Evidence for the participation of glutamate in reflexes involving afferent, substance P‐containing nerve fibres in the rat

Abstract

Responses mediated, either peripherally or centrally, by substance P‐containing primary afferent C‐fibres were investigated in the rat following impairment of axonal transport by colchicine (120 μg kg−1 i.p., daily for 3 days), and after treatment with the tachykinin antagonist SR‐140333 (10–100 μg kg−1, i.v.) or the N‐methyl‐D‐aspartate (NMDA) antagonist MK‐801 (100 μg kg−1). Peripheral effects mediated by afferent C‐fibres were measured by plasma protein extravasation (Evans blue method), following antidromic stimulation of the sciatic nerve, topical application of mustard oil and, as control, i.v. injection of substance P. SR‐140333 (100 μg kg−1) reduced the effects by 86%, 75% and 74%, respectively. Colchicine reduced the effects of the first two stimuli by 31% and 33% and, as expected not the effect of substance P. The increase of paw skin temperature following capsaicin i.v. was inhibited by SR‐140333, but not by colchicine. MK‐801 had no effect on the plasma protein extravasation following antidromic sciatic nerve stimulation or on the rise of paw skin temperature induced by capsaicin i.v., thus excluding an effect of MK‐801 on peripheral terminals of afferent neurones. Depressor reflexes, which are known to be mediated by capsaicin‐sensitive afferent neuones, such as those elicited (A) by a stimulating dose of 30 ng capsaicin i.a., (B) by distension of the ascending colon or (C) by afferent sciatic nerve stimulation were studied. Colchicine significantly reduced depressor reflexes A and B, but had no effect on reflex C. None of the reflexes was affected by SR‐140333. MK‐801 significantly inhibited all three reflexes. Capsaicin, injected either i.v. (200 μg kg−1) or into the nucleus caudatus/putamen (i.c., 30 μg), induced an increase in paw skin temperature and a decrease in colon temperature. The rise in fore paw skin temperature (Δt = 2.3 ± 0.4°C) evoked by capsaicin i.v. was almost completeley blocked by SR‐140333 (100 μg kg−1, i.v.), but no inhibition was observed with MK‐801, indicating that capsaicin had brought about a release of substance P from peripheral nerve terminals. Colchicine did not influence heat dissipation induced by i.v. capsaicin. When capsaicin was injected i.c., the rise in paw skin temperature in colchicine‐ and SR‐140333‐pretreated groups did not differ from that of the control group. MK‐801 totally prevented the heat loss reaction to i.c. capsaicin administration. Colchicine did not change the effects of i.v. or i.c. injected capsaicin: this excludes the involvement of a mechanism dependent on axonal transport of neurotransmitters. The reduction of axonal transport by colchicine reduced plasma extravasation induced by mustard oil and antidromic sciatic nerve stimulation (peripheral functions) and depressor reflexes evoked by i.a. capsaicin and colon distension (central functions). It can be argued that afferent stimulation of the sciatic nerve includes the stimulation of A‐fibres, which might be less sensitive to colchicine. SR‐140333 was effective only on peripherally mediated ...

In vivo effects of the NMDA receptor agonist tetrazolyl-glycine related to the function of small-diameter primary afferents

“…The depressor reflex evoked by electrical stimulation of the sciatic nerve was inhibited by MK-801 but not by the tachykinin antagonist L-742694 (10 mg kg -1 ), confirming results of Juránek and Lembeck (1996) with the tachykinin antagonist SR-140333, and also confirming the inhibition of the depressor effect by MK-801.…”

“…by electrical stimulation, by capsaicin i.a. and by intestinal distension; Juránek and Lembeck 1996). The effect of TG was inhibited by MK-801 in a dose which inhibited the depressor reflex induced by afferent nerve stimulation (see Fig.…”

“…The afferent nerve fibres contain substance P, CGRP, other peptides, and glutamate which are co-released at their central terminals in the spinal cord (Maehara et al 1995;Ueda et al 1993Ueda et al , 1994Ueda et al , 1995. The resulting depressor reflex has been shown to be inhibited by the NMDA receptor antagonist MK-801, but not by the tachykinin antagonist CP-96,345 and other tachykinin antagonists, indicating that glutamate might be the main neurotransmitter at the central terminals (Donnerer and Amann 1994;Juránek and Lembeck 1996) whereas tachykinins play a facilitatory role (Urban et al 1994). In contrast to central terminals, at the peripheral terminals only substance P and CGRP seem to be released, because the resulting plasma protein extravasation was completely inhibited by the tachykinin antagonist CP-96,345 (Lembeck et al 1992) and the neurogenic vasodilatation by a CGRP antagonist (Escott and Brain 1993).…”

N-Methyl-d-aspartate Receptor Blockade Inhibits Cardiac Inflammation in the Mg2+-Deficient Rat

“…However, taken alone, these data do not directly implicate neural SP in MgD pathology. Thus, based upon the fact that presynaptic NMDA receptors mediate, at least in part, SP release from neural terminals (Juranek and Lembeck, 1996;Liu et al, 1997;Marvizon et al, 1997), we treated MgD animals with the noncompetitive NMDA-receptor blocker dizolcipine maleate. Blockade of the NMDA receptor in MgD animals resulted in conservation of SP immunofluorescence in DRG of these animals throughout the length of the experiment.…”

Intracisternal Octreotide Does Not Ameliorate Orthodromic Trigeminovascular Nociception

“…Moreover, a small percentage of the trigeminal afferents employ somatostatin as a neuropeptide cotransmitter (24, 25). Trigeminovascular stimulation induces a glutamate release from the primary afferents (45, 46) that is mediated both by NMDA and by AMPA type glutamate receptors in the TNC I-II. Somatostatin modulates glutamate-mediated nociceptive signals (48, 49) and as such, somatostatin analogue's could be an alternative for glutamate antagonists like MK801 (44) that may have significant adverse effects.…”