Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-05T14:23:16.725Z Has data issue: false hasContentIssue false
  • English
  • Français

In major depression, increased kappa and mu opioid receptor levels are associated with immune activation

Published online by Cambridge University Press:  14 January 2020

Hussein Kadhem Al-Hakeim ,
Suhaer Zeki Al-Fadhel ,
Arafat Hussein Al-Dujaili  and
Michael Maes Open the ORCID record for Michael Maes [Opens in a new window]
Hussein Kadhem Al-Hakeim
Affiliation:
Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq
Suhaer Zeki Al-Fadhel
Affiliation:
Department of Clinical Laboratory Sciences, College of Pharmacy, University of Kufa, Kufa, Iraq
Arafat Hussein Al-Dujaili
Affiliation:
Faculty of Medicine, University of Kufa, Kufa, Iraq
Michael Maes*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria IMPACT Research Center, Deakin University, Geelong, Australia
*
Author for correspondence: Michael Maes, Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin – mu opioid receptor (MOR) and immune-inflammatory system.

Methods:

The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males.

Results:

Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence.

Conclusion:

Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

Keywords

depressioncytokinesneuro-immuneendorphinopioid receptor
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 2 , April 2020 , pp. 99 - 108
Copyright
© Scandinavian College of Neuropsychopharmacology 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Al-Fadhel, SZ, Al-Hakeim, HK, Al-Dujaili, AH and Maes, M (2019) IL-10 is associated with increased mu-opioid receptor levels in major depressive disorder. European Psychiatry 57, 46–51.CrossRefGoogle ScholarPubMed
Al-Hakeim, HK (2008) Serum cortisol, immunoglobulins and some complements among depressed patients. Indian Journal of Clinical Biochemistry 23, 76–80.CrossRefGoogle ScholarPubMed
Al-Hakeim, HK, Al-Kufi, SN, Al-Dujaili, AH and Maes, M (2018a) Serum interleukin levels and insulin resistance in major depressive disorder. CNS and Neurological Disorders Drug Targets 17, 626–633.CrossRefGoogle ScholarPubMed
Al-Hakeim, HK, Al-Rammahi, Da and Al-Dujaili, AH (2015) IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. Journal of Affective Disorders 182, 106–114.CrossRefGoogle ScholarPubMed
Al-Hakeim, HK, Twayej, AJ and Al-Dujaili, AH (2018b) Reduction in serum IL-1β, IL-6, and IL-18 levels and Beck Depression Inventory-II score by combined sertraline and ketoprofen administration in major depressive disorder: a clinical trial. Neurology, Psychiatry and Brain Research 30, 148–153.CrossRefGoogle Scholar
Alicea, C, Belkowski, S, Eisenstein, TK, Adler, MW and Rogers, TJ (1996) Inhibition of primary murine macrophage cytokine production in vitro following treatment with the kappa-opioid agonist U50, 488H. Journal of Neuroimmunology 64, 83–90.CrossRefGoogle ScholarPubMed
American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th Edn. text revision. Washington, DC: American Psychiatric Association.Google Scholar
Bailey, S and Husbands, S (2018) Targeting opioid receptor signalling in depression: do we need selective kappa opioid receptor antagonists? Neuronal Signaling 2, NS20170145.CrossRefGoogle Scholar
Berczi, I and Quintanar-Stephano, A. (2016). An update on neural regulators of the hypothalamic-pituitary-adrenal axis. In Istvan Berczi (ed.), Insights to Neuroimmune Biology, 2nd Edn. Cambridge, MA, Elsevier, Chapter 4, pp, 63–83.CrossRefGoogle Scholar
Bewick, V, Cheek, L and Ball, J (2004) Statistics review 13: receiver operating characteristic curves. Critical Care 8, 508–512.CrossRefGoogle ScholarPubMed
Bidlack, JM, Khimich, M, Parkhill, AL, Sumagin, S, Sun, B and Tipton, CM (2006) Opioid receptors and signaling on cells from the immune system. Journal of Neuroimmune Pharmacology 1, 260–269.CrossRefGoogle ScholarPubMed
