Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study

Lazzeri, Massimo; Calò, Girolamo; Spinelli, M.; Guerrini, Remo; Salvadori, Severo; Beneforti, P.; Sandri, S; Regoli, Doménico; Turini, Damiano

doi:10.1016/s0090-4295(02)02587-6

Cited by 44 publications

(27 citation statements)

References 25 publications

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“…These pharmacological features are highly desirable especially for investigating those conditions and states in which a selective and prolonged stimulation of NOP receptor is beneficial, including anxiety states [21,28], drug addiction [15,48], anorectic conditions [16], spinal analgesia (as indicated by laboratory animals [54] as well as primate [35] studies), cough and possibly other respiratory diseases [40], acute heart failure [26,34], and, as indicated by clinical studies, urinary incontinence due to overactive bladder [37][38][39]. Peak changes in mean arterial pressure and heart rate produced immediately following i.v.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

et al. 2007

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Abstract[(pF)Phe 4 Aib 7 Arg 14 Lys 15 ]N/OFQ-NH 2 (UFP-112) has been designed as a novel ligand for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) by combining into the same peptide different chemical modifications reported to increase N/OFQ potency. In vitro data obtained in the electrically stimulated mouse vas deferens demonstrated that UFP-112 behaved as a high potency (pEC 50 9.43) full agonist at the NOP receptor. UFP-112 effects were sensitive to the NOP antagonist UFP-101 but not to naloxone and no longer evident in tissues taken from NOP −/− mice. In vitro half life of UFP-112 in mouse plasma and brain homogenate was 2.6 and 3.5 fold higher than that of N/ OFQ. In vivo, in the mouse tail withdrawal assay, UFP-112 (1-100 pmol, i.c.v.) mimicked the actions of N/OFQ producing pronociceptive effects after i.c.v. administration and antinociceptive effects when given i.t; in both cases, UFP-112 was approx. 100 fold more potent than the natural peptide and produced longer lasting effects. UFP-112 also mimicked the hyperphagic effect of N/OFQ producing a bell shaped dose response curve with the maximum reached at 10 pmol. The hyperphagic effects of N/OFQ and UFP-112 were absent in NOP −/− mice. Equi-effective high doses of UFP-112 (0.1 nmol) and N/OFQ (10 nmol) were injected i.c.v. in mice and spontaneous locomotor activity recorded for 16 h. N/OFQ produced a clear inhibitory effect which lasted for 60 min while UFP-112 elicited longer lasting effects (> 6h). In conscious rats, UFP-112 (0.1 and 10 nmol/kg, i.v.) produced a marked and sustained decrease in heart rate, blood pressure, and urinary sodium excretion and a profound increase in urine flow. Collectively, these findings demonstrate that UFP-112 behaves in vitro and in vivo as a highly potent and selective ligand able to produce full and long lasting activation of NOP receptors.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

et al. 2007

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“…In the patients, there was a statistically significant increase in mean bladder capacity and volume threshold for the appearance of detrusor overactivity. A randomized, placebo-controlled, doubleblind study was then performed in a selected group of 14 patients who had neurogenic detrusor overactivity due to spinal cord injury (Lazzeri et al, 2003). Intravesical infusion of a solution containing nociceptin/orphanin FQ, but not placebo, increased significantly bladder capacity and volume threshold for the appearance of detrusor overactivity.…”

Section: Peripheral Targetsmentioning

confidence: 99%

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Andersson

Wein²

2004

Pharmacol Rev

456

364

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“…Clinical validation of NOP agonists in human diseases awaits the arrival of a selective, nonpeptide, orally active NOP agonist. With this being said, a few small clinical studies have provided proof of activity of the N/OFQ peptide in patients with detrusor overactivity incontinence [13][14][15] . Nevertheless, comprehensive preclinical pharmacological profiling of novel selective NOP agonists is essential to the progression of this class of drug to human testing [16,17] .…”

Section: Introductionmentioning

confidence: 99%

Effect of a Novel NOP Receptor Agonist (SCH 225288) on Guinea Pig Irritant-Evoked, Feline Mechanically Induced and Canine Infectious Tracheobronchitis Cough

McLeod

Tulshian²,

Ho³

et al. 2009

Pharmacology

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Background: Previous studies have demonstrated that nociceptin/orphanin FQ (N/OFQ), the endogenous peptide ligand for the G-protein-coupled NOP receptor, inhibits cough in experimental models. SCH 225288 is a nonpeptide, orally active NOP agonist that may provide the foundation for the development of novel treatments for cough. Methods: First we characterized the selectivity of SCH 225288 in human receptor binding assays. Afterwards, the antitussive activity of SCH 225288 was studied in three mechanistically distinct cough models. Specifically, we observed the cough-suppressant effect of SCH 225288 in a guinea pig capsaicin irritant-evoked cough model, a feline mechanically induced cough model and finally in a canine Bordetella bronchiseptica disease model. Results: SCH 225288 selectively binds human NOP receptor (K_i = 0.38 ± 0.02 nmol/l) over classical opioid receptors (COR). In a guinea pig capsaicin cough model, SCH 225288 (0.1–1 mg/kg) suppressed cough at 2, 4, and 6 h after oral administration. The antitussive effect of SCH 225288 (3.0 mg/kg, p.o.) was blocked by the NOP antagonist J113397 (12 mg/kg, i.p.) but not by the classical opioid receptor (COR) antagonist, naltrexone (3.0 mg/kg, i.p.). In the anesthetized cat, we evaluated the effects of SCH 225288 given either intravenously or via the intravertebral artery against the increases in cough number and respiratory expiratory and inspiratory muscle (rectus abdominis and parasternal) electromyographic (EMG) activities due to perturbations of the intrathoracic trachea. SCH 225288 (0.03–3.0 mg/kg, i.v.) inhibited both cough number and abdominal EMG amplitudes. Similarly, SCH 225288 (0.001–0.3 mg/kg) administered intra-arterially also diminished cough number and abdominal EMG amplitudes. No significant effect of the drug was noted on parasternal EMG activity. Finally, we studied the antitussive actions of SCH 225288 (1.0 mg/kg) in a canine B. bronchiseptica disease model. In this model, dogs were challenged intranasally with B. bronchiseptica. Comparisons were made between a vehicle group, an SCH 225288 (1.0 mg/kg, p.o., q.d.) and a butorphanol (0.6 mg/kg, p.o., b.i.d.) group on the mean change in cough scores from baseline values and days 6–9 after B. bronchiseptica challenge. SCH 225288 (1.0 mg/kg, p.o., q.d.) displayed a positive antitussive tendency (p = 0.06) to inhibit B. bronchiseptica cough whereas butorphanol (0.6 mg/kg, p.o., b.i.d.) was devoid of antitussive activity. Conclusions: Taken together, the present data show that SCH 225288 is a potent and effective antitussive agent in animal models of cough. Furthermore, these findings indicate that NOP agonists represent a promising new therapeutic approach for the treatment of cough without the side effect liabilities associated with opioid antitussives.

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Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study

Cited by 44 publications

References 25 publications

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Effect of a Novel NOP Receptor Agonist (SCH 225288) on Guinea Pig Irritant-Evoked, Feline Mechanically Induced and Canine Infectious Tracheobronchitis Cough

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