Pharmacological characterization of GR82334, a tachykinin NK 1 receptor antagonist, in the isolated spinal cord of the neonatal rat

Abstract

Pharmacological characteristics of [ d-Pro 9,[spiro-γ-lactam]Leu 10,Trp 11]physalaemin-(1–11) (GR82334), a tachykinin NK 1 receptor antagonist, and its effects on slow depolarizing responses of lumbar ventral roots evoked by primary afferent stimulation were examined in isolated spinal cord preparations of neonatal rats. GR82334 (1–3 μM) caused dose-dependent rightward shifts of the concentration-response curves for substance P, substance P methyl ester, δ-aminovaleryl [Pro 9, N-Me-Leu 10]substance P-(7–11) (GR73632) and neurokinin A in normal artificial cerebrospinal fluid and those for substance P methyl ester, GR73632 and neurokinin A in the presence of tetrodotoxin. GR82334 (10 μM) did not evoke γ-aminobutyric acid (GABA) release from spinal cords of neonatal rats, whereas [ d-Pro 9,[spiro-γ-lactam] Leu 10,Trp 11]substance P (GR71251), another tachykinin NK 1 receptor antagonist, induced a significant increase in GABA release. GR82334 (1–3 μM) markedly depressed the slow depolarizing response of ventral roots, referred to as slow ventral root potential, evoked by stimulation of the contralateral dorsal root or the ipsilateral saphenous nerve. In contrast, cyclo[Gln,Trp,Phe,Gly,Leu,Met] (L-659,877, 1 μM), a selective tachykinin NK 2 receptor antagonist, did not depress the saphenous nerve-evoked slow ventral root potential and did not antagonize the action of neurokinin A to induce ventral root depolarization. The present results provide further evidence for the involvement of substance P, neurokinin A and tachykinin NK 1 receptors in the primary afferent-evoked slow ventral root potentials.