Endogenous and Exogenous Opioids in Pain

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Abstract

<p class="first" id="P1">Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience. </p>

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Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

Aashish Manglik, Andrew C. Kruse, Tong Kobilka … (2012)

Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

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Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.

A I Basbaum, H L Fields (1984)

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A Circuit Mechanism for Differentiating Positive and Negative Associations

Praneeth Namburi, Anna Beyeler, Suzuko Yorozu … (2015)

The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive 1,2 and negative 3–7 . Different populations of BLA neurons may encode fearful or rewarding associations 8–10 , but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained an enigma. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) underwent opposing synaptic changes following fear or reward conditioning. We found that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impaired fear conditioning and enhanced reward conditioning. We then characterized these functionally-distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. We provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

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Author and article information

Journal

Title: Annual Review of Neuroscience

Abbreviated Title: Annu. Rev. Neurosci.

Publisher: Annual Reviews

ISSN (Print): 0147-006X

ISSN (Electronic): 1545-4126

Publication date Created: July 08 2018

Publication date (Print): July 08 2018

Volume: 41

Issue: 1

Pages: 453-473

Affiliations

[1 ]Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California 94304, USA;

[2 ]Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, California 94304, USA

[3 ]Department of Neurosurgery, Stanford University, Palo Alto, California 94304, USA

[4 ]Stanford Neurosciences Institute, Palo Alto, California 94304, USA

[5 ]Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63130, USA;

[6 ]Division of Basic Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63130, USA

[7 ]Washington University Pain Center, Washington University School of Medicine, St. Louis, Missouri 63130, USA

[8 ]Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63130, USA

[9 ]Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA

[10 ]New York Stem Cell Foundation – Robertson Investigator, Stanford University, Palo Alto, California 94304, USA

Article

DOI: 10.1146/annurev-neuro-080317-061522

PMC ID: 6428583

PubMed ID: 29852083

SO-VID: e8d24199-ad58-49bd-9aac-4ca06b14facc

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