Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation.

Stein, Christoph; Hassan, A.H.S.; Przewłocki, Ryszard; Gramsch, Christian; Peter, K.; Herz, A.

doi:10.1073/pnas.87.15.5935

Cited by 509 publications

(303 citation statements)

References 37 publications

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“…This is demonstrated by the blockade of swim stress-induced antinociception by antibodies against b-endorphin and opioid receptor antagonists (Stein et al, 1990a;Machelska et al, 2003). Furthermore, immunosuppression abolishes this antinociception, demonstrating the functional relevance of immunocytes (Stein et al, 1990b;Przewlocki et al, 1992).…”

Section: Introductionmentioning

confidence: 95%

Selectins and integrins but not platelet–endothelial cell adhesion molecule‐1 regulate opioid inhibition of inflammatory pain

Machelska

Brack

Mousa

et al. 2004

British J Pharmacology

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1 Control of inflammatory pain can result from activation of opioid receptors on peripheral sensory nerves by opioid peptides secreted from leukocytes in response to stress (e.g. experimental swim stress or surgery). The extravasation of immunocytes to injured tissues involves rolling, adhesion and transmigration through the vessel wall, orchestrated by various adhesion molecules. 2 Here we evaluate the relative contribution of selectins, integrins a 4 and b 2 , and platelet-endothelial cell adhesion molecule-1 (PECAM-1) to the opioid-mediated inhibition of inflammatory pain. 3 We use flow cytometry, double immunofluorescence and nociceptive (paw pressure) testing in rats with unilateral hind paw inflammation induced by complete Freund's adjuvant. 4 In inflamed tissue, 43-58% of hematopoietic cells (CD45 þ ) expressed opioid peptides. L-selectin and b 2 were coexpressed by 7 and 98% of opioid-containing leukocytes, respectively. Alpha 4 integrin was expressed in low levels by the majority of leukocytes. Opioid-containing cells, vascular P-and E-selectin and PECAM-1 were simultaneously upregulated. 5 Swim stress produced potent opioid-mediated antinociception in inflamed tissue, unaffected by blockade of PECAM-1. However, blockade of L-and P-selectins by fucoidin, or of a 4 and b 2 by monoclonal antibodies completely abolished peripheral stress-induced antinociception. This coincided with a 40% decrease in the migration of opioid-containing leukocytes to inflamed tissue. 6 These findings establish selectins and integrins a 4 and b 2 , but not PECAM-1, as important molecules involved in stress-induced opioid-mediated antinociception in inflammation. They point to a cautious use of anti-inflammatory treatments applying anti-selectin, anti-a 4 and anti-b 2 strategies because they may impair intrinsic pain inhibition.

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Section: Introductionmentioning

confidence: 95%

Selectins and integrins but not platelet–endothelial cell adhesion molecule‐1 regulate opioid inhibition of inflammatory pain

Machelska

Brack

Mousa

et al. 2004

British J Pharmacology

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“…Recently, an increasing number of reports have supported this possibility (2)(3)(4)6). Anatomic, molecular, and electrophysiologic data have demonstrated the presence of all 3 opioid receptors ( , ␦, and ) on the cell bodies of primary sensory neurons in the dorsal root ganglia as well as their peripheral terminals (2,6).…”

mentioning

confidence: 97%

“…Anatomic, molecular, and electrophysiologic data have demonstrated the presence of all 3 opioid receptors ( , ␦, and ) on the cell bodies of primary sensory neurons in the dorsal root ganglia as well as their peripheral terminals (2,6). The endogenous ligands of these receptors, opioid peptides, can be secreted from immunocytes and evoke antinociception by inhibiting the excitability of sensory nerve endings and/or the release of pronociceptive, proinflammatory neuropeptides such as substance P and calcitonin gene-related peptide (2,4,6). This latter finding has been confirmed by the ability of opioid receptor agonists to inhibit neurogenic plasma protein extravasation evoked by these sensory neuropeptides (7).…”

mentioning

confidence: 99%

“…Because systemic (intravenous or intraperitoneal) or central nervous system administration of opioids can result in severe side effects such as disruption of cognitive and motor functions, confusion, hallucinations, or vomiting (10,14), peripheral administration of opioids during periods of inflammation has been proposed (3,4,6). Inflammation increases the number of sensory nerve terminals and disrupts the perineurium, the diffusion barrier for hydrophilic substances such as endogenous or exogenous opioids (15).…”

mentioning

confidence: 99%

“…The mechanisms by which peripheral inflammatory injury enhances the effects of opioids in the periphery have been well established. Up-regulation of opioid receptors on the peripheral terminals of primary sensory fibers (17,18), increased efficiency of opioid receptor coupling to G proteins resulting in elevated neuronal cAMP levels (19), and secretion of opioid peptides by immune cells at the site of injury (3,4,6,15,20) can all occur.…”

mentioning

confidence: 99%

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

Helyes¹

2005

Arthritis & Rheumatism

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Neuropeptides

Schäffer¹,

Beiter²,

Becker³

et al. 1998

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uccessful repair of injured tissues requires diverse interactions between cells, biochemical mediators, and the cellular microenvironment. [1][2][3] Much has been learned about the individual events that are involved in this process, but their integration is clearly far more complex than has been imagined, and the important role of neurogenic stimuli is only recently being recognized.Neurogenic stimuli profoundly affect cellular events that are involved in inflammation, proliferation, and matrix, as well as cytokine and growth factor synthesis. Immune cells regulated by neuropeptides include lymphocyte subsets, macrophages, and mast cells. In addition, neuropeptides may affect the proliferative and synthetic activity of epithelial, vascular, and connective tissue cells. Furthermore, a close interaction between the nervous and the immune systems has become obvious. 4 The peripheral nervous system (PNS), acting through neuropeptides, not only relays sensory information to the central nervous system (CNS) but also plays an effector role in the inflammatory, proliferative, and reparative processes after injury. These effects range from growth factor and cytokine responses to control of local blood flow. Neuropeptides mediate many of the actions important in tissue-nervous system communication.We review the accumulated knowledge about the role of neuropeptides in inflammation as it pertains to tissue repair. NEUROPEPTIDES OF THE PNSNeuropeptides constitute one of the largest families of extracellular messengers, having a long phylogenetic history. They can act as neurotransmitters, hormones, and paracrine factors.

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Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation.

Abstract: ABSTRACT

Cited by 509 publications

References 37 publications

Selectins and integrins but not platelet–endothelial cell adhesion molecule‐1 regulate opioid inhibition of inflammatory pain

Selectins and integrins but not platelet–endothelial cell adhesion molecule‐1 regulate opioid inhibition of inflammatory pain

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

Neuropeptides

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