Role of peripheral μ‐opioid receptors in arthritis: Are they potential targets for therapy?

Helyes, Zsuzsanna

doi:10.1002/art.21360

Cited by 5 publications

(3 citation statements)

References 29 publications

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“…Downregulation of MOR in dorsal root ganglia (DRG) and concomitant loss of analgesic effects following the administration of EM‐1 have been reported in a rat model of chronic monoarthritis 37 . This has raised a question over the long‐term utility of opioids as analgesic agents, 38 although studies into any concomitant loss of anti‐inflammatory effects (as opposed to analgesic properties) have not been performed. However, receptors that are expressed in low amounts on resting lymphocytes can be upregulated by activation during chronic inflammation 15,39 and upregulation of MOR, with no loss of affinity, has been reported in DRG of PAN neurons in a rat model of monoarthritis 40 .…”

Section: Clinical Prospectsmentioning

confidence: 99%

Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis

Jessop

Faßold

Wolff

et al. 2010

Annals of the New York Academy of Sciences

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The opioid tetrapeptides endomorphins (EM)-1 and EM-2 are widely expressed in central nervous system and immune tissues of rats and humans. Their analgesic properties are well characterized but they also have anti-inflammatory properties. EM-1 significantly attenuated the onset of hindpaw inflammation in adjuvant-induced arthritis in rats. Immunohistochemical staining demonstrated the presence of EMs in T cells, macrophages, and fibroblasts in synovial tissues from patients with osteo- or rheumatoid arthritis (RA). In an ex vivo superfusion system, EM-1 potently inhibited the release of proinflammatory cytokines interleukin (IL)-6 and IL-8 from synovial tissues from patients with osteo- or RA. These results demonstrate that EMs are endogenously synthesized within human immune cells and have the potential to act as potent therapeutic agents in the treatment of chronic inflammatory disease. We discuss the clinical potential for EM analogues chemically modified to resist proteolytic degradation and identify modified protease-resistant analogues with enhanced bioactivity.

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Section: Clinical Prospectsmentioning

confidence: 99%

Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis

Jessop

Faßold

Wolff

et al. 2010

Annals of the New York Academy of Sciences

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“…Endogenous opioids such as β‐endorphin, methionine–enkephalin, and leucine–enkephalin counteract pain pathways and related inflammation (for review, see refs 5. and6). This is achieved by binding of endogenous opioids to opioid receptors on peripheral sensory nerve terminals inhibiting substance P release (7–10), and by directly influencing immune and other cells involved in the proinflammatory process (11).…”

mentioning

confidence: 99%

Antiinflammatory role of endomorphins in osteoarthritis, rheumatoid arthritis, and adjuvant‐induced polyarthritis

Straub¹,

Wolff²,

Faßold³

et al. 2008

Arthritis & Rheumatism

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Objective. Pain sensitization and the related secretion of neuropeptides from sensory nerve terminals are proinflammatory in osteoarthritis (OA), rheumatoid arthritis (RA), and adjuvant-induced polyarthritis. In contrast, endogenous opioids such as the recently discovered endomorphins (EMs) are antiinflammatory. However, the role of endogenous EMs such as EM-1 and EM-2 has never been investigated in OA and RA.Methods. We established a highly sensitive radioimmunoassay to detect EM-1 and EM-2. In patients with RA and patients with OA, immunohistochemistry for EM-1 and EM-2 was performed, and double-staining was used to identify EM-positive cells. The effects of EM-1 and EM-2 on the secretion of interleukin-6 (IL-6) and IL-8 from human synovial tissue were studied by tissue superfusion, and the therapeutic effects of EM-1 were tested in a rat model of adjuvant-induced polyarthritis.Results. EM-positive cells were located in the sublining area and vessel walls but were particularly evident in the highly inflamed lining area. Human macrophages, T cells, and fibroblasts stained positive for EMs. The synovial density of EM-positive cells was higher in patients with OA than in those with RA.

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“…1). [7,8] Compounds containing a guanidine functionality have previously been shown to prevent blood-brain barrier (BBB) permeation [9][10][11] as they protonate to form more hydrophilic salts at physiological pH. [12] This concept has previously been extended to the morphine molecule by our group [10] in order to synthesize a selective, peripherally acting analgesic without the above mentioned side effects.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Potentially Transdermal Morphine Derivatives

et al. 2011

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Three new morphine-based compounds bearing arginyl moieties, compounds 7, 9a, and 9b, have been synthesized using solid phase and solution phase techniques with the aim of obtaining new transdermal analgesics. Preliminary biological assays have shown that these compounds have a relatively high affinity for opioid receptors, achieving ≥94 % inhibition of radioligand binding at a concentration of 10 µM in non-selective opioid binding assays. Further testing on two of the analogues, 9a and 9b, demonstrated that these compounds were acting as agonists, rather than antagonists, at the opioid receptors and 9b achieved the significant result of 73 % inhibition of contractile responses in the electrically stimulated guinea pig ileum assay at a concentration of 30 µM. Unfortunately, none of the molecules showed evidence of transdermal activity.

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Role of peripheral μ‐opioid receptors in arthritis: Are they potential targets for therapy?

Cited by 5 publications

References 29 publications

Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis

Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis

Antiinflammatory role of endomorphins in osteoarthritis, rheumatoid arthritis, and adjuvant‐induced polyarthritis

Synthesis and Evaluation of Potentially Transdermal Morphine Derivatives

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