Agonist and antagonist binding to tachykinin peptide NK-2 receptors

The saphenous nerve-evoked slow v.r.p. was depressed by [Met5] enkephalin (0.1-1 EM), dynorphin (1-13X0.2 gM) and morphine (1-2 pM), and these effects were reversed by naloxone (1 pM).6 Two endogenous peptides, galanin (1-2 pM) and somatostatin (1-2.5 pM), inhibited the slow v.r.p. evoked by saphenous nerve stimulation, whereas another endogenous peptide, calcitonin generelated peptide (0.1-0.5 pM), potentiated the slow v.r.p. The slow v.r.p. was also inhibited by yaminobutyric acid (GABA, 20pM) and muscimol (0.2 pM), and their effects were antagonized by bicuculline (1 pM). 7 The present results suggest that substance P and neurokinin A are involved in the saphenous nerve-evoked C-fibre response in the spinal cord of the newborn rat.

Section: Discussionmentioning

confidence: 98%

Pharmacological properties of a C‐fibre response evoked by saphenous nerve stimulation in an isolated spinal cord‐nerve preparation of the newborn rat

Nussbaumer

Yanagisawa

Otsuka

1989

“…The amino acid sequences of TK antagonists studied are shown in Table 1: spantide is a well known SP antagonist with some selectivity (about 10 times) for NK1 over NK2 receptors (Buck & Shatzer, 1988) Maggi et al, 1990a) in which Arg in position 11 has been replaced by Lys. Both MEN 10,207 and MEN 10,376 are highly selective NK2 receptor antagonists which discriminate between putative NK2 receptor subtypes (Maggi et al, 1990a;Van Giesbergen et al, 1991;Maggi et al, unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…Although quantitatively small, this inhibitory effect further suggested an involvement of TKs. However, the 'first generation' of TK antagonists, developed by insertion of multiple D-Trp on the backbone of SP, suffers from several drawbacks, including (a) a poor ability to discriminate between NK, and NK2 receptors (Buck & Shatzer, 1988) and (b) ability to antagonize peptides not related to TKs, such as bombesin (Jensen et al, 1984). The latter finding is particularly important for the topic for capsaicin-induced contraction of the rat bladder, inasmuch as bombesin-like peptides have been described as present in capsaicin-sensitive primary afferents (see Holzer 1988 for review) and bombesin itself is a powerful spasmogen in the rat isolated urinary bladder (Abdel-Hakim et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

“…The working hypothesis was that both SP and NKA contribute to the overall response to capsaicin and that both NK1 and NK2 receptors may be involved. With this aim, we first evaluated the effect of low concentrations of SP and NKA alone and in combination in comparison with the response to capsaicin and then assessed the effect of spantide, a SP antagonist of the first generation endowed with some selectivity for the NK1 receptor (Leander et al, 1981;Buck & Shatzer, 1988) and of some newly developed selective antagonists which discriminate between NK1 and NK2 receptors Williams et al, 1988;Maggi et al, 1990a). The effects of bombesin and P2X purinoceptor desensitization by the stable ATP analogue ac,f8-methylene ATP were also investigated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tachykinin antagonists and capsaicin‐induced contraction of the rat isolated urinary bladder: evidence for tachykinin‐mediated cotransmission

Maggi

Patacchini

Santicioli

et al. 1991

1 The possible involvement of tachykinins (TKs) in the contraction produced by capsaicin in the rat isolated urinary bladder was addressed on the hypothesis that co-release of substance P (SP) and neurokinin A (NKA) occurs from sensory nerve terminals. 2 A low concentration of SP (30 nM) produced a rapid contraction which faded to baseline within 10min. A low concentration of NKA (10nM) produced a slowly developing contraction which was still evident at 10min. Capsaicin (1 pM) produced a rapid phasic response and a tonic response (late response to capsaicin). Co-administration of SP and NKA mimicked the response to capsaicin more than each TK alone. 3 Fading of the response to SP was not caused by receptor desensitization and was partially prevented by peptidase inhibitors.4 Spantide (3pM) selectively antagonized the SP-induced contraction while L-659,877 (3-lOpM) or MEN 10,376 (10-30pM) which are NK2 receptor selective antagonists selectively blocked the response to NKA.Co-administration of spantide and L-659,877 inhibited the response to both SP and NKA by an amount not greater than that produced by each antagonist alone. 5 Spantide selectively reduced the peak response to capsaicin, while leaving the late response unaffected.L-659,877 (3 pM) and MEN 10,376 (10pM) selectively inhibited the late response to capsaicin while, at higher concentrations, also reduced the peak response to capsaicin. Co-administration of spantide and L-659,877 reduced the peak response to capsaicin more than that produced by each antagonist alone. 6 Bombesin (10nM) produced a tonic contraction similar to that induced by NKA. The response to bombesin was not affected by spantide, L-659,877 or MEN 10,376. 7 P2. purinoceptor desensitization by repeated administration of a,fl-methylene ATP depressed the twitch response to electrical stimulation of postganglionic nerves but did not affect the peak or the late response to capsaicin. 8 We conclude that multiple TKs are coreleased by capsaicin in the rat bladder and mediate the capsaicin-induced contraction by activating both NKI and NK2 receptors. Endogenous TK with preferential affinity for the NK, receptor (putatively SP) are selectively involved in the peak response to capsaicin while endogenous TK with preferential affinity for the NK2 receptor (putatively NKA) are selectively involved in the late response to capsaicin and partly contribute to the peak response. These findings provide pharmacological evidence for tachykinin-mediated cotransmission in the rat urinary bladder. ATP is unlikely to be involved in the efferent function of capsaicin-sensitive sensory nerves in the rat bladder.

