Attacking pain at its source: new perspectives on opioids

Stein, Christoph; Schäfer, Michael; Machelska, Halina

doi:10.1038/nm908

Cited by 538 publications

(465 citation statements)

References 93 publications

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“…These receptors are G i/o members of the G-protein coupled receptor family, with binding typically decreasing neuronal excitability via inhibition of adenylyl cyclase, activation of potassium channels and inhibition of calcium channels. Immune cells are known to secrete opioids, and T cell derived β-endorphin, a MOR preferring agonist, has previously been shown to be essential for setting the colo-rectal afferent activation threshold to distension in healthy mice (Hughes et al, 2013b;Stein et al, 2003;Verma-Gandhu 7 et al, 2006). However, little is known of how these studies translate to humans, and opioid secretion by immune cells is yet to be directly investigated in IBS.…”

Section: Introductionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients, Brain, Behavior, and Immunity (2014), doi: http://dx.doi.org/10. 1016/j.bbi.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-endorphin was identified predominantly in monocyte / macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in µ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte / macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.

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Section: Introductionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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“…This pain can be locally inhibited by leukocyte-derived opioid peptides without eliciting central side effects (Stein, 1995;Stein et al, 2003). Opioid-containing immune cells migrate to inflamed tissues (Przewlocki et al, 1992;Stein et al, 1996;Cabot et al, 1997) and, concurrently, opioid receptors are upregulated on peripheral terminals of sensory neurons .…”

Section: Introductionmentioning

confidence: 99%

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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“…The potential target of the immunosuppressive effect of opiates is not fully understood, but different investigations appear to indicate bidirectional connections between the neural, endocrine and immune systems, placing it peripherally based on the expression of the MOP receptor on immune cells with implications at the central nervous system level. 12,13 The administration of opioids affects the immune system in different degrees and manners. 2 The clinical relevance of this immunological role is not well-known.…”

Section: Introductionmentioning

confidence: 99%