ArticleThe Journal of clinical investigation2008
Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04213196 (A Phase I Clinical Study Evaluating the Safety, Tolerability and Pharmacokinetics of HSK21542 in Healthy Volunteers), which is not on this map. Cited by 59 papers.
What it found
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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.
A Phase I Clinical Study Evaluating the Safety, Tolerability and Pharmacokinetics of HSK21542 in Healthy Volunteers
Who cites it
59 citing papers in PubMed, 129 citations in OpenAlex.
- HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials.Nature communications · 2025Trial
- Blockade of intra-articular adrenergic receptors increases analgesic demands for pain relief after knee surgery.Rheumatology international · 2011Trial
- Article
- Mu-opioid receptor expression on B cells as a potential biomarker for chronic pain: a follow-up study with patients with fibromyalgia.Pain reports · 2025Article
- A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.British journal of pharmacology · 2025Article
- Ferroptosis inhibitor ferrostatin-1 attenuates morphine tolerance development in male rats by inhibiting dorsal root ganglion neuronal ferroptosis.The Korean journal of pain · 2024Article
- A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy.Annual review of physiology · 2024Review
- Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model.Nature communications · 2023Article
- Overexpression of GDNF in Spinal Cord Attenuates Morphine Analgesic Tolerance in Rats with Bone Cancer Pain.Brain sciences · 2022Article
- Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis.Journal of neuroinflammation · 2022Article
- Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- Recent Advances in Peripheral Opioid Receptor Therapeutics.Current pain and headache reports · 2021Review
- Pharmacological Chaperones Attenuate the Development of Opioid Tolerance.International journal of molecular sciences · 2020Article
- On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance.Molecules (Basel, Switzerland) · 2020Review
- Opioid Receptors in Immune and Glial Cells-Implications for Pain Control.Frontiers in immunology · 2020Review
- The multifunctional peptide DN-9 produced peripherally acting antinociception in inflammatory and neuropathic pain via μ- and κ-opioid receptors.British journal of pharmacology · 2020Article
- Inflammation-associated changes in DOR expression and function in the mouse colon.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Opioids and the immune system - friend or foe.British journal of pharmacology · 2018Review
- Advances in Achieving Opioid Analgesia Without Side Effects.Frontiers in pharmacology · 2018Review
- Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.Frontiers in pharmacology · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral mu-opioid receptors (micro-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of mu-receptors was significantly increased and G protein coupling of mu-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of mu-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance.
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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.