Bilkei-Gorzo, A, Racz, I, Michel, K, Mauer, D, Zimmer, A, Klingmüller, D and Zimmer, A (2008) Control of hormonal stress reactivity by the endogenous opioid system. Psychoneuroendocrinology 33, 425–436.CrossRefGoogle ScholarPubMed
Bruchas, MR, Land, BB and Chavkin, C (2010) The dynorphin-kappa opioid system as a modulator of stress-induced and pro-addictive Behaviors. Brain Research 1314C, 44.CrossRefGoogle Scholar
Carlezon, WA and Thomas, MJ (2009) Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology 56, 122–132.CrossRefGoogle ScholarPubMed
Castilla, A, Subirà, ML, Civeira, MP, Cuende, JI and Prieto, J (1992) Monocytic dysfunction by opioid peptides in patients with major depression. Medicina Clínica (Barc) 99, 241–243.Google ScholarPubMed
Catena-Dell’osso, M, Rotella, F, Dell’osso, A, Fagiolini, A and Marazziti, D (2013) Inflammation, serotonin and major depression. Current Drug Targets 14, 571–577.CrossRefGoogle ScholarPubMed
Darko, DF, Irwin, MR, Risch, SC and Gillin, JC (1992) Plasma beta-endorphin and natural killer cell activity in major depression: a preliminary study. Psychiatry Research 43, 111–119.CrossRefGoogle ScholarPubMed
Di Chiara, G (2000) Role of dopamine in the behavioural actions of nicotine related to addiction. European Journal of Pharmacology 393, 295–314.CrossRefGoogle ScholarPubMed
Escriba, PV, Ozaita, A and García-Sevilla, JA (2004) Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of suicide victims. Neuropsychopharmacology 29, 1512–1521.CrossRefGoogle ScholarPubMed
Facchinetti, F, Petraglia, F, Sances, G, Garuti, C, Tosca, P, Nappi, G and Genazzani, AR (1986) Dissociation between CSF and plasma B-endorphin in major depressive disorders: evidence for a different regulation. Journal of Endocrinological Investigation 9, 11–14.CrossRefGoogle ScholarPubMed
Galeote, L, Berrendero, F, Bura, SA, Zimmer, A and Maldonado, R (2009) Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice. The International Journal of Neuropsychopharmacology 12, 615–625.CrossRefGoogle ScholarPubMed
Gaspersz, R, Lamers, F, Wittenberg, G, Beekman, ATF, van Hemert, AM, Schoevers, RA and Penninx, BW (2017) The role of anxious distress in immune dysregulation in patients with major depressive disorder. Translational Psychiatry 7, 1268.CrossRefGoogle ScholarPubMed
Guan, L, Eisenstein, TK, Adler, MW and Rogers, TJ (1997) Inhibition of T cell super antigen responses following treatment with the kappa-opioid agonist U50, 488H. Journal of Neuroimmunology 75, 163–168.CrossRefGoogle Scholar
Haapakoski, R, Mathieu, J, Ebmeier, Kp, Alenius, H and Kivimaki, M (2015) Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain, Behavior, and Immunity 49, 206–215.CrossRefGoogle ScholarPubMed
Hahn, B, Stolerman, Ip and Shoaib, M (2000) Kappa-opioid receptor modulation of nicotine-induced behaviour. Neuropharmacology 39, 2848–2855.CrossRefGoogle ScholarPubMed
Hurd, YL (2002) Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Molecular Psychiatry 7, 75–81.CrossRefGoogle ScholarPubMed
Iremonger, KJ and Bains, JS (2009) Retrograde opioid signaling regulates glutamatergic transmission in the hypothalamus. The Journal of Neuroscience 29, 7349–7358.CrossRefGoogle ScholarPubMed
Ismayilova, N and Shoaib, M (2010) Alteration of intravenous nicotine self-administration by opioid receptor agonist and antagonists in rats. Psychopharmacology 210, 211–220.CrossRefGoogle ScholarPubMed
Isola, R, Zhang, H, Tejwani, GA, Neff, NH and Hadjiconstantinou, M (2009) Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum. Psychopharmacology 201, 507–516.CrossRefGoogle ScholarPubMed
Jin, W, Terman, GW and Chavkin, C (1997) Kappa opioid receptor tolerance in the guinea pig hippocampus. The Journal of Pharmacology and Experimental Therapeutics 281, 123–128.Google ScholarPubMed
