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.1-5

In a human study, PET scans compared opioid system activity in healthy controls vs patients with MDD in response to social rejection.5

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.1-5

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.1-4,9,10

  • 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 disorder5,10,13-15
  • 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 activity4,12,16
  • Delta (δ-) opioid receptors: Similar to mu, agonism is linked to improved mood and antidepressant-like activity2,3
Achieving an antidepressant effect through modulation of the endogenous system may involve the balance and modulation of multiple receptors.1-4,17
  • Prefrontal cortex: Contains varying levels of all 3 opioid receptors, with high delta concentrations. Associated with apathy, punishment sensitivity, anxiety, and rumination17-22
  • Hypothalamus: High concentration of kappa. Associated with mood regulation10,17,18
  • Brain stem: High mu receptor concentrations. Along with nucleus accumbens, associated with reward and motivation10,17,18
  • Nucleus accumbens: High concentrations of all receptors. With brain stem, associated with reward and motivation17,18,23

References: 1. Filliol D, Ghozland S, Chluba J, et al. Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses. Nat Gen. 2000;25(2):195-200. 2. Peppin JF, Raffa RB. Delta opioid agonists: a concise update on potential therapeutic applications. J Clin Pharm Ther. 2015;40(2):155-166. 3. Jutkiewicz EM, Rice KC, Traynor JR, Woods JH. Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats. Psychopharmacology (Berl). 2005;182(4):588-596. 4. 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. 5. 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. 6. Saanijoki T, Tuominen L, Tuulari JJ, et al. Opioid release after high-intensity interval training in healthy human subjects. Neuropsychopharmacology. 2018;43(2):246-254. 7. Sharon H, Maron-Katz A, Simon EB, et al. Mindfulness meditation modulates pain through endogenous opioids. Am J Med. 2016;129(7):755-758. 8. Dunbar RI, Baron R, Frangou A, et al. Social laughter is correlated with an elevated pain threshold. Proc Biol Sci. 2012;279(1731):1161-1167. 9. Manninen S, Tuominen L, Dunbar RI, et al. Social laughter triggers endogenous opioid release in humans. J Neurosci. 2017;37(25):6125-6131. 10. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013. 11. Nguyen AT, Marquez P, Hamid A, et al. The rewarding action of acute cocaine is reduced in β-endorphin deficient but not in μ opioid receptor knockout mice. Eur J Pharmacol. 2012;686(1-3):50-54. 12. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774-776. 13. Zubieta J-K, Ketter TA, Bueller JA, et al. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry. 2003;60(11):1145-1153. 14. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Anatomy of CNS opioid receptors. Trends Neurosci. 1988;11(7):308-314. 15. Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18(1):22-29. 16. 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. 17. Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206. 18. George SR, Zastawny RL, Briones-Urbina R, et al. Distinct distributions of mu, delta and kappa opioid receptor mRNA in rat brain. Biochem Biophys Res Commun. 1994;205(2):1438-1444. 19. Fazio L, Logroscino G, Taurisano P, et al. Prefrontal activity and connectivity with the basal ganglia during performance of complex cognitive tasks is associated with apathy in healthy subjects. PLoS One. 2016;11(10):e0165301. doi: 10.1371/journal.pone.0165301. 20. Monosov IE, Hikosaka O. Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex. J Neurosci. 2012;32(30):10318-10330. 21. Bishop SJ. Trait anxiety and impoverished prefrontal control of attention. Nat Neurosci. 2009;12(1):92-98. 22. Cooney RE, Joormann J, Eugène F, Dennis EL, Gotlib IH. Neural correlates of rumination in depression. Cogn Affect Behav Neurosci. 2010;10(4):470-478. 23. Routtenberg A, Malsbury C. Brainstem pathways of reward. J Comp Physiol Psychol. 1969;68(1):22-30.

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