“…Pharmacological evidence for an involvement of endogenous TKs in atropine-resistant peristalsis of the ileum comes from studies using TK antagonists of the first generation, such as Spantide I or substance P. These substances have been shown to inhibit atropine-resistant, nerve-mediated longitudinal contractions (Bjbrkroth, 1983;Bartho et al, 1983) as well as the atropine-resistant components of the peristaltic reflex and of the ascending enteric reflex (Bartho et al, 1982a,b;Costa et al, 1985a,b;Grider, 1989;Holzer, 1989 (Regoli, 1985;Buck & Shatzer, 1988) and consequently, the relative role of substance P (SP) and NKA in the overall response cannot be deduced. With the introduciton of new, second generation TK antagonists, specific for different types of TK receptors, it has become possible to obtain more information about the relative contributions of different receptor types and, consequently, of the various TKs, in nerve-mediated responses in different tissues (Maggi et al, 1991a,b).…”

Section: Acteristicsmentioning

confidence: 99%

Tachykininergic transmission to the circular muscle of the guinea‐pig ileum: evidence for the involvement of NK₂ receptors

Barthó

Santicioli

Patacchini

et al. 1992

1 The effect of newly developed, receptor-selective tachykinin antagonists (GR 71,251 for NK1 receptors, MEN 10,376 and L 659,877 for NK2 receptors) on noncholinergic transmission to the circular muscle of the guinea-pig ileum has been investigated. 2 In circular muscle strips of the ileum, electrical field stimulation in the presence of atropine (2 jM) and apamin (0.1 jAM) evoked a complex motor response. The tonic primary contraction in this response was reduced by GR 71,251 (10 jM) and MEN 10,376 (3-10 I1M) but not by L 659,877 (up to 10 jM). The presence of apamin was necessary in this experimental arrangement to unmask an atropine-resistant primary contraction, sensitive to tachykinin antagonists. The motor response was abolished by tetrodotoxin.3 In circular strips of the ileum GR 71,251 (10 jM) inhibited the tonic contraction produced by [Sar9] substance P sulphone, a selective NK1 receptor agonist but not that produced by [,B Alal] neurokinin A (4-10), a selective NK2 receptor agonist. By contrast, MEN 10,376 antagonized the effect of the NK2 agonist while leaving the response to the NK, agonist unaffected. 4 In whole segments of the ileum, distension of the gut wall by an intraluminal balloon placed at about 1 cm from the point of recording of mechanical activity of the circular muscle produced atropinesensitive phasic contractions (ascending enteric reflex). In the presence of atropine (2 jiM), a noncholinergic response was elicited, which required larger volumes of distension that the cholinergic one. The atropine-resistant ascending enteric reflex was enhanced by apamin (0.1 j1M) and abolished by tetrodotoxin, either in the presence or absence of apamin. 5 MEN 10,376 (3-lOM) inhibited the atropine-resistant ascending enteric reflex in the presence of apamin while GR 71,251 or L 659,877 (10 lM each) were ineffective. MEN 10,376 inhibited the atropine-resistant ascending enteric reflex to a larger extent in the absence than in the presence of apamin and also slightly inhibited the ascending enteric reflex in the absence of atropine. 6 These findings provide evidence for an involvement of NK2 tachykinin receptors in excitatory transmission to the circular muscle of the guinea-pig ileum. NK2 receptors are also involved in the physiological-like circular muscle activation produced by stimulation of intramural neuronal pathways which subserve the atropine-resistant ascending enteric reflex.