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Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that develops as a consequence of prolonged hyperglycaemia-induced injury to the long nerves. Apart from pain, PDN is also characterized by morphine hyposensitivity. Intriguingly, in streptozotocin (STZ)-induced diabetic rats exhibiting marked morphine hyposensitivity, dietary administration of the nitric oxide (NO) precursor, L-arginine at 1g/day, progressively rescued morphine efficacy and potency over an 8-week treatment period. In earlier work, single bolus doses of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde), evoked dose-dependent pain relief in STZ-diabetic rats but the efficacious doses were 3-4 orders of magnitude higher in advanced diabetes than that required in early STZ-diabetes. Together, these findings suggested a role for NO in the modulation of μ-opioid (MOP) receptor signalling. Therefore, the present study was designed to assess a role for NO released from PRG150, in modulating MOP receptor function in vitro. Here, we show an absolute requirement for the MOP receptor, but not the δ-opioid (DOP) or the κ-opioid (KOP) receptor, to transduce the cellular effects of PRG150 on forskolin-stimulated cAMP responses in vitro. PRG150 did not interact with the classical naloxone-sensitive binding site of the MOP receptor and its effects on cAMP responses in HEK-MOP cells were also naloxone-insensitive. Nevertheless, the inhibitory effects of PRG150 on forskolin-stimulated cAMP responses in HEK-MOP cells were dependent upon pertussis toxin (PTX)-sensitive G proteins as well as membrane lipid rafts and src kinase. Together, our findings implicate a role for NO in modulating MOP receptor function in vivo. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: Clinical and experimental pharmacology & physiology
To correlate outflow function and outflow tract vessel diameter changes induced by nitric oxide (NO).
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To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE.
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Previous studies have shown that κ-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MI/R) injury. The current study was designed to investigate wheth...
This blinded, placebo-controlled study will administer inhaled nitric oxide to patients undergoing liver transplantation. The purpose of the study is to test if inhaled nitric oxide preven...
Obese people have a disturbed postprandial metabolism and thereby a decreased postprandial vascular function. Nitric oxide plays an important role in the postprandial vascular function. Mu...
The purpose of this study is to conduct experiments to examine subjective and reinforcing effects of nitrous oxide. Mood altering and psychomotor effects will be tested on non-drug abuser...
A minimum of 100 patients will be enrolled in the study to demonstrate which diagnostic treatment (oxygen or nitric oxide) is most capable of identifying patients with a reactive pulmonary...
The purpose of this study is to determine whether inhaled nitric oxide is an effective treatment for microcirculatory dysfunction and acute organ system failure in the early stage of sepsi...
A CALCIUM-independent subtype of nitric oxide synthase that may play a role in immune function. It is an inducible enzyme whose expression is transcriptionally regulated by a variety of CYTOKINES.
A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.
An NADPH-dependent enzyme that catalyzes the conversion of L-ARGININE and OXYGEN to produce CITRULLINE and NITRIC OXIDE.
A CALCIUM-dependent, constitutively-expressed form of nitric oxide synthase found primarily in NERVE TISSUE.
A CALCIUM-dependent, constitutively-expressed form of nitric oxide synthase found primarily in ENDOTHELIAL CELLS.
Diabetes is a lifelong condition that causes a person's blood sugar level to become too high. The two main types of diabetes are: type 1 diabetes type 2 diabetes In the UK, diabetes affects approximately 2.9 million people. There are a...
An anesthesiologist (US English) or anaesthetist (British English) is a physician trained in anesthesia and perioperative medicine. Anesthesiologists are physicians who provide medical care to patients in a wide variety of (usually acute) situations. ...
Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...