ReviewCellular and molecular neurobiology2021
Synthesis of the Mechanisms of Opioid Tolerance: Do We Still Say NO?
Review in Cellular and molecular neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- Modulatory effect of opioid administration on the activity of cholinesterase enzyme: a systematic review of mice/rat models.Environmental science and pollution research international · 2021Pooled it
- Preventive effects of crocin and meloxicam on morphine withdrawal symptoms in mice: behavioral and biochemical insights.BMC pharmacology & toxicology · 2025Article
- Benefits ofInternational journal of molecular sciences · 2025Article
- Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine.International journal of molecular sciences · 2024Article
- Opioid system and related ligands: from the past to future perspectives.Journal of anesthesia, analgesia and critical care · 2024Review
- Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance.Biomedicines · 2024Review
- The epigenetic signatures of opioid addiction and physical dependence are prevented by D-cysteine ethyl ester and betaine.Frontiers in pharmacology · 2024Article
- A Guide to Expanding the Use of Buprenorphine Beyond Standard Initiations for Opioid Use Disorder.Drugs in R&D · 2023Review
- Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance.Pharmaceuticals (Basel, Switzerland) · 2023Review
- L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.Frontiers in pharmacology · 2023Article
- Adeno-associated virus-mediated gene transfer of arginine decarboxylase to the central nervous system prevents opioid analgesic tolerance.Frontiers in pain research (Lausanne, Switzerland) · 2023Article
- Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats.Frontiers in pharmacology · 2023Article
- Identification and characterization of N6-methyladenosine circular RNAs in the spinal cord of morphine-tolerant rats.Frontiers in neuroscience · 2022Article
- Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak.Cellular and molecular neurobiology · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The use of morphine as a first-line agent for moderate-to-severe pain is limited by the development of analgesic tolerance. Initially opioid receptor desensitization in response to repeated stimulation, thought to underpin the establishment of tolerance, was linked to a compensatory increase in adenylate cyclase responsiveness. The subsequent demonstration of cross-talk between N-methyl-D-aspartate (NMDA) glutamate receptors and opioid receptors led to the recognition of a role for nitric oxide (NO), wherein blockade of NO synthesis could prevent tolerance developing. Investigations of the link between NO levels and opioid receptor desensitization implicated a number of events including kinase recruitment and peroxynitrite-mediated protein regulation. Recent experimental advances and the identification of new cellular constituents have expanded the potential signaling candidates to include unexpected, intermediary compounds not previously linked to this process such as zinc, histidine triad nucleotide-binding protein 1 (HINT1), micro-ribonucleic acid (mi-RNA) and regulator of G protein signaling Z (RGSZ). A further complication is a lack of consistency in the protocols used to create tolerance, with some using acute methods measured in minutes to hours and others using days. There is also an emphasis on the cellular changes that are extant only after tolerance has been established. Although a review of the literature demonstrates a lack of spatio-temporal detail, there still appears to be a pivotal role for nitric oxide, as well as both intracellular and intercellular cross-talk. The use of more consistent approaches to verify these underlying mechanism(s) could provide an avenue for targeted drug development to rescue opioid efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.