scholarly journals On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2473 ◽  
Author(s):  
Susanna Fürst ◽  
Zoltán S. Zádori ◽  
Ferenc Zádor ◽  
Kornél Király ◽  
Mihály Balogh ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Molecular Mechanisms ◽  
Opioid Analgesic ◽  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Analgesic Tolerance ◽  
Peripheral Analgesia ◽  
Peripheral Opioid Receptors ◽  
Peripheral Sensory

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

scholarly journals Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway

2018 ◽  
Vol 115 (9) ◽  
pp. E2085-E2094 ◽  
Author(s):  
Sevasti Gaspari ◽  
Immanuel Purushothaman ◽  
Valeria Cogliani ◽  
Farhana Sakloth ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Protein Signaling ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Biochemical Assays ◽  
Morphine Administration ◽  
Promising Target

Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/β-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2–Gαz complexes near the membrane and promotes β-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gαz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction.

scholarly journals Combination Opioid Analgesics

2008 ◽  
Vol 2;11 (3;2) ◽  
pp. 201-214
Author(s):  
Howard Smith
Keyword(s):  
Adverse Effects ◽  
Opioid Analgesic ◽  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Active Metabolites ◽  
Analgesic Tolerance ◽  
Key Words Pain ◽  
Long Duration ◽  
Wide Range ◽  
Opioid Induced Hyperalgesia

Although there is no “ideal analgesic,” scientists and clinicians alike continue to search for compounds with qualities which may approach the “ideal analgesic.” Characteristics of an “ideal” analgesic may include: the agent is a full agonist providing optimal/maximal analgesia for a wide range/variety of pain states (e.g., broad spectrum analgesic activity), it does not exhibit tolerance, it produces no unwanted effects and minimal adverse effects, it has no addictive potential, it does not facilitate pain/hyperalgesia, it has a long duration, it has high oral bioavailability, it is not vulnerable to important drug interactions, it is not significantly bound to plasma proteins, it has no active metabolites, it has linear kinetics, and it is eliminated partly by hydrolysis to an inactive metabolite (without involvement of oxidative and conjugative enzymes). Investigators have concentrated on ways to alter existing analgesics or to combine existing analgesic compounds with compounds which may improve efficacy over time or minimize adverse effects. The addition of an analgesic with a second agent (which may or may not also be an analgesic) to achieve a “combination analgesic” is a concept which has been exploited for many years. Although there may be many reasons to add 2 agents together in efforts to achieve analgesia, for purposes of this article — reasons for combining an opioid with a second agent to produce a combination opioid analgesic may be classified into 6 major categories: 1.) combinations to prolong analgesic duration; 2.) combinations to enhance or optimize analgesic efficacy (e.g., analgesic synergy); 3.) combinations to diminish or minimize adverse effects; 4.) combinations to diminish opioid effects which are not beneficial (or contrariwise to or enhance beneficial opioid effects); 5.) combinations to reduce opioid tolerance/opioid-induced hyperalgesia; and 6.) combinations to combat dependency issues/addiction potential/craving sensations. Combination opioid analgesics are one avenue which may give rise to “pain pills” with improved analgesic profiles over existing analgesic medications. Key words: Pain, combination opioid analgesic, tolerance, opioid-induced hyperalgesia

The role of peripheral opioid receptors in orofacial pain

Oral Diseases ◽  
2020 ◽  
Author(s):  
Qing Liu ◽  
Wenguo Fan ◽  
Hongwen He ◽  
Fang Huang
Keyword(s):  
Opioid Receptors ◽  
Orofacial Pain ◽  
Peripheral Opioid Receptors

Morphine initiates migrating myoelectric complexes by acting on peripheral opioid receptors

1985 ◽  
Vol 249 (5) ◽  
pp. G557-G562 ◽  
Author(s):  
G. L. Telford ◽  
M. Hoshmonai ◽  
A. J. Moses ◽  
J. H. Szurszewski
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Silver Chloride ◽  
Phase Iii ◽  
Opioid Receptor Antagonists ◽  
Peripheral Opioid Receptors ◽  
Silver Silver ◽  
Silver Silver Chloride ◽  
Higher Doses

The role of peripheral and central opioid receptors in morphine-induced migrating myoelectric complexes (MMECs) was studied in conscious dogs implanted with silver-silver chloride electrodes. In normal fasted dogs morphine (100-200 micrograms/kg iv) initiated phase III of the MMEC in the duodenum. Once initiated the MMEC propagated distally. This effect of morphine was blocked by the opioid receptor antagonists naloxone (2 mg/kg iv) and N,N-diallylnormorphinium bromide (4 mg/kg iv). Higher doses of morphine (300-600 micrograms/kg iv) initiated phase III activity in fed dogs as early as 20 min after feeding, while lower doses (150 micrograms/kg iv) initiated phase III activity routinely when administered 100 min after feeding. In dogs with bilateral vagotomies and bilateral thoracolumbar sympathetic chain ganglionectomies, morphine (150 micrograms/kg iv) initiated phase III activity in the duodenum, which then migrated distally. This study demonstrates that morphine initiates phase III of the MMEC by acting through peripheral opioid receptors.

scholarly journals The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David Perekopskiy ◽  
Anum Afzal ◽  
Shelley N. Jackson ◽  
Ludovic Muller ◽  
Amina S. Woods ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Brain Hypoxia ◽  
Peripheral Opioid Receptors

Role of central versus peripheral opioid receptors in analgesia induced by repeated administration of opioid antagonists

1991 ◽  
Vol 104 (2) ◽  
pp. 164-166 ◽  
Author(s):  
M. J. Katharine Walker ◽  
A. D. Lê ◽  
Constantine X. Poulos ◽  
Howard Cappell
Keyword(s):  
Opioid Receptors ◽  
Repeated Administration ◽  
Opioid Antagonists ◽  
Peripheral Opioid Receptors

scholarly journals GRKs as Key Modulators of Opioid Receptor Function

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2400
Author(s):  
Laura Lemel ◽  
J Robert Lane ◽  
Meritxell Canals
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Analgesics ◽  
Mu Opioid ◽  
Protein Receptor ◽  
The Family ◽  
Receptor Kinases ◽  
Induced Tolerance ◽  
Shed Light

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mechanisms responsible for opioid-induced tolerance and addiction. The family of G protein receptor kinases (GRKs) play a pivotal role in such processes, mediating phosphorylation of residues at the C-tail of opioid receptors. Numerous strategies, such as phosphosite specific antibodies and mass spectrometry have allowed the detection of phosphorylated residues and the use of mutant knock-in mice have shed light on the role of GRK regulation in opioid receptor physiology. Here we review our current understanding on the role of GRKs in the actions of opioid receptors, with a particular focus on the MOR, the target of most commonly used opioid analgesics such as morphine or fentanyl.

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