共查询到20条相似文献,搜索用时 31 毫秒
1.
Neuronal discriminator formed by metabotropic gamma-aminobutyric acid receptors. J. Neurophysiol. 80: 3365-3368, 1998. Neurotransmitters function in one of two modes, promoting either inhibition or excitation. However, the metabotropic gamma-aminobutyric acid receptor (GABABR) system can switch between these modes. In the presence of a small excitatory stimulus, the GABABR mediates a shunting inhibition that suppresses excitation. However, in the presence of a strong excitatory stimulus, the GABABR potentiates the response. This bipartite action is accomplished by linking the GABABR to two electrogenic mechanisms; one activates an outward current and another reduces an outward current. As a consequence, the GABABR serves as a discriminator that reduces the influence of weak signals while augmenting responses to strong signals. In retinal ganglion cells, this mechanism acts to promote the communication of phasic information. 相似文献
2.
It has been established that GABAA and GABAB receptors can exist separately and/or co-exist in the membrane of dorsal root ganglion neurons. In our previous investigation it has been shown that co-existence of these two kinds of receptors is about 80% of the neurons examined (20/25). The present study was aimed to explore whether the activation of these two kinds of receptors could interact with each other using intracellular and whole-cell patch-clamp recordings. Baclofen, a specific GABAB receptor agonist, was found to exert negative modulatory effects on the responses mediated by GABAA receptor. In experiments with intracellular recording, GABA (0.3-1000 microM)- and muscimol (100-1000 microM)-induced depolarization was attenuated markedly and reversibly by preapplication of baclofen (100 microM) (15/21 and 17/21, respectively). In whole-cell patch-clamp recordings GABA (100 microM) and two specific GABAA receptor agonists, muscimol (10 microM) and isoguvacine (50 microM), activated currents were inhibited markedly by preapplication of baclofen 30 s or more and the inhibition was concentration dependent (1-100 microM baclofen) and reversible. The possible mechanisms underlying the inhibition by baclofen of the responses mediated by GABAA receptor and the physiological significance implicated are discussed. 相似文献
3.
In the CNS, gamma-aminobutyric acid (GABA) affects neuronal activity through both the ligand-gated GABAA receptor channel and the G protein-coupled GABAB receptor. In the mature nervous system, both receptor subtypes decrease neural excitability, whereas in most neurons during development, the GABAA receptor increases neural excitability and raises cytosolic Ca2+ levels. We used Ca2+ digital imaging to test the hypothesis that GABAA receptor-mediated Ca2+ rises were regulated by GABAB receptor activation. In young, embryonic day 18, hypothalamic neurons cultured for 5 +/- 2 days in vitro, we found that cytosolic Ca2+ rises triggered by synaptically activated GABAA receptors were dramatically depressed (>80%) in a dose-dependent manner by application of the GABAB receptor agonist baclofen (100 nM-100 microM). Coadministration of the GABAB receptor antagonist 2-hydroxy-saclofen or CGP 35348 reduced the inhibitory action of baclofen. Administration of the GABAB antagonist alone elicited a reproducible Ca2+ rise in >25% of all synaptically active neurons, suggesting that synaptic GABA release exerts a tonic inhibitory tone on GABAA receptor-mediated Ca2+ rises via GABAB receptor activation. In the presence of tetrodotoxin the GABAA receptor agonist muscimol elicited robust postsynaptic Ca2+ rises that were depressed by baclofen coadministration. Baclofen-mediated depression of muscimol-evoked Ca2+ rises were observed in both the cell bodies and neurites of hypothalamic neurons taken at embryonic day 15 and cultured for three days, suggesting that GABAB receptors are functionally active at an early stage of neuronal development. Ca2+ rises elicited by electrically induced synaptic release of GABA were largely inhibited (>86%) by baclofen. These results indicate that GABAB receptor activation depresses GABAA receptor-mediated Ca2+ rises by both reducing the synaptic release of GABA and decreasing the postsynaptic Ca2+ responsiveness. Collectively, these data suggest that GABAB receptors play an important inhibitory role regulating Ca2+ rises elicited by GABAA receptor activation. Changes in cytosolic Ca2+ during early neural development would, in turn, profoundly affect a wide array of physiological processes, such as gene expression, neurite outgrowth, transmitter release, and synaptogenesis. 相似文献
4.
