Nociceptin and the micturition reflex.

The i.v. administration of nociceptin (10-100 nmol/kg) inhibits the micturition reflex in a naloxone-resistant manner.

Nociceptin and neurotransmitter release in the periphery.

Nociceptin exerts a general modulatory effect on transmitter release from sympathetic, parasympathetic, NANC and sensory nerve endings in the peripheral nervous system in various species. This effect occurs at a prejunctional level and is independent from the activation of mu, delta and kappa opioid receptors. Despite the growing evidence describing the peripheral activity of nociceptin since its discovery in 1995, the lack of selective and potent antagonists does not allow us to draw conclusions on the putative physiological role of this peptide at this level.

MRI of spinal cord in MS.

Over the last 10 - 15 years, magnetic resonance imaging techniques have had a major impact in understanding and managing multiple sclerosis. The present review briefly summarises the current usefulness of spinal cord MRI in MS disease, examining the frequency, distribution and main characteristics of spine MS plaques; the differential diagnosis with other spinal cord disease was also described. Finally we considered how newer imaging sequences when added to semi-automated quantitative methods, may give us a putative tool to reliably quantify subtle changes which develop on the spinal cord of MS patients over time.

Effect of nepadutant at tachykinin NK(2) receptors in human intestine and urinary bladder.

We have characterized the action of the tachykinin NK(2) receptor antagonist nepadutant (c¿[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2 beta-5 beta)¿) in the human isolated ileum, colon and urinary bladder. Nepadutant (30-1000 nM) competitively antagonized neurokinin A- or [beta Ala(8)]neurokinin A-(4-10)-induced contractions in all tissues, with pK(B)=8.3 (ileum and colon) and pK(B)=8.

Pharmacological evaluation of the role of cyclooxygenase isoenzymes on the micturition reflex following experimental cystitis in rats.

Prostanoids, generated from cyclooxygenase (COX) isoenzymes, play a role in the physiological function of the lower urinary tract and are important mediators of inflammatory hyperalgesia. The present work evaluates the effects of the COX-1/COX-2 inhibitor dexketoprofen as well as of a selective COX-2 inhibitor, NS-398, on urodynamic function following endotoxin (LPS) or cyclophosphamide (CYP)-induced inflammation of the urinary bladder. The application of arachidonic acid (330 microgram rat(-1)) onto the serosal surface of the urinary bladder in control rats elicited bladder contractions which could be blocked in a dose-dependent manner by dexketoprofen (0.

Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability.

Recent MRI studies in multiple sclerosis have highlighted the potential role of brain atrophy evaluation as a putative marker of disease progression. In the present study, we evaluated the supratentorial and infratentorial brain volume in patients with relapsing remitting multiple sclerosis (RR MS) and in healthy subjects. Moreover, we determined whether brain volumes of MS patients are associated with different aspects of brain MRI abnormalities and clinical findings.

Tachykinin-mediated effect of nociceptin in the rat urinary bladder in vivo.

The application of nociceptin (5-50 nmol/rat) onto the serosa in the urinary bladder of urethane-anaesthetized rats, with the intravesical volume kept below threshold for activation of the micturition reflex, induced a low amplitude tonic contraction (local, i.e., resistant to ganglionectomy) with high amplitude phasic contractions (reflex, i.

Characterization of bradykinin B(2) receptor antagonists in human and rat urinary bladder.

The effect of three selective bradykinin B(2) receptor antagonists, MEN11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-1 0alpha)), Icatibant (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH), and FR173567 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2, 4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl]acrylamide) was evaluated in the human and rat urinary bladder in vitro and in vivo in anaesthetized rats. Bradykinin evoked a concentration-dependent contraction of human (pD(2)=7.2) and rat (pD(2)=7.

Tachykinin NK(1)receptor-mediated inhibitory responses in the guinea-pig small intestine.

We used in vivo, in vitro studies and immunohistochemistry to elucidate the mechanisms activated by tachykinin NK(1)receptors in evoking inhibitory motor response in the guinea-pig small intestine. In vivo, the selective NK(1)receptor agonist GR 73,632 produced a dose-dependent suppression of the distension-induced duodenal contractions, and a decrease of basal tone. These effects were reduced by pretreatment with the NK(1)receptor antagonist SR 140,333.

Multiple sites of action in the inhibitory effect of nociceptin on the micturition reflex.

Purpose: Nociceptin, the endogenous peptide ligand for the opioid receptor-like1 (ORL1) receptors, exerts a naloxone-resistant suppressant effect on micturition reflex after intravenous administration. This work aims to elucidate the mechanism and the site of action of the inhibitory effect of nociceptin on the micturition reflex.

Materials And Methods: The bladder of urethane-anesthetized rats was cannulated through the dome (cystometries) or the urethra in isovolumetric conditions (distension-induced reflex contractions, DIRCs).

Nociceptin protects capsaicin-sensitive afferent fibers in the rat urinary bladder from desensitization.

Chemical stimulation of primary afferent nerves in the rat urinary bladder in vivo with topical capsaicin (1 microg in 50 microl saline) determines a dual motor response, consisting of a contractile effect mediated by tachykinins released from sensory nerves in the bladder wall and a transient activation of a bladder-to-bladder micturition reflex organized at the supraspinal level (chemoceptive micturition reflex). Both responses undergo complete desensitization upon repeated applications of capsaicin. The i.

Neurophysiological evaluation of areflexia in Holmes-Adie syndrome.

Purpose: To evaluate ankle areflexia in Holmes-Adie syndrome (HAS).

