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

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Abstract

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.e., abolished by ganglionectomy) superimposed. The pharmacology of the local contraction was studied in animals with acute bilateral ablation in the pelvic ganglia: the combined administration of tachykinin NK1 (S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl-acetyl)-piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2.]octane chloride (SR 140333) and NK2 c{[(β-d-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2β–5β)} (MEN 11420) receptor antagonists (given at doses of 1+0.1 μmol/kg, intravenous (i.v.), respectively) abolished the local bladder contraction induced by topical nociceptin (50 nmol/rat). These results indicate that the topical application of nociceptin onto the bladder evokes a tachykinin-mediated contraction.

Introduction

Nociceptin is a 17 aminoacid neuropeptide that acts as the endogenous ligand of opioid-like receptors (ORL1) (Henderson and McKnight, 1997). Previous studies have shown that nociceptin can inhibit transmitter release from sympathetic, parasympathetic and sensory nerves, thereby influencing several autonomic functions such as blood pressure, heart rate, and micturition (Giuliani et al., 1998). Nociceptin can inhibit the micturition reflex by acting at a peripheral and supraspinal site Giuliani et al., 1998, Lecci et al., 2000. In particular, we observed that the intravenous (i.v.) administration of nociceptin triggers a prolonged inhibition of the volume-evoked micturition reflex in urethane-anesthetized rats (Giuliani et al., 1998). This peripheral effect was ascribed to inhibition of afferent discharge from bladder sensory nerves and may also involve, to a minor extent, an inhibitory prejunctional modulation of pelvic efferent neurotransmission to the detrusor muscle (Giuliani et al., 1998). Capsaicin-sensitive afferent nerves play important roles in setting the gain for activation of micturition reflex (Lecci et al., 1998 for review). Subsequent studies showed that i.v. nociceptin can inhibit the reflex bladder contractions stimulated by topical application of capsaicin onto the rat urinary bladder (chemoceptive micturition reflex) (Giuliani et al., 1999). Moreover, systemic capsaicin pretreatment antagonizes the inhibitory effect induced by the systemic administration of nociceptin on the volume-evoked micturition reflex (Lecci et al., 2000).

Although an inhibitory effect of nociceptin on the release of sensory neuropeptides from peripheral endings of capsaicin-sensitive afferent nerves has been repeatedly described (e.g., Giuliani and Maggi, 1996, Helyes et al., 1997), there have also been reports suggesting that nociceptin may actually excite capsaicin-sensitive afferent nerves and induce the release of sensory neuropeptides such as tachykinins (Inoue et al., 1998).

In this study, we aim to assess whether nociceptin exerts a tachykinin-mediated stimulant effect on bladder motility if tested under experimental conditions suitable to detect such an excitatory effect, i.e., following its topical application onto the bladder when the volume of fluid in the viscus is kept below threshold for activation of the micturition reflex (cf. Maggi et al., 1984).

Section snippets

Material and methods

The experimental procedures used for this study have been carried out according to the Italian laws for the care and the use of laboratory animals. Male albino Wistar rats (Charles River, Calco, Italy) weighing 340–400 g were anaesthetized with urethane (1.2 g/kg, s.c.). The body temperature was kept constant at 36.5°C and the animals were tracheotomized. The right jugular vein was cannulated for i.v. administration of drugs. Both ureters were ligated to maintain a constant bladder volume

Results

When the urinary bladder was filled with an amount of fluid below the threshold (0.1–0.4 ml) for activating the micturition reflex, the application of nociceptin (5 or 50 nmol/rat) onto the serosal surface of the viscus triggered a low-amplitude tonic contraction (local) with high-amplitude phasic contractions (reflex) superimposed (Fig. 1A) in six out of eleven (dose, 5 nmol/rat) or six out of six (dose, 50 nmol/rat) preparations. The average number of nociceptin-induced reflex contractions

Discussion

Previous studies have shown that i.v. administration of nociceptin inhibits the volume- or capsaicin-evoked micturition reflex in anesthetized rats and this effect involves the inhibition of excitability of capsaicin-sensitive bladder afferent nerves Giuliani et al., 1999, Lecci et al., 2000. The present results indicated that, when nociceptin is applied topically onto the rat urinary bladder, its inhibitory effect of on distension-induced micturition reflex contractions is preceded by a

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