The trk gene family members; the neurotrophic receptors for neurotrophins, are implicated in the survival and the differentiation of neurons. The roles of these protooncogenes have been argued in the pathological conditions and in the specific developmental stage when the programmed cell death occurs to neurons. Here we studied a physiological role of the trk family members in the retina through observations of their gene regulation by light/darkness exposure. Northern blot analysis and immunohistochemistry demonstrate that trkB and trkC are up-regulated by light exposure and down-regulated by darkness in the rod/cone layer, the outer nuclear layer, and the ganglion cell layer. This physiological regulation suggests that these trk family members play a protective role from the damaging effect of light exposure in the retinal neurons. 相似文献
5.
A Meyer-Franke GA Wilkinson A Kruttgen M Hu E Munro MG Hanson LF Reichardt BA Barres 《Canadian Metallurgical Quarterly》1998,21(4):681-693
Here, we describe a novel mechanism for the rapid regulation of surface levels of the neurotrophin receptor TrkB. Unlike nodose ganglion neurons, both retinal ganglion cells (RGCs) and spinal motor neurons (SMNs) in culture display only low levels of surface TrkB, though high levels are present intracellularly. Within minutes of depolarization or cAMP elevation, surface TrkB levels increase by nearly 4-fold, and this increase is not blocked by cycloheximide. These findings suggest that activity and cAMP elevation rapidly recruit TrkB to the plasma membrane by translocation from intracellular stores. We propose that a fundamental difference between peripheral nervous system (PNS) and central nervous system (CNS) neurons is the activity dependence of CNS neurons for responsiveness to their peptide trophic factors and that differences in membrane compartmentalization of the receptors underlie this difference. 相似文献
6.
GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals. 相似文献
7.
The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABAA agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABAA receptor antagonist bicuculline. In contrast, the GABAB agonist baclofen decreased, while 2-OH-saclofen (a GABAB antagonist) increased DA release in the NAcc. However, when VTA GABAB receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABAA receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABAA determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABAA receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABAA receptors on both tegmental DA and non-DA neurons. 相似文献
8.
GABABR1 clones were isolated from a human cerebellum library. The human sequence is very similar to rat GABABR1 with the cDNAs sharing 91.3% sequence identity and the receptors sharing 98.6% amino acid sequence identity. Northern blotting has shown that the receptor is brain-specific with a widespread distribution throughout the brain but none detected in the spinal cord. 相似文献
9.
10.
gamma-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5-7 day old) and adult (27-34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and D(-)2-amino-5-phosphovaleric acid (-AP5, 50 microM) with 2(triethylamino)-N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blocked by P-3-aminoprophyl -P-diethoxymethylphosphoric acid (CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 microM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites. 相似文献
11.
The actions of dopamine are mediated by specific, high-affinity, G protein-coupled receptors. Multiple subtypes of dopamine receptors have been characterized, including the D2 subtype (D2R). Cells within the dorsal root and petrosal ganglia of the rat express D2R messenger RNA (mRNA) consistent with D2R expression by primary sensory neurons. We hypothesized that neurons of the trigeminal ganglion express D2R mRNA. Total cellular RNA from rat trigeminal ganglia was analyzed on Northern blots under high stringency conditions. Hybridization of trigeminal ganglion RNA resulted in a signal which comigrated with striatal, pituitary, and hypothalamic D2R mRNA. To determine the distribution of D2R expressing cells in the trigeminal ganglion, cryostat sections were analyzed by in situ hybridization followed by emulsion autoradiography. We identified a population of clustered cells labeled with dense grain concentrations over their cytoplasms. These findings demonstrate the expression of D2 dopamine receptor mRNA in discrete subpopulations of neurons in the rat trigeminal ganglion. Our observations suggest that drugs active at dopamine receptors of the D2 subtype are potential modulators of sensory activity of neurons whose cell bodies reside in the trigeminal ganglion. D2 dopamine receptors may thus have a role in clinical pain syndromes involving the head and neck. 相似文献
12.
