Central tachykinin NK3 receptors in the inhibitory action on the rat colonic propulsion of a new tachykinin, PG-KII
Introduction
Tachykinins are widely distributed in the central nervous system (Saffroy et al., 1988) and in the gastrointestinal tract (Mussap et al., 1993). Although they participate in the control of many gastrointestinal functions, their central and peripheral physiological role in the control of peristalsis remains unclear.
The most investigated action of tachykinins in the gut relates to their role as neuromuscular excitatory transmitters through the activation of tachykinin NK1 (substance P-preferring) or tachykinin NK2 (neurokinin A-preferring) receptors (Barthó and Holzer, 1985; Holzer-Petsche, 1995; Shuttleworth and Keef, 1995; Maggi et al., 1997). Tachykinins can also affect intestinal motility by releasing inhibitory transmitters via tachykinin NK1 and NK3 receptors (Holzer and Holzer-Petsche, 1997). Evidence for tachykinin NK1 and NK3 receptor agonist inhibition of motor activity comes mainly from in vitro studies in the canine colon (Hou et al., 1989), the rat distal colon (Scheurer et al., 1994) and the guinea pig small and large intestine (Maggi et al., 1993, Maggi et al., 1994a, Maggi et al., 1994b, Maggi et al., 1994c, Maggi et al., 1994d; Giuliani and Maggi, 1995). The role of tachykinin NK3 receptors in intestinal motility under in vivo conditions remains less clear, because of the lack of potent and selective tachykinin NK3 receptor agonists and antagonists. One study only has reported preliminary in vivo evidence that tonic activation of peripheral tachykinin NK3 receptors by endogenous tachykinins stimulates inhibitory reflexes during prolonged localised distension of the rat colon (Lecci et al., 1996). Nothing is known about the role of central tachykinin NK3 receptors in the regulation of colonic motility.
Recently, a novel kassinin-like peptide, PG-KII, (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Val-Gly-Leu-Met-NH2), has been isolated from the skin of the Australian myobatrachid frog, Pseudophryne güntheri (Simmaco et al., 1990). Our previous reports (Improta et al., 1996; Polidori et al., 1997) indicated that in the rat, after central administration, PG-KII modulates inhibition of gastric acid secretion and alcohol intake, two functions thought to be mediated mainly by tachykinin NK3 receptors. Furthermore, after peripheral administration, PG-KII stimulates saliva secretion through cholinergic pathways, as does neurokinin B (Broccardo et al., 1996). All these data provide evidence confirming PG-KII as a potent and selective tachykinin NK3 receptor agonist.
This newly available highly selective tachykinin NK3 receptor agonist seemed an important tool for investigating the role of central tachykinin NK3 receptors in the regulation of in vivo colonic motility. Continuing research into the possible physiological role of the central tachykinin NK3 receptor system in the mediation of gut motility in the rat, our main aim in this study was to characterize the actions of this novel natural tachykinin on colonic transit. Hence, we compared the effects induced on rat colonic propulsion by intracerebroventricular (i.c.v.) injection of PG-KII with those induced by various tachykinins including substance P (a tachykinin NK1-preferring receptor agonist), neurokinin A (a tachykinin NK2-preferring receptor agonist), neurokinin B (a tachykinin NK3-preferring receptor agonist) and senktide (a synthetic and selective tachykinin NK3 receptor agonist). We also evaluated the activity of PG-KII at central tachykinin receptors in rats pretreated with selective tachykinin NK1, NK2 and NK3 receptor antagonists. The fundamental role of the central opioid receptor system in modulating colonic motility (Broccardo and Improta, 1992, Broccardo and Improta, 1998) prompted us also to investigate a possible central tachykinin–opioid receptor system interaction.
Section snippets
Animals
All animal experiments complied with the Italian D.L. no. 116 of 27 January 1992 and associated guidelines in the European Communities Council Directive of 24 November 1986 (86/609/EEC). Male Wistar rats (Morini, S. Polo D'Enza, Italy) weighing 200–250 g were used for the experiments. All rats were examined at 09:00 h. Rats were placed individually in plastic cages under standard temperature conditions (22°), with 12-h light/dark cycles and food and water ad libitum.
