Watch a video on evolving theories in MDD pathophysiology and patient management.

THE OPIOID SYSTEM: A KEY TO
ADVANCING UNDERSTANDING OF MDD

Jon-Kar Zubieta, MD, PhD, discusses the potential role of the endogenous opioid system in MDD.

THE OPIOID SYSTEM IN MDD

A dysfunctional opioid system may be linked to depression

THE OPIOID SYSTEM IN MDD

A dysfunctional opioid system may be linked to depression

The core symptoms of major depressive disorder (MDD) are depressed mood and lack of interest or pleasure in normal activities.1 Evidence suggests that key areas of the brain, including the prefrontal cortex and the limbic areas, are involved in the processing of emotion, mood, and reward. Anatomical studies have shown that neurons containing endogenous opioids provide input to most of these key brain areas.2,3

A study of PET scans from 89 healthy volunteers showed that the location of opioid system receptors overlaps with brain regions responsible for emotional processing.4

Overlap between the human emotion circuit and the opioid receptors in the brain4
image of PET scans showing mu opioid receptor in the brain

Distribution of mu opioid receptors in the brain.

image of PET scans showing the overlap between the human emotion circuit

Brain regions known to be involved in emotional experience and perception.

Reproduced with permission from Nummenmaa and Tuominen.

FDR, false discovery rate.

Watch a video on evolving theories in MDD pathophysiology and patient management.

THE OPIOID SYSTEM: A KEY TO ADVANCING UNDERSTANDING OF MDD

Jon-Kar Zubieta, MD, PhD, discusses the potential role of the endogenous opioid system in MDD.

The possible link between MDD and the endogenous opioid system

Both animal models and human studies suggest that the endogenous opioid system is involved in mood regulation.5,6

  • Research in rodents with genetically modified opioid receptors revealed changes in behavioral models of depressive and anxious states5
  • In a human study, patients with MDD showed reduced opioid-receptor activity in response to negative emotional stimuli indicating impaired system function vs healthy controls6

Overall, these studies suggest that the opioid system must be functioning properly to maintain normal mood regulation.5,6

A deeper dive into the biology of the opioid system

The endogenous opioid system is a natural neurotransmitter system in your brain. In fact, you may be familiar with the endogenous opioid neurotransmitter, endorphin. Changes in endorphin levels have been associated with natural stimuli and experiences, such as exercise, meditation, laughter, and music.5,7-10 Looking in greater detail, the endogenous opioid system actually includes 3 different peptide neurotransmitters—beta endorphin, enkephalin, and dynorphin—and 3 receptor types—the mu, delta, and kappa opioid receptors. Each of these receptors is involved in mood regulation as well as other wider functions.2,5

Opioid receptors are involved in mood regulation

  • Mu (μ-) opioid receptors: These receptors are known for their role in reward and analgesia. Overstimulation of these receptors can be associated with addiction. However, these receptors are intricately involved in mood regulation. Agonism, or activation, of these receptors is associated with improved mood, or what is considered antidepressant-like activity2,5
  • Delta (δ-) opioid receptors: Similar to mu opioid receptors, agonism of these receptors is linked to improved mood and antidepressant-like activity11
  • Kappa (κ-) opioid receptors: In contrast to the mu and delta receptors, agonism of the kappa receptors is associated with dysphoria, or prodepressive activity. However, antagonism, or inhibition of these receptors, is associated with a return to normal mood, or antidepressant-like activity12-14
Achieving an antidepressant effect through modulation of the endogenous system may involve the appropriate balance and modulation of these multiple receptors.5
Image of the opioid receptors involved in mood regulation.

Opioid receptors are involved in mood regulation

  • Mu (μ-) opioid receptors: These receptors are known for their role in reward and analgesia. Overstimulation of these receptors can be associated with addiction. However, these receptors are intricately involved in mood regulation. Agonism, or activation, of these receptors is associated with improved mood, or what is considered antidepressant-like activity2,5
  • Delta (δ-) opioid receptors: Similar to mu opioid receptors, agonism of these receptors is linked to improved mood and antidepressant-like activity11
  • Kappa (κ-) opioid receptors: In contrast to the mu and delta receptors, agonism of the kappa receptors is associated with dysphoria, or prodepressive activity. However, antagonism, or inhibition of these receptors, is associated with a return to normal mood, or antidepressant-like activity12-14
Achieving an antidepressant effect through modulation of the endogenous system may involve the appropriate balance and modulation of these multiple receptors.5
Learn about the potential role of the endogenous opioid system in MDD. WATCH THE VIDEO
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References: 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. 2. Stahl SM. Stahl's Essential Psychopharmacology Online. 2008. http://stahlonline.cambridge.org/essential_4th.jsf. Accessed July 7, 2017. 3. Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology. 2012;79(12):807-814. 4. Nummenmaa L, Tuominen L. Opioid system and human emotions [published online April 10, 2017]. Br J Pharmacol. 2017. 5. Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206. 6. 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. 7. 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. 8. 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. 9. 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. 10. Tarr B, Launay J, Dunbar RI. Music and social bonding: "self-other" merging and neurohormonal mechanisms. Front Psychol. 2014;5:1096. 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. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774-776. 13. 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. 14. 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.

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