Effects of RP 67580, a tachykinin NK1 receptor antagonist, on a primary afferent-evoked response of ventral roots in the neonatal rat spinal cord.
1. The pharmacological characteristics of RP 67580, a non-peptide tachykinin NK1 receptor antagonist, and its effects on a reflex response evoked by stimulation of primary afferent fibres, were examined in isolated neonatal spinal cord preparations of the rat. Potentials were recorded extracellularly from a lumbar ventral root and drugs were bath-applied in normal artificial cerebrospinal fluid (CSF) or in the presence of tetrodotoxin (TTX). 2. In normal artificial CSF, RP 67580 (0.1-0.3 microM) caused rightward shifts of the concentration-response curves for substance P (SP), neurokinin A (NKA) and substance P methyl ester (SPOMe), an NK1-selective agonist, with pA2 values of 7.25, 7.47 and 7.49, respectively. 3. In the presence of TTX (0.3 microM), RP 67580 also caused rightward shifts of the concentration-response curves for SPOMe and NKA. The pA2 value of RP 67580 against SPOMe (6.75) was significantly lower than that against NKA (7.22). RP 67580 (0.3-1 microM) did not cause a clear parallel shift of the concentration-response curves for SP, and it depressed the depolarizations induced by low concentrations of SP, but slightly potentiated those induced by high concentrations of SP. 4. RP 67580 (1 microM) did not depress the depolarizing responses to bombesin, L--glutamate, gamma-aminobutyric acid (GABA), thyrotropin-releasing hormone and muscarine. RP 67580 (1 microM), however, depressed the response to acetylcholine in the presence of atropine and the response to nicotine. RP 68651 (1 microM), the enantiomer of RP 67580 devoid of activity at tachykinin NK1 receptors, also depressed the response to acetylcholine in the presence of atropine. 5. RP 67580 (1 gAM) did not induce GABA release from the rat spinal cord.6. In the neonatal gerbil spinal cord, the antagonist effects of RP 67580 (0.3-1 JAM) against SPOMe were much less potent than in the neonatal rat spinal cord.7. In the rat spinal cord-saphenous nerve preparation, electrical stimulation of the saphenous nerve atC-fibre strength evoked a prolonged depolarization of the ipsilateral L3 ventral root (slow VRP).RP 67580 (0.1-1 JM) depressed the saphenous nerve-evoked slow VRP. In contrast, RP 68651 (0.3 JAM)had no effect on the slow VRP.8. The results of the present study indicate that RP67580 acts as a high affinity NK, receptor antagonist in the neonatal rat spinal cord, although it also possesses an antinicotinic action. This study further suggests the existence of a subpopulation of tachykinin NK, receptors that are activated by NKA and SPOMe, as well as by low concentrations of SP, and are sensitive to the antagonist action of RP 67580 in the neonatal rat spinal cord. This study also provides further evidence for the involvement of SP and NKA in the slow VRP evoked by C-fibre stimulation in the neonatal rat spinal cord.
Hosoki
R
R
Department of Pharmacology, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Yanagisawa
M
M
Guo
J Z
JZ
Yoshioka
K
K
Maehara
T
T
Otsuka
M
M
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D004558:Electric Stimulation; D005260:Female; D005849:Gerbillinae; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000037:antagonists & inhibitors*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D009467:Neuromuscular Depolarizing Agents; D018040:Receptors, Neurokinin-1; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid