Nociceptin, a novel endogenous ligand for the ORL1 receptor, has potent erectile activity in the cat

1997 ◽  
Vol 273 (1) ◽  
pp. E214-E219 ◽  
Author(s):  
H. C. Champion ◽  
R. Wang ◽  
W. J. Hellstrom ◽  
P. J. Kadowitz
Keyword(s):  
Drug Combination ◽  
Nitric Oxide Donor ◽  
The Novel ◽  
Orphanin Fq ◽  
Endogenous Ligand ◽  
Intracavernosal Injection ◽  
Orl1 Receptor ◽  
Arterial Blood ◽  
Intracavernosal Injections ◽  
G Protein Coupled

The heptadecapeptide nociceptin, also known as orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G protein-coupled receptor ORL1. The present study was undertaken to investigate the effects of intracavernosal injections of nociceptin on penile erection in anesthetized cats. Responses to nociception were compared with erectile responses elicited by intracavernosal injection of vasoactive intestinal polypeptide (VIP), adrenomedullin (ADM), the novel nitric oxide donor diethylaminenitric oxide complex sodium (DEA/NO), and the control triple-drug combination (papaverine, phentolamine, and prostaglandin E1). The order of potency was VIP > ADM > nociceptin > DEA/NO. Intracavernosal injections of nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure and penile length that were comparable to those induced by the triple-drug combination, which is used in the treatment of erectile dysfunction. The response to nociceptin was rapid in onset, and the duration of the peak pressure increase and total response was significantly shorter than the response to the control triple-drug combination but longer in duration than responses to VIP and ADM. Intracavernosal injection of the triple-drug combination resulted in a greater decrease in mean systemic arterial blood pressure than did nociceptin. These data demonstrate that intracavernosal injection of this novel endogenous ligand for the ORL1 receptor induces a potent and relatively long-lasting erectile response in the cat.

scholarly journals The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

2021 ◽  
Vol 22 (8) ◽  
pp. 3872
Author(s):  
Anna Laitakari ◽  
Lingzhi Liu ◽  
Thomas M. Frimurer ◽  
Birgitte Holst
Keyword(s):  
The Novel ◽  
Rodent Models ◽  
Therapeutic Approaches ◽  
Endogenous Ligand ◽  
Physiological Functions ◽  
Saliva Secretion ◽  
Depression Disorders ◽  
Zinc Sensing ◽  
Pharmacological Potential ◽  
G Protein Coupled

The G-protein coupled receptor GPR39 is abundantly expressed in various tissues and can be activated by changes in extracellular Zn2+ in physiological concentrations. Previously, genetically modified rodent models have been able to shed some light on the physiological functions of GPR39, and more recently the utilization of novel synthetic agonists has led to the unraveling of several new functions in the variety of tissues GPR39 is expressed. Indeed, GPR39 seems to be involved in many important metabolic and endocrine functions, but also to play a part in inflammation, cardiovascular diseases, saliva secretion, bone formation, male fertility, addictive and depression disorders and cancer. These new discoveries offer opportunities for the development of novel therapeutic approaches against many diseases where efficient therapeutics are still lacking. This review focuses on Zn2+ as an endogenous ligand as well as on the novel synthetic agonists of GPR39, placing special emphasis on the recently discovered physiological functions and discusses their pharmacological potential.

Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain

Pain ◽  
2004 ◽  
Vol 110 (1) ◽  
pp. 236-245 ◽  
Author(s):  
Christine Courteix ◽  
Marie-Ange Coudoré-Civiale ◽  
Anne-Marie Privat ◽  
Teresa Pélissier ◽  
Alain Eschalier ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Animal Models ◽  
Antinociceptive Effect ◽  
Orphanin Fq ◽  
Endogenous Ligand ◽  
Orl1 Receptor

Functional linkage as a direction for studies in oxidative stress: α-adrenergic receptorsThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 220-232 ◽  
Author(s):  
Natalia Ziolkowski ◽  
Ashok K. Grover
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Arterial Blood Flow ◽  
Arterial Blood ◽  
Functional Linkage ◽  
Protein Kinase C Activity ◽  
Downstream Effects ◽  
Fine Regulation ◽  
Health And Disease ◽  
G Protein Coupled