Perigeniculate neurons form an interactive sheet of cells that inhibit one another as well as thalamocortical neurons in the dorsal lateral geniculate nucleus (LGNd). The inhibitory influence of the GABAergic neurons of the perigeniculate nucleus (PGN) onto other PGN neurons was examined with intracellular recordings in vitro. Intracellular recordings from PGN neurons during the generation of spindle waves revealed barrages of EPSPs and IPSPs. The excitation of local regions of the PGN with the local application of glutamate resulted in activation of IPSPs in neighboring PGN neurons. These IPSPs displayed an average reversal potential of -77 mV and were blocked by application of bicuculline methiodide or picrotoxin, indicating that they are mediated by GABAA receptors. In the presence of GABAA receptor blockade, the activation of PGN neurons with glutamate could result in slow IPSPs that were mediated by GABAB receptors in a subset (40%) of cells. Similarly, application of specific agonists muscimol and baclofen demonstrated that PGN neurons possess both functional GABAA and GABAB receptors. Examination of the axon arbors of biocytin-filled PGN neurons often revealed the presence of beaded axon collaterals within the PGN, suggesting that this may be an anatomical substrate for PGN to PGN inhibition. Functionally, activation of inhibition between PGN neurons could result in a shortening or a complete abolition of the low threshold Ca2+ spike or an inhibition of tonic discharge. We suggest that the mutual inhibition between PGN neurons forms a mechanism by which the excitability of these cells is tightly controlled. The activation of a point within the PGN may result in the inhibition of neighboring PGN neurons. This may be reflected in the LGNd as a center of inhibition surrounded by an annulus of disinhibition, thus forming a "center-surround" mechanism for thalamic function. 相似文献
13.
Chick ciliary ganglion neurons receive innervation from a single source, the accessory oculomotor nucleus (AON), and nicotinic ACh receptors (AChRs) mediate chemical synaptic transmission through the ganglion. Previous experiments examining the developmental expression of AChRs in embryonic chick ciliary ganglion neurons in situ have shown that AChR levels increase substantially in the neurons at the time of innervation. Prior to synapse formation, few AChRs are detected in the neurons. In the present experiments, the role of presynaptic inputs in inducing an increase in AChRs was established by examining AChR levels in ciliary ganglion neurons that have been deprived of innervation by surgical ablation of the AON prior to synapse formation. AChR levels were dramatically reduced in neurons of input-deprived ganglia as compared to control innervated neurons at all developmental stages examined from embryonic day (ED) 5 to ED 12 as determined by indirect immunocytochemical labeling of frozen ganglion sections with the anti-AChR monoclonal antibody mAb 35, and light microscopy. In contrast, neuronal somata of input-deprived and control ganglia had equivalent levels of immunolabeling for three other components, a transmembrane glycoprotein of synaptic vesicles, SV2, and two microtubule-associated proteins, MAP 1B and MAP 2, from ED 5 up to ED 10. The results demonstrate that presynaptic inputs specifically increase the levels of AChR expression in developing neurons. In addition, changes in the levels of immunolabeling for AChRs, SV2, MAP 1B, and MAP 2 in neuronal somata after ED 10 demonstrate that other major developmental events also influence the levels of these components in neurons. Declines in the intensity of AChR, SV2, MAP 1B, and MAP 2 immunolabeling within a subset of neuronal somata in both operated and control ganglia at ED 10 and 12 coincide with the period of neuronal cell death. Increases in AChR labeling in the rest of the neuronal population of input-deprived ganglia at ED 12 suggest that, in addition to innervation, synapse formation with the peripheral target tissue influences AChR levels in developing neurons in situ. 相似文献
14.
Characterization of the role of kainate receptors in excitatory synaptic transmission has been hampered by a lack of subtype-selective pharmacological agents. (S)-5-Iodowillardiine (IW), an analog of willardiine [(S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione], a heterocyclic amino acid found in Acacia and Mimosa seeds, was previously shown to be highly potent on native kainate receptors in dorsal root ganglion neurons. We examined the responses evoked by IW from recombinant homomeric and heteromeric kainate receptors expressed in human embryonic kidney 293 cells. IW potently elicited currents from glutamate receptor 5 (GluR5)-expressing cells, but showed no activity on homomeric GluR6 or GluR7 receptors. Co-expression of these receptor subunits with KA-2 subunits produced receptors that were weakly sensitive to IW. GluR5/KA-2 receptors had a higher EC50 value than homomeric GluR5 and exhibited a much faster recovery from desensitization. Finally, we found that the IW selectivity for GluR5 compared with GluR6 was determined by amino acid 721, which was previously shown to control alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate sensitivity of these kainate receptor subunits. The pharmacological selectivity and commercial availability of IW suggests that this compound may be of use in characterizing the molecular constituents of native kainate receptor responses. 相似文献
15.
JH White A Wise MJ Main A Green NJ Fraser GH Disney AA Barnes P Emson SM Foord FH Marshall 《Canadian Metallurgical Quarterly》1998,396(6712):679-682
GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABA(B) receptor (GABA(B)R1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABA(B)R2-receptor subtype forms heterodimers with GABA(B)R1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABA(B)R2 in HEK293T cells, GABA(B)R1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABA(B) receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. 相似文献
16.
Placode-derived general visceral afferent neurons of the nodose ganglion transmit visceral sensory information from specialized sensory endings of the vagus nerve and its branches to the nucleus of the solitary tract. These neurons are critical in relaying information such as elevations in blood pressure, changes in blood oxygenation, passage of contents through the esophagus and intestines, and distention of the heart, stomach, and lungs to the CNS for reflex maintenance of visceral functions. Multiple neurotransmitters, neuropeptides, calcium binding proteins, and other neuroactive substances are associated with neurons of the nodose ganglion. Many neurons colocalize 2 or more neuroactive substances creating the potential for complex interactions of neurochemical signals in the NTS. Neurons of the nodose ganglion also contain a variety of receptors which respond to transmitters, inflammatory mediators, and neurotrophic factors. The contents of these neurochemicals and receptors are not static as alterations in their expression are noted in response to epigenetic influences. Although not yet well understood, potential factors and mechanisms regulating neurochemical events in the nodose ganglion neurons are discussed. 相似文献
17.
JK Ivins H Colognato JA Kreidberg PD Yurchenco AD Lander 《Canadian Metallurgical Quarterly》1998,18(23):9703-9715
Embryonic retinal neurons lose the ability to extend neurites on laminin-1 (LN-1) with increasing developmental age yet still do so on other laminin isoforms. However, after treatment of LN-1 with antibodies to "short-arm" regions or removal of the short arms proteolytically, LN-1 supports attachment and extension of neurites even by late embryonic retinal neurons. We have mapped a domain for antibody-mediated "activation" of LN-1 to the N-terminal end of the alpha1 chain. Furthermore, we show that the primary receptors used in the retinal neuron response to "activated" LN-1 are integrins alpha3 beta1 and alpha6 beta1; these are the same receptors used by these neurons for outgrowth on other LN isoforms. Interestingly, alpha3 beta1 is preferentially involved in neurite outgrowth, whereas alpha6beta1 preferentially mediates attachment and spreading. However, in cultures from alpha3 integrin-deficient mice, alpha6 beta1 mediates retinal ganglion cell neurite outgrowth and compensates for the absence of alpha3 beta1. Finally, we show that key features of the retinal neuron response to LN-1 also characterize neurons of the hippocampus, thalamus, and cerebral cortex; these include poor response to untreated LN-1, extensive neurite outgrowth on antibody-activated LN-1 or on fragment E8, and dependence of this response on integrin alpha6 beta1 and at least one other long arm-binding beta1 integrin. These data suggest that regulation of LN-1 function via the process of activation could have important consequences for axonal regeneration. Curiously, the data also imply that the mechanism of laminin activation involves enhanced function at sites that cannot be considered cryptic. 相似文献
18.