Kennedy, SE, Koeppe, RA, Young, EA and Zubieta, JK (2006) Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Archives of General Psychiatry 63, 1199–1208.CrossRefGoogle ScholarPubMed
Khairova, Ra, Machado-Vieira, R, Du, J and Manji, HK (2009) A potential role for proinflammatory cytokines in regulating synaptic plasticity in major depressive disorder. The International Journal of Neuropsychopharmacology 19, 1–18.Google Scholar
Knoll, AT and Carlezon, WA (2010) Dynorphin, stress, and depression. Brain Research 1314C, 56.CrossRefGoogle Scholar
Köhler, CA, Freitas, TH, Maes, M, de Andrade, NQ, Liu, CS, Fernandes, BS, Stubbs, B, Solmi, M, Veronese, N, Herrmann, N, Raison, CL, Miller, BJ, Lanctôt, KL and Carvalho, AF (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatrica Scandinavica 135, 373–387.CrossRefGoogle ScholarPubMed
Krishnadas, R and Cavanagh, J (2012) Depression: an inflammatory illness? Journal of Neurology, Neurosurgery & Psychiatry 83, 495–502.CrossRefGoogle Scholar
Lalanne, L, Ayranci, G, Kieffer, BL and Lutz, PE (2014) The kappa opioid receptor: from addiction to depression, and back. Frontiers in Psychiatry 5, 170.CrossRefGoogle Scholar
Land, BB, Bruchas, MR, Lemos, JC, Xu, M, Melief, EJ and Chavkin, C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. The Journal of Neuroscience 28, 407–414.CrossRefGoogle ScholarPubMed
Le Merrer, J, Becker, JA, Befort, K and Kieffer, BL (2009) Reward processing by the opioid system in the brain. Physiological Reviews 89, 1379–1412.CrossRefGoogle Scholar
Leonard, B and Maes, M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neuroscience & Biobehavioral Reviews 36, 764–785.CrossRefGoogle ScholarPubMed
Lesperance, F, Frasure-Smith, N, Theroux, P and Irwin, M (2004) The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. American Journal of Psychiatry 161, 271–277.CrossRefGoogle ScholarPubMed
Lim, GY, Tam, WW, Lu, Y, Ho, CS, Zhang, MW and Ho, RC (2018) Prevalence of depression in the community from 30 countries between 1994 and 2014. Scientific Reports 8, 2861.CrossRefGoogle ScholarPubMed
Ludwig, M and Leng, G (2006) Dendritic peptide release and peptide-dependent behaviours. Nature Reviews Neuroscience 7, 126–136.CrossRefGoogle ScholarPubMed
Lutz, PE and Kieffer, BL (2013) Opioid receptors: distinct roles in mood disorders. Trends in Neurosciences 36, 195–206.CrossRefGoogle ScholarPubMed
Machelska, H, Schopohl, JK, Mousa, SA, Labuz, D, Schäfer, M and Stein, C (2003) Different mechanisms of intrinsic pain inhibition in early and late inflammation. Journal of Neuroimmunology 141, 30–39.CrossRefGoogle ScholarPubMed
Maes, M, Bosmans, E, Suy, E, Minner, B and Raus, J (1991a) A further exploration of the relationships between immune parameters and the HPA-axis activity in depressed patients. Psychological Medicine 21, 313–320.CrossRefGoogle ScholarPubMed
Maes, M and Carvalho, AF (2018) The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Molecular Neurobiology 55, 8885–8903.CrossRefGoogle ScholarPubMed
Maes, M, Claes, M, Vandewoude, M, Schotte, C, Martin, M, Blockx, P and Cosyns, P (1992) Adrenocorticotropin hormone, beta-endorphin and cortisol responses to oCRF in melancholic patients. Psychological Medicine 22, 317–329.CrossRefGoogle ScholarPubMed
Maes, M, Jacobs, MP, Suy, E, Leclercq, C, Christiaens, F and Raus, J (1990) An augmented escape of beta-endorphins to suppression by dexamethasone in severely depressed patients. Journal of Affective Disorders 18, 149–156.CrossRefGoogle ScholarPubMed
Maes, M, Vandervorst, C, Suy, E, Minner, B and Raus, J (1991b) A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients. Acta Psychiatrica Scandinavica 83, 480–491.CrossRefGoogle ScholarPubMed
