scholarly journals Nitric Oxide Stimulates Acute Pancreatitis Pain via Activating the NF-κB Signaling Pathway and Inhibiting the Kappa Opioid Receptor

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mengwen Xue ◽  
Liang Han ◽  
Weikun Qian ◽  
Jie Li ◽  
Tao Qin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Pancreatitis ◽  
Opioid Receptor ◽  
Pain Treatment ◽  
Kappa Opioid Receptor ◽  
Clinical Feature ◽  
Kappa Opioid ◽  
No Donor

Pain is the most important clinical feature of acute pancreatitis (AP); however, its specific mechanism is currently unclear. In this study, we showed that AP caused an increase in nitric oxide (NO) secretion, activated the NF-κB pathway in the dorsal root ganglia (DRGs), and caused pain. We established an AP model in vivo and tested the expression of NO, the kappa opioid receptor (KOR), and pain factors. We showed that NO in AP was significantly elevated and increased the expression of pain factors. Next, by treating DRGs in vitro, it was found that NO activated the NF-κB pathway; conversely, NF-κB had no effect on NO. Moreover, inhibition of NF-κB promoted the KOR, whereas NF-κB did not change after KOR activation. Finally, behavioral experiments showed that a NO donor increased the pain behavior of mice, while a NO scavenger, NF-κB inhibitor, or KOR agonist attenuated the pain response in mice. These results suggest that iNOS/NO/NF-κB/KOR may be a key mechanism of pain in AP, providing a theoretical basis for the use of peripheral-restricted KOR agonists for pain treatment in AP.

scholarly journals Tackling the opioid crisis - development of kappa-opioid receptor peptide agonists for safer analgesic therapy

2021 ◽  
Author(s):  
Rink-Jan Lohman ◽  
Karnaker Reddy Tupally ◽  
Ajit Kandale ◽  
Peter Cabot ◽  
Harendra Parekh
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Specific Activity ◽  
Opioid Analgesic ◽  
Kappa Opioid Receptor ◽  
Metabolic Stability ◽  
Clinical Translation ◽  
Kappa Opioid

The kappa opioid receptor (KOPr) has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side effects have the limited their clinical translation. Here, we modify an active endogenous Dynorphin peptide with the aim of improving drug-likeness and developing safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from Dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, KOPr specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in Freund’s complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling. In vivo, KA305 and KA311 showed anti-nociception opioid receptor-specific activity comparable to morphine and U50 844. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide KOPr agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.

Signaling Properties of Structurally Diverse Kappa Opioid Receptor Ligands: Toward in Vitro Models of in Vivo Responses

2019 ◽  
Vol 10 (8) ◽  
pp. 3590-3600 ◽  
Author(s):  
Amelia D. Dunn ◽  
Brian Reed ◽  
Jose Erazo ◽  
Ariel Ben-Ezra ◽  
Mary Jeanne Kreek
Keyword(s):  
Opioid Receptor ◽  
In Vitro Models ◽  
Kappa Opioid Receptor ◽  
Receptor Ligands ◽  
Kappa Opioid ◽  
Opioid Receptor Ligands

scholarly journals Kappa opioid receptor (KOR) signaling on peripheral sensory neurons in vitro and in vivo

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Matthew Rowan ◽  
Teresa Sanchez ◽  
Yamille Silva ◽  
Blaine McGuire ◽  
William Clarke ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Sensory Neurons ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Autologous nitric oxide protects mouse and human keratinocytes from ultraviolet B radiation-induced apoptosis

2003 ◽  
Vol 284 (5) ◽  
pp. C1140-C1148 ◽  
Author(s):  
Richard Weller ◽  
Ann Schwentker ◽  
Timothy R. Billiar ◽  
Yoram Vodovotz
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Ultraviolet B ◽  
Skin Damage ◽  
Wild Type ◽  
No Donor ◽  
Ultraviolet B Radiation ◽  
Inducible Nos

