Urodynamic and Clinical Evidence of Acute Inhibitory Effects of Intravesical Nociceptin/Orphanin Fq on Detrusor Overactivity in Humans: A Pilot Study

Lazzeri, Massimo; Calò, Girolamo; Spinelli, M.; Guerrini, Renzo; Beneforti, P.; Sandri, S; Zanollo, A; Regoli, Doménico; Turini, Damiano

doi:10.1016/s0022-5347(05)65541-3

Cited by 41 publications

(20 citation statements)

References 22 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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“…Altogether these results indicate that ORL1 receptors are present at several sites for the integration of the micturition reflex, and that their activation may produce both excitatory and inhibitory effects, depending on the route of administration and the experimental conditions. Lazzeri et al (2001) investigated the urodynamic and clinical effects of intravesical instillation of nociceptin/ orphanin FQ (1 M) in five normal subjects and nine patients with neurogenic detrusor overactivity refractory to standard therapy. Intravesical instillation of nociceptin/orphanin FQ produced no significant functional changes in the controls.…”

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

453

364

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“…28 A study in humans investigated the effect of nociceptin/orphanin FQ in healthy subjects and patients with neurogenic detrusor overactivity. 29 After intravesical instillation of 1 mM nociceptin/orphanin FQ, a significant increase in mean bladder cystometric capacity and volume threshold for the appearance of neurogenic detrusor overactivity in patients compared to healthy subjects group was observed. However, the clinical and urodynamic effect lasted for 2 weeks only.…”

Section: Intravesical Nociceptin/orphanin Fqmentioning

confidence: 90%

“…In this study, it was also hypothetised that nociceptin/orphanin FQ acts on the afferent limb of the micturition reflex in spinal cord injured patients and activates inhibitory opoid receptorlike OP 4 expressed on afferent type C fibres of the bladder. 29 Recently, a randomised, placebo-controlled and double-blind study on 14 patients with neurogenic detrusor overactivity has been published and the results indicated that 1 mM nociceptin/orphanin FQ provides an acute inhibitory effect on the micturition reflex in this patient population. 30 The bladder capacity and the threshold for the appearance of detrusor overactivity increased significantly from 139 to 240 ml and from 84 to 201 ml, respectively.…”

Section: Intravesical Nociceptin/orphanin Fqmentioning

confidence: 99%

Intravesical therapy options for neurogenic detrusor overactivity

Reitz

Schurch

2004

Spinal Cord

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Objectives: This review considers intravesical treatment options of neurogenic detrusor overactivity and discusses the underlying mechanism of action, clinical safety and efficacy, and the future trends. Methods: The available literature was reviewed using medline services. Results: Oral anticholinergic drugs are widely used to treat detrusor overactivity, but they are ineffective in some patients or cause systemic side effects such as blurred vision or dry mouth. As an alternative, topical therapy strategies have been suggested to achieve a profound inhibition of the overactive detrusor and to avoid high systemic drug levels. Currently available intravesical treatment options either act on the afferent arc of the reflex such as local anaesthetics or vanilloids or on the efferent cholinergic transmission to the detrusor muscle such as intravesical oxybutynin or botulinum toxin. Although an established and effective therapy, intravesical oxybutynin is not widely used. Evidence for clinical significance of intravesical atropine and local anaesthetic is missing. Intravesical capsaicin has been shown to improve clinical and urodynamic parameters, but cause pain in some patients. The intravesical instillation of resiniferatoxin and the injection of botulinum-A toxin into the detrusor muscle are promising new options; however, randomised placebo-controlled studies to prove their safety and efficacy are still missing. Conclusion: Intravesical treatment strategies in patients with neurogenic detrusor overactivity may provide alternatives to established therapies such as oral anticholinergics. The selectivity of the intravesical treatment and the reduction or even the absence of side effects are major advantages of this topical approach.

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Urodynamic and Clinical Evidence of Acute Inhibitory Effects of Intravesical Nociceptin/Orphanin Fq on Detrusor Overactivity in Humans: A Pilot Study

Abstract: Our results demonstrate that nociceptin/orphanin FQ is able to elicit a robust inhibitory effect on voiding reflex in group 2 but not 1. The ideal dosage, route of administration of nociceptin/orphanin FQ and treatment interval are not yet established.

Cited by 41 publications

References 22 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

Intravesical therapy options for neurogenic detrusor overactivity

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