2236(95)93946-U
Gonzalez-Maeso J, Torre I, Rodriguez-Puertas R, Garcia-Sevilla JA, Guimon J, Meana JJ. Effects of age, postmortem delay and storage time on receptor-mediated activation of G-proteins in human brain. Neuropsychopharmacology. 2002;26:468–78.
pubmed: 11927171
doi: 10.1016/S0893-133X(01)00342-6
Oertel BG, Kettner M, Scholich K, Renne C, Roskam B, Geisslinger G, et al. A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem. 2009;284:6530–5.
pubmed: 19116204
doi: 10.1074/jbc.M807030200
Wang YJ, Huang P, Blendy JA, Liu-Chen LY. Brain region- and sex-specific alterations in DAMGO-stimulated [(35) S]GTPgammaS binding in mice with Oprm1 A112G. Addict Biol. 2014;19:354–61.
pubmed: 22862850
doi: 10.1111/j.1369-1600.2012.00484.x
Escriba PV, Ozaita A, Garcia-Sevilla JA. Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of suicide victims. Neuropsychopharmacology. 2004;29:1512–21.
pubmed: 15199368
doi: 10.1038/sj.npp.1300459
Lutz PE, Courtet P, Calati R. The opioid system and the social brain: implications for depression and suicide. J Neurosci Res. 2018. https://doi.org/10.1002/jnr.24269 .
Nummenmaa L, Saanijoki T, Tuominen L, Hirvonen J, Tuulari JJ, Nuutila P, et al. mu-opioid receptor system mediates reward processing in humans. Nat Commun. 2018;9:1500.
pubmed: 29662095
pmcid: 5902580
doi: 10.1038/s41467-018-03848-y
Pecina M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0117-2 .
Eisenberger NI Social ties and health: a social neuroscience perspective. Curr Opin Neurobiol. 2013. https://doi.org/10.1016/j.conb.2013.01.006 .
Castro DC, Berridge KC. Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula. Proc Natl Acad Sci USA. 2017;114:E9125–E9134.
pubmed: 29073109
doi: 10.1073/pnas.1705753114
pmcid: 5664503
Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.
pubmed: 23942470
doi: 10.1038/nrn3381
Fava M, Thase ME, Trivedi MH, Ehrich E, Martin WF, Memisoglu A, et al. Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies. Mol Psychiatry. 2020;25:1580–91.
pubmed: 30374191
doi: 10.1038/s41380-018-0284-1
Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491–8.
pubmed: 26684923
doi: 10.1176/appi.ajp.2015.15040535