SUMMARY1. The pharmacological profile of Spantide, Leu1"] substance P, as a substance P (SP) antagonist was examined in isolated spinal cords of newborn rats. Potential changes were recorded extracellularly from a lumbar ventral root (L1-L5). Application of SP to the perfusion bath with a brief pressure pulse of 0 05-0-8 s duration produced a dose-dependent depolarization of the ventral root. Spantide in concentrations of 2-16 /1M depressed the depolarizing responses of the ventral root to SP in a concentration-dependent manner. The log dose-response curve of SP was shifted to the right in the presence of 16 /sM-Spantide by log 5. The responses to neurokinin A (NKA) and bombesin were similarly depressed by 16 fIMSpantide whereas the responses to noradrenaline, y-aminobutyric acid (GABA), neurotensin and thyrotrophin-releasing hormone were not affected by 16 /LMSpantide.2. In an isolated spinal cord-tail preparation of the newborn rat, brief pulse injection of capsaicin into the perfusion solution of the tail induced a depolarizing response in a lumbar ventral root (L3-L5). This response probably represents a nociceptive C fibre reflex.3. The capsaicin-induced nociceptive reflex was markedly depressed by 16#UM-Spantide and the reflex recovered its original amplitude and shape 30-60 min after removal of Spantide.4. The oapsaicin-induced nociceptive reflex was depressed by morphine (2 /SM) and dynorphin (1-13) (0-2 ,LM), and these effects were reversed by 1 /LM-naloxone. 5. In an isolated spinal cord preparation of the newborn rat, stimulation of a dorsal root with single or double shocks induced depolarizing responses of slow time course in both ipsilateral and contralateral ventral roots of the same segment. These slow depolarizing responses were also depressed by 16 /LM-Spantide. In contrast the monosynaptic reflex was not affected by 16 /sim-Spantide.6. The present results suggest that SP and NKA are involved as neurotransmitters in the capsaicin-induced nociceptive reflex in the isolated spinal cord-tail preparation of the newborn rat.
1 In order to reveal the spinal reflexes involving the transmitter action of substance P (SP), the effects of capsaicin and an SP antagonist on the isolated spinal cord of the neonatal rat were studied. 2 When a single shock stimulus was given to a dorsal root (L3 -L5) or a sciatic nerve, depolarizing responses of various time courses were recorded extracellularly from both ipsi-and contra-lateral ventral roots of the corresponding segments. The reflex response recorded from the contralateral ventral root consisted of fast and slow components, which will be referred to as contralateral fast and slow ventral root potentials (v.r.ps). The latter contralateral slow v.r.p. had a time-to-peak of 2-5 s and lasted 10-30 s. 3 The threshold for the contralateral slow v.r.p. was about two times higher than that for the monosynaptic reflex, and it coincided with the threshold for activating the slow-conducting afferent fibres. depressed the SP-induced depolarizing response recorded from the ventral root whereas the responses to noradrenaline, 5-hydroxytryptamine, neurotensin and thyrotrophin releasing hormone (TRH) were unaffected by the SP antagonist. The response of the ventral root to acetylcholine was slightly depressed by the antagonist. The SP antagonist at 5 -10IM did not exert any agonist action on the motoneurones. 6 The present results in conjunction with those of previous studies support the hypothesis that SP released from certain primary afferent fibres acts as a neurotransmitter, producing in dorsal horn neurones slow excitatory postsynaptic potentials which lead to the generation of the contralateral slow v.r.p.
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.
1 The pharmacological profile of a tachykinin antagonist, [D-Arg1, D-Trp7'9, Leu"] substance P (spantide), was studied on motoneurones of the isolated spinal cord of the newborn rat. For this purpose, potentials were recorded from a lumbar ventral root extracellularly and drugs were bath-applied in the presence of tetrodotoxin (TTX). 2 Neurokinin A (NKA), a NK2-receptor selective agonist, induced concentration-dependent depolarizations, which were antagonized by spantide. Analyses of concentration-response curves suggested a competitive type antagonism with a pA2 of 6.5.3 Depolarizations induced by acetyl-Arg6-septide, a NK,-receptor selective agonist, were also antagonized by spantide with a pA2 of 6.5.4 Spantide (0.5-16 pM) had no depolarizing action on the ventral root in the presence of TTX.5 Spantide antagonized the depolarizing action of substance P (SP) when SP was applied at low concentrations (0.1-0.3 pM) or by short duration pulses in artificial cerebrospinal fluid containing TTX, but much higher concentrations of spantide (4-10UM) were needed to exert an antagonistic action against SP than against acetyl-Arg6-septide or NKA. 6 Thyrotrophin-releasing hormone, L-glutamate, GABA, and noradrenaline, also induced depolarizations of the ventral root in the presence of TTX but the responses to these agonists were not depressed by spantide (16pM). 7 These results suggest that there is a subtype of tachykinin receptors on neonatal rat spinal motoneurones to which NKA, acetyl-Arg6-septide and spantide bind competitively with high affinity. The present results also suggest the existence on rat motoneurones of another class or other classes of tachykinin receptors that are less sensitive to the antagonistic action of spantide.
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