Endogenous opioid systems alterations in pain and opioid use disorder

Abstract

Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids—primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies.

Modulation of endogenous opioid signaling by inhibitors of puromycin sensitive aminopeptidase

“…We thus incorporated a larger hydrophobic character in our design of new analogs. Synthesis of this series of compounds with 5′-hydroxy substituent was accomplished by coupling of PAN (7) with the appropriate N-Boc protected amino acids (11) (Scheme 2) [26]. Deprotection of N-Boc was achieved by anhydrous trifluoroacetic acid (TFA).…”

“…These opioid peptides share a common N -terminal sequence, Tyr-Gly-Gly-Phe-(Met/Leu), referred to as the “opioid motif.” The presence of Tyr and Phe is necessary for binding to the opioid receptors. Apart from their role in neuropsychiatric conditions, analgesia, and learning, they modulate respiration, blood pressure, embryonic development, angiogenesis, wound repair, and hepatoprotective mechanisms [7]. PENK knockout mice characterized previously by Konig et al displayed hyperalgesia in response to painful stimuli, supporting the importance of these peptides in pain perception [12].…”

“…Attempts to disconnect undesirable effects of opioids from their potent pain-relieving properties have been mostly unsuccessful. One approach to reduce or eliminate opioid use altogether is by harnessing the body’s own ability to block pain, which is imparted by endogenous pain-relieving neuropeptides, but with regulation of reward-related behaviors [7, 8]. Among the opioid neuropeptides, enkephalins are known to modulate pain through MOR (µ-opioid receptor) and DOR (δ-opioid receptor), with slightly greater affinity for DOR [9].…”

Synthesis, characterization and evaluation of anti‐hyperalgesia, anticonvulsant and antioxidant activity of novel VV‐hemorphin‐5 analogs

“…[7,28] The opioid system is a member of the endogenous pain-controlling machinery that includes four major types of opioid receptors (OR): mu-OR with high affinity for β-endorphins, delta-OR for dynorphins, kappa-OR for enkephalins, and nociception/orphanin FQ receptor, as the latter is not considered "classical" opioid receptor, arguing with the lack of sensitivity to opioid ligands like naloxone. [29] Despite some receptor type selectivity, most endogenous and exogenous opioid ligands also have some affinity for all OR types. [30] ORs are involved in processing pain transmission at different levels, from the peripheral nerve endings through the spinal cord to higher subcortical and cortical centers responsible for the emotional experience and localization of pain.…”

Managing Opioid Withdrawal Symptoms During the Fentanyl Crisis: A Review

“…The endogenous opioid receptor system consists of four primary G-protein coupled receptors, including mu, delta, kappa, and opioid receptor-like 1. 5 Opioid receptors exist throughout the nervous system and are expressed by most major organs. 6 Both endogenous and exogenous ligands interact with these receptors.…”