To understand the role of opioids and their receptors in chronic pain following peripheral nerve injury, we have studied the mu-opioid receptor in rat and monkey lumbar 4 and 5 dorsal root ganglion neurons and the superficial dorsal horn of the spinal cord under normal circumstances and after peripheral axotomy. Our results show that many small neurons in rat and monkey dorsal root ganglia, and some medium-sized and large neurons in rat dorsal root ganglia, express mu-opioid receptor-like immunoreactivity. Most of these neurons contain calcitonin gene-related peptide. The mu-opioid receptor was closely associated with the somatic plasmalemma of the dorsal root ganglion neurons. Both mu-opioid receptor-immunoreactive nerve fibers and cell bodies were observed in lamina II of the dorsal horn. The highest intensity of mu-opioid receptor-like immunoreactivity was observed in the deep part of lamina II. Most mu-opioid receptor-like immunoreactivity in the dorsal horn originated from spinal neurons. A few mu-opioid receptor-positive peripheral afferent terminals in the rat and monkey dorsal horn were calcitonin gene-related peptide-immunoreactive. In addition to pre- and post-junctional receptors in rat and monkey dorsal horn neurons, mu-opioid receptors were localized on the presynaptic membrane of some synapses of primary afferent terminals in the monkey dorsal horn. Peripheral axotomy caused a reduction in the number and intensity of mu-opioid receptor-positive neurons in the rat and monkey dorsal root ganglia, and of mu-opioid receptor-like immunoreactivity in the dorsal horn of the spinal cord. The decrease in mu-opioid receptor-like immunoreactivity was more pronounced in the monkey than in the rat dorsal root ganglia and spinal cord. It is probable that there was a parallel trans-synaptic down-regulation of mu-opioid-like immunoreactivity in local dorsal horn neurons of the monkey. These data suggest that one factor underlying the well known insensitivity of neuropathic pain to opioid analgesics could be due to a marked reduction in the number of mu-opioid receptors in the axotomized sensory neurons and in interneurons in the dorsal horn of the spinal cord. 相似文献
19.
High levels of activity at a synapse can lead to spillover of neurotransmitter from the synaptic cleft. This extrasynaptic neurotransmitter can diffuse to neighboring synapses and modulate transmission via presynaptic receptors. We studied such modulation at the synapse between granule cells and Purkinje cells in rat cerebellar slices. Brief tetanic stimulation of granule cell parallel fibers activated inhibitory neurons, leading to a transient elevation of extracellular GABA, which in turn caused a short-lived heterosynaptic depression of the parallel fiber to Purkinje cell EPSC. Fluorometric calcium measurements revealed that this synaptic inhibition was associated with a decrease in presynaptic calcium influx. Heterosynaptic inhibition of synaptic currents and calcium influx was eliminated by antagonists of the GABAB receptor. The magnitude and time course of the depression of calcium influx were mimicked by the rapid release of an estimated 10 microM GABA using the technique of flash photolysis. We found that inhibition of presynaptic calcium influx peaked within 300 msec and decayed in <3 sec at 32 degrees C. These results indicate that presynaptic GABAB receptors can sense extrasynaptic GABA increases of several micromolar and that they rapidly regulate the release of neurotransmitter primarily by modulating voltage-gated calcium channels. 相似文献
20.
Previous studies indicated that antidromic stimulation of capsaicin-sensitive vagal afferent fibers activated, via peripheral release of tachykinins, nonadrenergic, noncholinergic parasympathetic ganglion neurons that mediate relaxations of guinea pig trachealis. On the basis of the effects of selective agonists and inhibition with a nonselective receptor antagonist (SR 48968), we speculated that tachykinin-mediated activation of neurokinin3 (NK3) receptors might be involved. Using the recently developed NK3-selective receptor antagonist SR 142801, we further assessed the role of NK3 receptors in these relaxant responses. Relaxations of the guinea pig trachea elicited by antidromic stimulation of capsaicin-sensitive vagal afferent nerves were markedly inhibited by 0.3 microM SR 142801 and were abolished by a combination of SR 142801 and either of the NK1-selective receptor antagonists SR 140333 and CP 99994 (0.3 microM each). The NK3 receptor antagonist had similar effects on the relaxant responses elicited by capsaicin and substance P, but it had no effect on relaxations of the trachealis elicited by electrical field stimulation of the postganglionic nerves that innervate the trachealis or by stimulation of the preganglionic parasympathetic vagal nerves that innervate the trachea. These results and the observation that the ganglion neurons that mediate these responses are densely innervated by substance P-containing nerve fibers lead us conclude that stimulation of capsaicin-sensitive visceral afferent fibers activates, upon peripheral release of tachykinins, nonadrenergic, noncholinergic inhibitory neurons innervating guinea pig trachealis via activation of both NK3 and NK1 receptors. 相似文献