The α-adrenergic receptors (adrenoceptors) are activated by the endogenous agonists epinephrine and norepinephrine. They are G protein-coupled receptors that may be broadly classified into α1 (subclasses α1A, α1B, α1D) and α2 (subclasses α2A, α2B, α2C). The α1-adrenoceptors act by binding to Gαq subunits of the G proteins, causing activation of phospholipase C (PLC). PLC converts phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG), which have downstream effects on cytosolic Ca2+ concentration. The α2-adrenoceptors bind to Gαi thus inhibiting adenylyl cyclase and decreasing cAMP levels. DAG alters protein kinase C activity and cAMP activates protein kinase A. The downstream pathways of the two receptors may also interact. Activation of α1- and α2-adrenoceptors in vascular smooth muscle results in vasoconstriction. However, the densities of individual receptor subclasses vary between vessel beds or between vessels of various sizes within the same bed. In vasculature, the densities of adrenoceptor subclasses differ between conduit arteries and arterioles. These differences, along with differences in coupling mechanisms, allow for fine regulation of arterial blood flow. This diversity is enhanced by interactions resulting from homo- and heterodimer formation of the receptors, metabolic pathways, and kinases. Reactive oxygen species generated in pathologies may alter α1- and α2-adrenoceptor cascades, change vascular contractility, or cause remodeling of blood vessels. This review emphasizes the need for understanding the functional linkage between α-adrenoceptor subtypes, coupling, cross talk, and oxidative stress in cardiovascular pathologies.

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

scholarly journals Central G-alpha subunit protein-mediated control of cardiovascular function, urine output, and vasopressin secretion in conscious Sprague-Dawley rats

2008 ◽  
Vol 295 (2) ◽  
pp. R535-R542 ◽  
Author(s):  
Richard D. Wainford ◽  
Kristine Kurtz ◽  
Daniel R. Kapusta
Keyword(s):  
Produced Water ◽  
The Novel ◽  
Orphanin Fq ◽  
Sprague Dawley ◽  
Water Diuresis ◽  
Excretory Function ◽  
Subunit Protein ◽  
Sprague Dawley Rats ◽  
Vasopressin Secretion ◽  
Saline Vehicle

The role(s) of central Gα-proteins in the regulation of cardiovascular and renal function is unknown. We examined how inhibition/downregulation of central Gαi/Gαo, Gαz or Gαq proteins altered the characteristic cardiovascular (depressor), renal excretory (diuretic), and plasma AVP (inhibitory) responses to intracerebroventricular injection of nociceptin/orphanin FQ (N/OFQ) in rats. Before investigation, rats were pretreated intracerebroventricularly with saline vehicle (5 μl, 48 h, n = 6), pertussis toxin (PTX; 48-h, 1 μg, n = 6), or Gαz, Gαq, or scrambled oligodeoxynucleotide (ODN) (25 μg, 24 h, n = 6 per group). On the study day, intracerebroventricular N/OFQ (5.5 nmol) or vehicle (5 μl) was injected into pretreated conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were recorded, and urine was collected for 90 min. In vehicle or scrambled ODN groups, intracerebroventricular N/OFQ decreased MAP and HR and produced water diuresis (sensitive to UFP-101, N/OFQ receptor antagonist). The hypotension and bradycardia, but not diuresis, to N/OFQ were abolished in PTX-pretreated rats. In contrast, intracerebroventricular ODN pretreatment markedly blunted (Gαz) or augmented (Gαq) the diuresis to intracerebroventricular N/OFQ. In separate studies, the action of central N/OFQ to decrease plasma AVP levels in naïve water-restricted rats was differentially altered by intracerebroventricular Gαz ODN (blunted) and Gαq ODN (augmented) pretreatment. These studies demonstrate central Gαi/Gαo activity mediates intracerebroventricular N/OFQ's cardiovascular depressor function. Alternatively, central Gαz (inhibitory) and Gαq (stimulatory) activity differentially modulates AVP release to control the pattern of diuresis to intracerebroventricular N/OFQ. These findings highlight the novel selective central Gα-subunit protein-mediated control of cardiovascular vs. renal excretory function.

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