Nitric oxide (NO) can either prevent or promote apoptosis, depending on cell type. In the present study, we tested the hypothesis that NO suppresses ultraviolet B radiation (UVB)-induced keratinocyte apoptosis both in vitro and in vivo. Irradiation with UVB or addition of the NO synthase (NOS) inhibitor N G-nitro-l-arginine methyl ester (l-NAME) increased apoptosis in the human keratinocyte cell line CCD 1106 KERTr, and apoptosis was greater when the two agents were given in combination. Addition of the chemical NO donor S-nitroso- N-acetyl-penicillamine (SNAP) immediately after UVB completely abrogated the rise in apoptosis induced by l-NAME. An adenoviral vector expressing human inducible NOS (AdiNOS) also reduced keratinocyte death after UVB. Caspase-3 activity, an indicator of apoptosis, doubled in keratinocytes incubated with l-NAME compared with the inactive isomer, d-NAME, and was reduced by SNAP. Apoptosis was also increased on addition of 1,H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Mice null for endothelial NOS (eNOS) exhibited significantly higher apoptosis than wild-type mice both in the dermis and epidermis, whereas mice null for inducible NOS (iNOS) exhibited more apoptosis than wild-type mice only in the dermis. These results demonstrate an antiapoptotic role for NO in keratinocytes, mediated by cGMP, and indicate an antiapoptotic role for both eNOS and iNOS in skin damage induced by UVB.

Effects of Nitric Oxide on Blood Flow and Mucociliary Activity in the Human Nose

1998 ◽  
Vol 107 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Thomas Runer ◽  
Sven Lindberg
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Maximum Increase ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Human Nose

In an animal model, nitric oxide (NO) has been shown to increase mucociliary activity in vivo and ciliary beat frequency in vitro. The aim of the present study was to investigate the effects of NO on blood flow and mucociliary activity in the human nose. The concentration of NO in nasal air was measured with a chemiluminescence technique after nebulizing the NO donor sodium nitroprusside (SNP) at a dose of 3.0 mg into the nose in six volunteers, and was found to increase by 50.1% ± 10.0% (mean ± SEM; p <.001) after the SNP challenge. Blood flow measured by laser Doppler flowmetry increased by 67.3% ± 15.5% (p <.05) after challenge with SNP at 1.0 mg, and by 75.4% ± 18.5% at 3.0 mg (p <.01; n = 6). The higher dose, which produced no subjective side effects, was then used in the mucociliary experiments. The maximum increase in nasal mucociliary activity was 57.2% ± 6.7% at 3.0 mg of SNP (n = 5). The findings support the view that NO regulates mucociliary activity and blood flow in the human nasal mucosa.

scholarly journals Glucagon-Like Peptide 2 (GLP-2) Stimulates Postprandial Chylomicron Production and Postabsorptive Release of Intestinal Triglyceride Storage Pools via Induction of Nitric Oxide Signaling in Male Hamsters and Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3538-3547 ◽  
Author(s):  
Joanne Hsieh ◽  
Karin E. Trajcevski ◽  
Sarah L. Farr ◽  
Christopher L. Baker ◽  
Elizabeth J. Lake ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Early Mobilization ◽  
No Donor ◽  
Nitric Oxide Signaling ◽  
Insulin Resistant ◽  
Postprandial State ◽  
Glucagon Like Peptide ◽  
Storage Pools

The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME), and in GLP-2-treated endothelial NOS knockout mice. L-NAME blocked GLP-2-stimulated apoB48 secretion and reduced triglycerides (TGs) in the TG-rich lipoprotein (TRL) fraction of the plasma in the postprandial state. Endothelial NOS-deficient mice were resistant to GLP-2 stimulation and secreted fewer large apoB48-particles. When TG storage pools were allowed to accumulate, L-NAME mitigated the GLP-2-mediated increase in TRL-TG, suggesting that NO is required for early mobilization and secretion of stored TG and preformed chylomicrons. Importantly, the NO donor S-nitroso-L-glutathione was able to elicit an increase in TRL-TG in vivo and stimulate chylomicron release in vitro in primary enterocytes. We describe a novel role for GLP-2-mediated NO-signaling as a critical regulator of intestinal lipid handling and a potential contributor to postprandial dyslipidemia.

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