Understanding the Potential Role of the Endogenous Opioid System in MDD

Stephen M. Stahl, MD, PhD, discusses current insights into the neurobiology of mood, reward, and emotion.

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THE OPIOID SYSTEM IN MDD

A dysfunctional opioid system may be linked to MDD

Both animal models and human studies suggest that the endogenous opioid system is involved in mood regulation.1,2

In a human study, PET scans compared opioid system activity in healthy controls vs patients with MDD in response to social rejection.2

In healthy controls, the negative emotional stimuli activated the endogenous opioid system in key brain regions involved in regulating mood.

In patients with MDD, the endogenous opioid system showed significantly less activation, indicating impaired function of this system.

Overall, these studies suggest that the opioid system must be functioning properly to maintain normal mood regulation.1,2

Key roles of the opioid receptors in regulating behavioral traits affected by MDD

Opioid receptors are generally believed to play a role in the expression of mood, emotion, reward, and motivation. Agonism or antagonism of the different opioid receptors may lead to varying behavioral and/or physiological outcomes.1,7,8-11

  • Mu (μ-) opioid receptors: Mu receptors are known for their role in reward and analgesia. Agonism (activation) of these receptors is associated with improved mood, or what is considered antidepressant activity. Overstimulation can be associated with substance use disorder1,7
  • Kappa (κ-) opioid receptors: In contrast to mu and delta, agonism of kappa receptors is associated with dysphoria, or prodepressive activity. However, antagonism (inhibition) of these receptors is associated with a return to normal mood, or antidepressant-like activity8-10
  • Delta (δ-) opioid receptors: Similar to mu, agonism is linked to improved mood and antidepressant-like activity11
Achieving an antidepressant effect through modulation of the endogenous system may involve the balance and modulation of multiple receptors.1
  • Prefrontal cortex: Contains varying levels of all 3 opioid receptors, with high delta concentrations. Associated with apathy, punishment sensitivity, anxiety, tension, and rumination1,12
  • Limbic structures: Limbic structures: High concentration of mu and kappa. Associated with mood and emotional regulation13
  • Brain stem: High mu receptor concentrations. Along with nucleus accumbens, associated with reward and motivation1,13,14
  • Nucleus accumbens: High concentrations of all receptors. With brain stem, associated with reward and motivation1,13,14

References: 1. Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195–206. 2. Hsu DT, Sanford BJ, Meyers KK, 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(2):193–200. 3. Arida RM, da Silva SG, de Almeida AA, et al. Differential effects of exercise on brain opioid receptor binding and activation in rats. J Neurochem. 2015;132(2):206–217. 4. Sharon H, Maron-Katz A, Ben Simon E, et al. Mindfulness meditation modulates pain through endogenous opioids. Am J Med. 2016;129(7):755–758. 5. Dunbar RIM, Baron R, Frangou A, et al. Social laughter is correlated with an elevated pain threshold. Proc Biol Sci. 2012;279(1731):1161–1167. 6. Tarr B, Launay J, Dunbar RI. Music and social bonding: "self-other" merging and neurohormonal mechanisms. Front Psychol. 2014;5:1096. 7. Stahl SM. Stahl's Essential Psychopharmacology Online. 2008. http://stahlonline.cambridge.org/essential_4th.jsf. Accessed September 26, 2018. 8. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774–776. 9. Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res. 1995;681(1-2):147–152. 10. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305(1):323–330. 11. Filliol D, Ghozland S, Chluba J, et al. Mice deficient for δ- and µ-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet. 2000;25(2):195–200. 12. Willner P, Scheel-Krüger J, Belzung C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev. 2013;37(10 pt 1):2331-2371. 13. Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology. 2012;79(12):807–814. 14. Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59(12):1151-1159.

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