Surgery
At least 3 days before the
Results
The mean colonic bead expulsion time for vehicle-treated rats was 2.26±0.34 min. All the tachykinins tested inhibited colonic propulsion: the rank order of potency was PG-KII=senktide≫substance P⋙neurokinin A≥neurokinin B. PG-KII (0.1, 1, 10 and 100 ng/rat) increased the mean expulsion time significantly and in a dose-related manner; the highest dose tested (100 ng/rat) increased the colonic propulsion time to 37.32±6.4 min and even a very small dose (100 pg/rat) significantly inhibited colonic
Discussion
First of all, in this study, i.c.v. injection of the natural tachykinin PG-KII potently inhibited distal colonic propulsion increasing, in a significant and dose-dependent way, the mean expulsion time of a glass bead placed in the distal colon of rats. Because R820, the most suitable tachykinin NK3 receptor antagonist currently available for studies of the rat central nervous system (Cellier et al., 1997), prevented the PG-KII-induced inhibitory effect, whereas the tachykinin NK1 and NK2
Acknowledgements
We are grateful to Dr. D. Regoli (University of Sherbrooke, Quebec, Canada) for the donation of R820. We also acknowledge Dr. A. Maggi (Menarini, Florence) for the kind gift of Men 10,376. This study was supported by grants from the Italian Ministry of University and Scientific and Technological Research.
References (40)
- et al.
Search for a physiological role of substance P in gastrointestinal motility
Neuroscience
(1985) - et al.
Antidiarrheal and colonic antipropulsive effects of spinal and supraspinal administration of the natural delta opioid receptor agonist, d-Ala-deltorphin II, in the rat
Eur. J. Pharmacol.
(1992) - et al.
Central effect of SNC80, a selective and systematically active delta opioid agonist, on gastrointestinal propulsion in the mouse
Eur. J. Pharmacol.
(1998) - et al.
Effect of PG-SPI and PG-KII, two novel and natural tachykinins, on salivary secretion in the rat
Peptides
(1996) - et al.
Visualization of neurokinin 3 receptor binding sites brain using the highly selective ligand []senktide
Brain Res.
(1990) Tachykinin receptors in gastrointestinal motility
Regul. Pept.
(1995)- et al.
Tachykinins in the gut: Part I. Expression, release and motor function
Pharmacol. Ther.
(1997) - et al.
In vitro and in vivo biological activities of PG-KII, a novel kassinin-like peptide from the skin of the Australian frog, Pseudophryne güntheri
Peptides
(1996) - et al.
Involvement of neurokinin 1 and 2 receptors in viscerosensitive response to rectal distension in rats
Gastroenterology
(1994) - et al.
Localization of the tachykinin neurokinin B precursor peptide in rat brain by immunocytochemistry and in situ hybridization
Neuroscience
(1992)
Nitric oxide is the mediator of tachykinin NK3 receptor-induced relaxation in the circular muscle of the guinea pig ileum
Eur. J. Pharmacol.
Tachykinin NK3 receptor mediates NANC hyperpolarization and relaxation via nitric oxide release in the circular muscle of the guinea pig colon
Regul. Pept.
Specialization of tachykinin NK1 and NK2 receptors in producing fast and slow atropine-resistant neurotransmission to the circular muscle of the guinea pig colon
Neuroscience
Localization of neurokinin B in the central nervous system of the rat
Peptides
Further evidence that the tachykinin, PG-KII, is a potent agonist at central NK3, but not NK1 receptors
Peptides
Colonic bead expulsion time in normal μ-opioid receptor deficient (CXBK) mice following central administration of μ and δ agonists
Life Sci.
Neurokinin receptor subtypes characterized by biological assays
Life Sci.
Localization of tachykinin binding sites (NK1, NK2, NK3 ligands) in the rat brain
Peptides
Roles of peptides in enteric neuromuscular transmission
Regul. Pept.
Six novel tachykinin- and bombesin-related peptides from the skin of the Australian frog, Pseudophryne güntheri
Peptides
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