Pharmacological profile of a tachykinin antagonist, spantide, as examined on rat spinal motoneurones

Yanagisawa, Mitsuhiko; Otsuka, Masanori

doi:10.1111/j.1476-5381.1990.tb14080.x

Cited by 49 publications

(26 citation statements)

References 19 publications

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“…Since it was known in peripheral tissues that acetyl-Arg6-septide and NKA preferentially act on NK, and NK2 receptors, respectively, the receptor to which NKA and acetyl-Arg6-septide bind as observed in the present study appears to be distinct from NKI, NK2 or NK3 receptor found in peripheral tissues. The existence of this novel type of receptor was suggested previously based on the similar antagonist profile of spantide against the depolarizing responses of motoneurones to NKA and acetyl-Arg6-septide (Yanagisawa & Otsuka, 1990). On the other hand, the significantly lower pA2 of GR71251 against the SP-induced depolarizing responses than against the NKA-and acetyl-Arg6-septide-induced responses may reflect involvement of another type of tachykinin receptor in the SP-induced response.…”

Section: Effects Of Gr71251 On the Dorsal Root-evoked Spinal Reflexesmentioning

confidence: 83%

Depression of primary afferent‐evoked responses by GR71251 in the isolated spinal cord of the neonatal rat

Guo

Yoshioka

Yanagisawa

et al. 1993

British J Pharmacology

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1 The pharmacological profile of GR71251, a new tachykinin receptor antagonist, and its effect on the responses evoked by stimulation of primary afferent fibres were studied in isolated spinal cord preparations of neonatal rats. Potential changes were recorded extracellularly from a lumbar ventral root (L3-L5).2 Bath-application of substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) at 0.01-3 AM to the spinal cord induced depolarization of the ventral root in normal artificial cerebrospinal fluid (CSF). The NK, agonist, acetyl-Arg6-septide, and the NK3 agonist, senktide, at 0.01-3JaM, also had potent depolarizing actions whereas two NK2 agonists, P-Ala8NKA4-10 and Nle'"NKA410, showed little depolarizing effects at 1 llM.3 GR71251 (0.3-3 lAM) caused a rightward shift of the concentration-response curves for SP, acetylArg6-septide and NKA with pA2 values of 6.14, 6.75 or 6.70, respectively. The effects of GR71251 were readily reversible within 15-30 min after its removal. By contrast, GR71251 (1-5 jAM) had little effect on the depolarizing responses to NKB and senktide.4 GR71251 (1-3 JAM) did not depress the depolarizing responses to bombesin, neuromedin B and gastrin-releasing peptide in normal artificial CSF. 5 Application of capsaicin to the spinal cord induced a depolarizing response, which was partially depressed by GR71251 (3-l10pM).6 In the isolated spinal cord preparation, intense electrical stimulation of a dorsal root evoked a slow depolarizing response of the contralateral ventral root of the same segment. A similar slow ventral root depolarization was evoked by electrical stimulation of the ipsilateral saphenous nerve in an isolated spinal cord-saphenous nerve preparation. GR71251 (0.3-10 IAM) dose-dependently depressed these slow ventral root potentials. 7 In the spinal cord-peripheral nerve preparation, conditioning stimulation of the saphenous nerve evoked an inhibition of the muscle nerve-evoked monosynaptic reflex lasting about 20 s. The late part of the inhibition was markedly depressed by GR71251 (1-3 JAM). 8 The present results indicate that GR71251 is a potent and specific antagonist for tachykinin receptors in the spinal cord. The present study further provides evidence for the involvement of SP and NKA in the slow ventral root depolarization and the prolonged inhibition of monosynaptic reflex that are evoked by primary afferent stimulation.

