Endogenous Opioids at the Intersection of Opioid Addiction, Pain, and Depression: The Search for a Precision Medicine Approach

Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differences in endogenous opioid neurobiology and its contribution to opioid addiction susceptibility.

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Reward Processing by the Opioid System in the Brain

Physiological Reviews ◽

10.1152/physrev.00005.2009 ◽

2009 ◽

Vol 89 (4) ◽

pp. 1379-1412 ◽

Cited By ~ 480

Author(s):

Julie Le Merrer ◽

Jérôme A. J. Becker ◽

Katia Befort ◽

Brigitte L. Kieffer

Keyword(s):

Opioid Peptides ◽

Drugs Of Abuse ◽

Gene Knockout ◽

Reward Processing ◽

Endogenous Opioids ◽

Therapeutic Interventions ◽

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid ◽

Addictive Disorders

The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.

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Borderline personality disorder - a dysregulation of the endogenous opioid system?

European Psychiatry ◽

10.1016/s0924-9338(11)72713-4 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 1008-1008

Author(s):

B. Bandelow ◽

C. Schmahl ◽

P. Falkai ◽

D. Wedekind

Keyword(s):

Borderline Personality Disorder ◽

Personality Disorder ◽

Opioid Receptors ◽

Borderline Personality ◽

Endogenous Opioids ◽

The Body ◽

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid ◽

Self Injury

The neurobiology of borderline personality disorder (BPD) remains unclear. Dysfunctions of several neurobiological systems have been discussed, including serotoninergic, dopaminergic, and other neurotransmitter systems.Here we present a theory that alterations in the sensitivity of opioid receptors or the availability of endogenous opioids constitute part of the underlying pathophysiology of BPD.1 The alarming symptoms and self-destructive behaviors of the affected patients may be explained by uncontrollable and unconscious attempts to stimulate their endogenous opioid system (EOS) and the dopaminergic reward system, regardless of the possible harmful consequences. Neurobiological findings that support this hypothesis are reviewed: Frantic efforts to avoid abandonment, frequent and risky sexual contacts, and attention-seeking behavior may be explained by attempts to make use of the rewarding effects of human attachment mediated by the EOS. Anhedonia and feelings of emptiness may be an expression of reduced activity of the EOS. Patients with BPD tend to abuse substances that target μ-opioid receptors. Self-injury, food-restriction, aggressive behavior, and sensation-seeking may be interpreted as a desperate attempt to artificially set the body to “survival mode”, in order to mobilize the last reserves of the EOS. BPD-associated symptoms, such as substance abuse, anorexia, self-injury, depersonalization, and sexual overstimulation, can be treated successfully with μ-opioid receptor antagonists.An understanding of the neurobiology of BPD may help in developing new treatments for patients with this severe disorder.

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MODULATION BY CCK-B RECEPTORS OF THE ANTINOCICEPTIVE AND REWARDING PROPERTIES INDUCED BY THE ENDOGENOUS OPIOID SYSTEM

Analgesia ◽

10.3727/107156995819562835 ◽

1995 ◽

Vol 1 (4) ◽

pp. 809-812

Author(s):

O. Valverde ◽

M.-C. Fournié-Zaluski ◽

B. P. Roques ◽

R. Maldonado

Keyword(s):

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid

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Nicotine Effects and the Endogenous Opioid System

Journal of Pharmacological Sciences ◽

10.1254/jphs.14r03cp ◽

2014 ◽

Vol 125 (2) ◽

pp. 117-124 ◽

Cited By ~ 28

Author(s):

Shiroh Kishioka ◽

Norikazu Kiguchi ◽

Yuka Kobayashi ◽

Fumihiro Saika

Keyword(s):

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid

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The Roles of Endogenous Opioid System in the Antidepressant Actions of Ketamine

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.956 ◽

2021 ◽

Vol 89 (9) ◽

pp. S385

Author(s):

Cheng Jiang ◽

Ralph DiLeone ◽

Christopher Pittenger ◽

Ronald Duman

Keyword(s):

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid

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Role of the endogenous opioid system in the analgesic effect of ?-tocopherol in dysmenorrhea

Bulletin of Experimental Biology and Medicine ◽

10.1007/bf00835681 ◽

1988 ◽

Vol 105 (2) ◽

pp. 162-164 ◽

Cited By ~ 2

Author(s):

G. N. Kryzhanovskii ◽

L. P. Bakuleva ◽

N. L. Luzina ◽

V. A. Vinogradov ◽

K. N. Yarygin ◽

...

Keyword(s):

Analgesic Effect ◽

Opioid System ◽

Endogenous Opioid System ◽

Endogenous Opioid

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Modulation of the endogenous opioid system after morphine self-administration and during its extinction: A study in Lewis and Fischer 344 rats

Neuropharmacology ◽

10.1016/j.neuropharm.2006.10.011 ◽

2007 ◽

Vol 52 (3) ◽

pp. 931-948 ◽

Cited By ~ 36

Author(s):

Pilar Sánchez-Cardoso ◽

Alejandro Higuera-Matas ◽

Sonsoles Martín ◽

Nuria del Olmo ◽

Miguel Miguéns ◽

...

Keyword(s):

Opioid System ◽

Fischer 344 Rats ◽

Endogenous Opioid System ◽

Self Administration ◽

Endogenous Opioid ◽

Fischer 344

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Endogenous opioid system in developing normal and jimpy oligodendrocytes: ? and ? opioid receptors mediate differential mitogenic and growth responses

Glia ◽

10.1002/(sici)1098-1136(199802)22:2<189::aid-glia10>3.0.co;2-u ◽

1998 ◽

Vol 22 (2) ◽

pp. 189-201 ◽

Cited By ~ 58

Author(s):

Pamela E. Knapp ◽

Katalin Maderspach ◽

Kurt F. Hauser

Keyword(s):

Opioid Receptors ◽

Opioid System ◽

Growth Responses ◽

Endogenous Opioid System ◽

Endogenous Opioid

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Interleukin-6 is differently modulated by central opioid receptor subtypes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.3.r956 ◽

1997 ◽

Vol 273 (3) ◽

pp. R956-R959 ◽

Cited By ~ 1

Author(s):

M. Bertolucci ◽

C. Perego ◽

M. G. De Simoni

Keyword(s):

Opioid Receptor ◽

Fine Tuning ◽

Opioid System ◽

Receptor Subtypes ◽

Receptor Blockade ◽

Endogenous Opioid System ◽

Endogenous Opioid ◽

General Role ◽

Opioid Receptor Subtypes ◽

Mu Antagonist

The central endogenous opioid system is involved in the modulation of interleukin (IL)-6, an inflammatory cytokine that plays a major role in the acute phase response. The present study evaluates whether specific opioid receptor subtypes are selectively involved in this immunomodulatory action. IL-1 beta was administered either intracerebroventricularly or intraperitoneally at the dose of 400 ng to rats pretreated with the mu-antagonist beta-funaltrexamine, the delta-antagonist naltrindole, or the kappa-antagonist nor-binaltorphimine, each at the doses of 1, 10, and 100 micrograms/rat intracerebroventricularly. Serum IL-6 levels were measured 2 h later. The results show that mu-receptor blockade increases, whereas delta-receptor blockade decreases IL-6 induction, suggesting that the fine tuning exerted by opioids on the immune system may be achieved through a balance of opposing effects. Moreover the three antagonists affect IL-6 induction by central and peripheral IL-1 beta with a similar pattern, indicating that the brain endogenous opioid system plays a general role in the regulation of this cytokine.

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