Mague, SD, Pliakas, AM, Todtenkopf, MS, Tomasiewicz, HC, Zhang, Y, Stevens, WC, Jr, Jones, RM, Portoghese, PS and Carlezon, WA, Jr (2003) Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. The Journal of Pharmacology and Experimental Therapeutics 305, 323–330.CrossRefGoogle ScholarPubMed
Miller, JM, Zanderigo, F, Purushothaman, PD, DeLorenzo, C, Rubin-Falcone, H, Ogden, RT, Keilp, J, Oquendo, MA, Nabulsi, N, Huang, YH, Parsey, RV, Carson, RE, Mann, JJ (2018) Kappa opioid receptor binding in major depression: a pilot study. Synapse 72, e22042.CrossRefGoogle ScholarPubMed
Morgan, El (1996) Regulation of human B lymphocyte activation by opioid peptide hormones. Inhibition of IgG production by opioid receptor class (mu-, kappa-, and delta-) selective agonists. Journal of Neuroimmunology 65, 21–30.CrossRefGoogle Scholar
Mousa, SA, Shakibaei, M, Sitte, N, Schäfer, M and Stein, C (2004) Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology 145, 1331–1341.CrossRefGoogle ScholarPubMed
Ninković, J (2013) Role of the mu opioid receptor in opioid modulation of immune function. Amino Acids 45, 9–24.CrossRefGoogle ScholarPubMed
Nummenmaa, L and Tuominen, L (2018) Opioid system and human emotions. British Journal of Pharmacology 175, 2737–2749.CrossRefGoogle ScholarPubMed
Nunes, SO, Piccoli de Melo, LG, Pizzo de Castro, MR, Barbosa, DS, Vargas, HO, Berk, M and Maes, M (2015a) Atherogenic index of plasma and atherogenic coefficient are increased in major depression and bipolar disorder, especially when comorbid with tobacco use disorder. Journal of Affective Disorders 172, 55–62.CrossRefGoogle ScholarPubMed
Nunes, SO, Vargas, HO, Brum, J, Prado, E, Vargas, MM, de Castro, MR, Dodd, S and Berk, M (2012) A comparison of inflammatory markers in depressed and nondepressed smokers. Nicotine & Tobacco Research 14, 540–546.CrossRefGoogle ScholarPubMed
Nunes, SO, Vargas, HO, Prado, E, Barbosa, DS, de Melo, LP, Moylan, S, Dodd, S and Berk, M (2013) The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence. Neuroscience & Biobehavioral Reviews 37, 1336–1345.CrossRefGoogle ScholarPubMed
Nunes, SOV, De Castro, MRP, Moreira, EG, Guembarovski, RL and Barbosa, DS (2015b) Association of paraoxonase (PON) 1 activity, glutathione S-transferase GST T1/M1 and STin. 2 polymorphisms with comorbidity of tobacco use disorder and mood disorders. Neuroscience Letters 585, 132–137.CrossRefGoogle Scholar
Pecina, M, Bohnert, ASB, Sikora, M, Avery, ET, Langenecker, SA, Mickey, BJ and Zubieta, JK (2015b) Association between placebo-activated neural systems and antidepressant responses: neurochemistry of placebo effects in major depression. JAMA Psychiatry 72, 1087–1094.CrossRefGoogle ScholarPubMed
Peciña, M, Karp, JF, Mathew, S, Todtenkopf, MS, Ehrich, EW and Zubieta, JK (2019) Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Molecular Psychiatry 24, 576–587.CrossRefGoogle ScholarPubMed
Pecina, M, Love, T, Stohler, CS, Goldman, D and Zubieta, JK (2015a) Effects of the mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures. Neuropsychopharmacology 40, 957–965.CrossRefGoogle ScholarPubMed
Pecina, M and Zubieta, JK (2018) Expectancy modulation of opioid neurotransmission. International Review of Neurobiology 138, 17–37.CrossRefGoogle ScholarPubMed
Philippe, D, Dubuquoy, L, Groux, H, Brun, V, Chuoï-Mariot, MT, Gaveriaux-Ruff, C, Colombel, JF, Kieffer, BL and Desreumaux, P (2003) Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation. Journal of Clinical Investigation 111, 1329–1338.CrossRefGoogle ScholarPubMed
Piper, ME, Piasecki, TM, Federman, EB, Bolt, DM, Smith, SS, Fiore, MC and Baker, TB (2004) A multiple motives approach to tobacco dependence: the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68). Journal of Consulting and Clinical Psychology 72, 139–154.CrossRefGoogle Scholar
Pol, O, Alameda, F and Puig, MM (2001) Inflammation enhances mu-opioid receptor transcription and expression in mice intestine. Molecular Pharmacology 60, 894–899.CrossRefGoogle ScholarPubMed