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Section: Effects Of Gr71251 On the Dorsal Root-evoked Spinal Reflexesmentioning

confidence: 83%

Depression of primary afferent‐evoked responses by GR71251 in the isolated spinal cord of the neonatal rat

Guo

Yoshioka

Yanagisawa

et al. 1993

British J Pharmacology

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“…Thus a number of selective NK 1 agonists mimic effects of substance P on motoneurons, e.g., substance P methyl ester and [Sar 9 Met(O 2 ) 11 ]substance P, and those effects are blocked by some NK 1 receptor antagonists, i.e., SR-140,333 (52, 365, 726). However, a number of additional NK 1 antagonists are without effect on substance P responses, i.e., (±)-CP-96,345, RP-67580, and GR-82334, or display pharmacological profiles unlike that of the classical NK 1 receptor, i.e., spantide (51,726,1402). Motoneurons may express a distinct isoform of the NK 1 receptor that possesses atypical antagonist binding characteristics (1402).…”

Section: Functional Role Of Trh In Modulating Motoneuronal Excitabilimentioning

confidence: 99%

Synaptic Control of Motoneuronal Excitability

Rekling

Funk

Bayliss

et al. 2000

Physiological Reviews

537

482

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Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre-and postsynaptic actions, signal transduction, and functional role. Glutamate is the main excitatory, and GABA and glycine are the main inhibitory transmitters acting through ionotropic receptors. These amino acids signal the principal motor commands from peripheral, spinal, and supraspinal structures. Amines, such as serotonin and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre-and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K + current, cationic inward current, hyperpolarization-activated inward current, Ca 2+ channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior.

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“…Therefore, it is ap parent that in contrast to tissues rich in the NK1-receptor subtype such as the guinea pig ileum and vas deferens, the NK1-selective antagonist preferentially antagonizes the contractile response to NKA rather than SP in the rabbit iris sphincter muscle. A similar unexpected behavior has been noted in neonatal rat spinal motoneurones (20) and hamster trachea (21) to which NKA and spantide or L 668,169 bind competitively with a high affinity. Ueda et al (11) have reported that in the isolated rabbit iris sphin cter preparation, the contractile response to SP is more prolonged not only in the time to reach the maximal response but also in washout time required to restore the original level as compared to the case of the NKA response, and yet the contractile response declines grad ually upon repetitive application of SP in contrast to no development of such tachyphylaxis to NKA.…”

Section: Resultsmentioning

confidence: 78%

Pharmacological Profiles of Muscarinic Receptors in the Longitudinal Smooth Muscle of Guinea Pig Ileum

Kunitomo

Imaizumi

Sameshima

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We characterized the pharmacological nature of the tachykinin receptor subtype mediating the contractile response to electrical transmural stimulation (ETS) in the isolated rabbit iris sphincter muscle preparation by using selective NK,-receptor antagonists, spantide and L-668,169, and a selective NK2-recep tor antagonist, L-659,877. ETS caused a biphasic contraction in this preparation: a rapidly developing cholinergic component followed by a slowly decaying tachykininergic component. The tachykininergic contractile response to ETS was effectively attenuated by spantide and L-668,169, but only slightly by L 659,877, indicating that the tachykinin receptors mediating ETS-induced contraction are of the NK, type. In the same preparation, the contractile activity of substance P (SP) was slightly more potent than that of neurokinin A (NKA). Unlike in other tissues rich in NK,-receptor subtypes, spantide and L-668,169 an tagonized the contractile response to NKA more effectively than that to SP, and the reverse was observed for L-659,877. These results strongly suggest that the tachykininergic contraction induced by ETS in the rab bit iris sphincter preparation is mediated by NK,-receptors which are activated by endogenously released NKA.

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Pharmacological profile of a tachykinin antagonist, spantide, as examined on rat spinal motoneurones

Cited by 49 publications

References 19 publications

Depression of primary afferent‐evoked responses by GR71251 in the isolated spinal cord of the neonatal rat

Depression of primary afferent‐evoked responses by GR71251 in the isolated spinal cord of the neonatal rat

Synaptic Control of Motoneuronal Excitability

Pharmacological Profiles of Muscarinic Receptors in the Longitudinal Smooth Muscle of Guinea Pig Ileum

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