Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Electrical vagus nerve (VN) stimulation during sepsis attenuates tumor necrosis factor (TNF) production through the cholinergic anti-inflammatory pathway, which depends on the integrity of the VN and catecholamine production. To characterize the effect of electroacupuncture at ST36 (EA-ST36) on serum TNF, IL-6, nitrite, and HMGB1 levels and survival rates, based on VN integrity and catecholamine production, a sepsis model was induced in rats using cecal ligation and puncture (CLP). The septic rats were subsequently treated with EA-ST36 (CLP+ST36), and serum samples were collected and analyzed for cytokines levels. The serum TNF, IL-6, nitrite, and HMGB1 levels in the CLP+ST36 group were significantly lower compared with the group without treatment, the survival rates were significantly higher (P < 0.05), and the acute organ injury induced by CLP was mitigated by EA-ST36; however, when subdiaphragmatic vagotomy was performed, the serum levels of TNF in the CLP+ST36 group did not show a significant difference compared with the group without electrostimulation, and, similarly, no significant difference in serum TNF levels was found under the pharmacological blockade of catecholamines. These results suggest that in rats with CLP sepsis models EA-ST36 reduces serum TNF levels through VN- and atecholamine-dependent mechanisms.

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“…Consistent with these results, the highest serum TNF levels are observed at 2 hrs after CLP in a rat model of sepsis [21]. …”

Section: Discussionsupporting

confidence: 63%

Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve‐ and Catecholamine‐Dependent Mechanisms

Villegas-Bastida

Torres‐Rosas

Arriaga-Pizano

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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“…Tang et al [194], using rat CLP model, showed that DADLE (5 mg/kg, i.p. ), a synthetic analog of [Leu 5 ]enkephalin, protected against lethal endotoxemia in a DOR-dependent manner.…”

Section: Opioid System In Pathophysiological Conditions Of the Gi Tractmentioning

confidence: 99%

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

et al. 2013

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Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract.

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“…22,23 Literature data supports a correlation between DOR and TNF-a. [24][25][26] In a sepsis rat model, DOR activation was associated with a significant decrease in the serum levels of early and late pro-inflammatory citokines. 24 Wang et al 25 demonstrated that DOR activation inhibits TNF-a-mediated inflammation in response to severe hypoxia in both glial and neuron-like cells.…”

Section: Introductionmentioning

confidence: 99%

Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-α up-regulation in the sciatic nerve of rats with neuropathic pain

et al. 2016

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Despite mu opioid receptor agonists are the cornerstones of moderate-to-severe acute pain treatment, their effectiveness in chronic pain conditions is controversial. In contrast to mu opioid receptor agonists, a number of studies have reported the effectiveness of delta opioid receptor agonists on neuropathic pain strengthening the idea that delta opioid receptors gain importance when chronic pain develops. Among other effects, it has been shown that delta opioid receptor activation in optic nerve astrocytes inhibits tumor necrosis factor-α-mediated inflammation in response to severe hypoxia. Considering the involvement of tumor necrosis factor-α in the development and maintenance of neuropathic pain, with this study we sought to correlate the effect of delta opioid receptor agonist on the development of mechanical allodynia to tumor necrosis factor-α expression at the site of nerve injury in rats subjected to chronic constriction injury of the sciatic nerve. To this aim, we measured the levels of tumor necrosis factor-α in the sciatic nerve of rats with neuropathic pain after repeated injections with a delta opioid receptor agonist. Results obtained demonstrated that repeated administrations of the delta opioid receptor agonist SNC80 (10 mg/kg, i.p. for seven consecutive days) significantly inhibited the development of mechanical allodynia in rats with neuropathic pain and that the improvement of neuropathic symptom was timely related to the reduced expression of tumor necrosis factor-α in the rat sciatic nerve. We demonstrated also that when treatment with the delta opioid receptor agonist was suspended both allodynia and tumor necrosis factor-α up-regulation in the sciatic nerve of rats with neuropathic pain were restored. These results show that persistent delta opioid receptor activation significantly attenuates neuropathic pain and negatively regulates sciatic nerve tumor necrosis factor-α expression in chronic constriction injury rats.

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Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

Cited by 17 publications

References 31 publications

Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve‐ and Catecholamine‐Dependent Mechanisms

Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve‐ and Catecholamine‐Dependent Mechanisms

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-α up-regulation in the sciatic nerve of rats with neuropathic pain

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