Pomerleau, OF (1998) Endogenous opioids and smoking: a review of progress and problems. Psychoneuroendocrinology 23, 115–130.CrossRefGoogle ScholarPubMed
Pomorska, DK, Gach, K and Janecka, A (2014) Immunomodulatory effects of endogenous and synthetic peptides activating opioid receptors. Mini Reviews in Medicinal Chemistry 14, 1148–1155.CrossRefGoogle ScholarPubMed
Prossin, AR, Koch, AE, Campbell, PL, McInnis, MG, Zalcman, SS and Zubieta, JK (2011) Association of plasma interleukin-18 levels with emotion regulation and μ-opioid neurotransmitter function in major depression and healthy volunteers. Biological Psychiatry 69, 808–812.CrossRefGoogle ScholarPubMed
Rahiman, SS, Morgan, M, Gray, P, Shaw, PN and Cabot, PJ (2017) Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway. Peptides 90, 48–54.CrossRefGoogle ScholarPubMed
Reyes, BA, Chavkin, C and Van Bockstaele, EJ (2009) Subcellular targeting of kappa-opioid receptors in the rat nucleus locus coeruleus. The Journal of Comparative Neurology 512, 419–431.CrossRefGoogle ScholarPubMed
Reyes, BA, Johnson, AD, Glaser, JD, Commons, KG and Van Bockstaele, EJ (2007) Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neuroscience 145, 1077–1086.CrossRefGoogle ScholarPubMed
Rittner, H, Brack, A and Stein, C (2008) Pain and the immune system. British Journal of Anaesthesia 101, 40–44.CrossRefGoogle ScholarPubMed
Rittner, HL, Machelska, H and Stein, C (2005) Leukocytes in the regulation of pain and analgesia. Journal of Leukocyte Biology 78, 1215–1222.CrossRefGoogle ScholarPubMed
Schwarzer, C (2009) 30 years of dynorphins–new insights on their functions in neuropsychiatric diseases. Pharmacology Therapeutics 123, 353–370.CrossRefGoogle ScholarPubMed
Shippenberg, TS, Lefevour, A and Chefer, VI (2008) Targeting endogenous mu- and delta-opioid receptor systems for the treatment of drug addiction. CNS & Neurological Disorders Drug Targets 7, 442–453.CrossRefGoogle ScholarPubMed
Silberstein, S, Vogl, AM, Bonfiglio, JJ, Wurst, W, Holsboer, F, Arzt, E, Deussing, JM and Refojo, D (2009) Immunology, signal transduction, and behavior in hypothalamic-pituitary-adrenal axis-related genetic mouse models. Annals of the New York Academy of Sciences 1153, 120–130.CrossRefGoogle ScholarPubMed
Snyder, SH (2004) Opiate receptors and beyond: 30 years of neural signaling research. Neuropharmacology 47, 274–285.CrossRefGoogle ScholarPubMed
Stein, C, Schäfer, M and Machelska, H (2003) Attacking pain at its source: new perspectives on opioids. Nature Medicine 9, 1003–1008.CrossRefGoogle ScholarPubMed
Stengaard-Pedersen, K and Larsson, LI (1981) Comparative immunocytochemical localization of putative opioid ligands in the central nervous system. Histochemistry 73, 89–114.CrossRefGoogle ScholarPubMed
Suzuki, S, Chuang, LF, Doi, RH, Bidlack, JM and Chuang, RY (2001) Kappa-opioid receptors on lymphocytes of a human lymphocytic cell line: morphine-induced up-regulation as evidenced by competitive RT-PCR and indirect immunofluorescence. International Immunopharmacology 1, 1733–42.CrossRefGoogle ScholarPubMed
Szabo, I, Rojavin, M, Bussiere, JL, Eisenstein, TK, Adler, MW and Rogers, TJ (1993) Suppression of peritoneal macrophage phagocytosis of Candida albicans by opioids. The Journal of Pharmacology and Experimental Therapeutics 267, 703–706.Google ScholarPubMed
Taylor, TT and Manzella, F (2016) Kappa opioids, salvinorin A and major depressive disorder. Current Neuropharmacology 14, 165–176.CrossRefGoogle ScholarPubMed
Turnbull, AV and Rivier, CL (1999) Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiological Reviews 79, 1–71.CrossRefGoogle ScholarPubMed
Young, Jj, Bruno, D and Pomara, N (2014) A review of the relationship between proinflammatory cytokines and major depressive disorder. Journal of Affective Disorders 169, 15–20.CrossRefGoogle ScholarPubMed