Patients And Methods: Hoffmann (H) and Tendon (T) soleus reflexes, tonic vibration reflex (TVR), and polysynaptic extension reflex of soleus muscle (PERS) were evaluated in eight patients with idiopathic HAS. Motor (MNCV) and sensory (SNCV) nerve conduction velocities, compound motor-action potential (CMAP), and sensory action potential (SAP) were also determined in upper and lower limbs.

Kinin B1 receptor-mediated motor responses in normal or inflamed rat urinary bladder in vivo.

The rat urinary bladder is one of the few in vivo preparations in which kinin B1 receptor-mediated contractile responses have been described, but the nature (local or reflex) of these responses has not been characterized. We have investigated the motor effects of i.v.

Characterization of nociceptin receptors in the periphery: in vitro and in vivo studies.

Nociceptin (NC), a series of NC fragments, naloxone as well as the pseudopeptide [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2) were used to characterize NC receptors in peripheral isolated organs and in vivo. Experiments on isolated organs were performed in the mouse (mVD) and rat (rVD) vas deferens (noradrenergic nerve terminals), in the guinea pig ileum (gpI; cholinergic nerves) and in the renal pelvis (gpRP; sensory nerves), and, in vivo, by measuring the blood pressure (BP) and heart rate (HR) in anaesthetised rats. NC, NCNH2 and NC(1-13)NH2 acted as full agonists with similar affinities, while shorter fragments (e.

Effect of dexamethasone on cyclophosphamide-induced cystitis in rats: lack of relation with bradykinin B1 receptor-mediated motor responses.

We investigated the role of bradykinin B receptors in inducing urinary bladder contraction and maintaining bladder compliance in anaesthetized rats following cyclophosphamide-induced bladder inflammation and the influence of dexamethasone treatment on these responses. In the group treated with cyclophosphamide the amplitude of the contraction induced by the selective bradykinin B1 receptor agonist des-Arg9-bradykinin was larger than that in controls and dexamethasone prevented the up-regulation of this response induced by inflammation. The specific binding of [3H]des-Arg10-kallidin to bladder membranes was only detected in cyclophosphamide-treated rats: this binding was prevented by dexamethasone pretreatment.

Capsaicin pretreatment does not alter rat urinary bladder motor responses induced by a kinin B1 receptor agonist after endotoxin treatment.

The kinin B1 receptor is generally expressed after inflammation or tissue injury. Kinin B1 receptor stimulation induces excitatory motor responses in the urinary bladder and, in this preparation, the effect of many excitatory transmitters involves the stimulation of capsaicin-sensitive afferent nerves. In this study we have investigated the effect of capsaicin pretreatment on the bladder contractions induced by [Sar0, D-Phe8, des-Arg9]bradykinin (SDABK), a kinin B1 receptor agonist, by inducing the expression of B1 receptors via the intravesical administration of a bacterial endotoxin (LPS, 1 mg/ml) in urethane-anaesthetized rats.

Tachykinin NK2 receptors in the hamster urinary bladder: in vitro and in vivo characterization.

We have characterized the contractile responses produced by stimulation of the tachykinin NK2 receptor in the hamster urinary bladder in vitro and in vivo. In isolated bladder strips, neurokinin A (NKA, pD2 7.40, Emax 71% of the response to 80 mM KCl) and the synthetic tachykinin NK2 receptor selective agonist [betaAla8]NKA(4-10) (pD2 7.

The inhibitory effect of nociceptin on the micturition reflex in anaesthetized rats.

1. We have investigated the effect of nociceptin on the micturition reflex evoked by distension or topical application of capsaicin on the urinary bladder of urethane-anaesthetized rats. 2.

Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK2 receptor antagonist, in guinea-pigs.

We have investigated the antibronchoconstrictor activity of a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist, MEN 11420 c¿[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta++ +)¿, as compared to MEN 10627 c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2beta-5beta)] and to the nonpeptide antagonist SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenylpiperidino-2-3,4-dichlorophenyl)bu tyl] benzamide. In the guinea-pig isolated bronchus MEN 11420 (pK(B) 8.40+/-0.

Bladder distension and activation of the efferent function of sensory fibres: similarities with the effect of capsaicin.

1. The effects of the tachykinin NK2 receptor antagonist MEN 11420 (100 nmol kg(-1), i.v.

Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats.

1. We have developed and characterized a model of immediate hypersensitivity/inflammation of the urinary bladder in vivo induced by local application of ovalbumin (OA) in OA- sensitive female rats. Two parameters of the inflammatory response were assessed following OA challenge: plasma protein extravasation (PPE) and changes in smooth muscle reactivity.

The role of tachykinin NK1 and NK2 receptors in atropine-resistant colonic propulsion in anaesthetized guinea-pigs.

1. The role of endogenous tachykinins on guinea-pig colonic propulsion was investigated by using potent and selective tachykinin NK1 and NK2 receptor antagonists. Colonic propulsion and contractions were determined by means of a balloon-catheter device, inserted into the rectum of guanethidine (68 micromol kg(-1), s.

Effect of tachykinin NK2 receptor blockade on detrusor hyperreflexia induced by bacterial toxin in rats.

Purpose: To see whether a recently characterized model of bacterial toxin-induced urinary bladder inflammation (Stein et al., J. Urol.

MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist.

1. The pharmacological profile was studied of MEN 11420, or cyclo[[Asn(beta-D-GlcNAc)-Asp-Trp-Phe-Dap-Leu]cyclo(2beta-5beta )], a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2beta-5beta)). 2.

MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon.

We have characterized the action of the novel, water-soluble, tachykinin NK2 receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2 beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo. In organ bath experiments on guinea-pig colon MEN 11420 produced a concentration-dependent rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10) with a pKB value of 8.1.