Substance P Antagonist Research Articles

Tachykinins mediate non-adrenergic, non-cholinergic excitatory neurotransmission to the hamster ileum via NK1 and NK2 receptors

The present study was designed to investigate Substance P (SP) and a related tachykinin, Neurokinin A (NKA), contributions to the excitatory neurotransmission to the circular smooth muscle of the hamster ileum. In the presence of atropine (0.5 μM), guanethidine (3 μM) and N G-nitro-L-arginine methyl ester (L-NAME) (200 μM), electrical field stimulation (EFS) evoked a non-adrenergic, non-cholinergic (NANC) excitatory junction potential (EJP) and contraction of circular smooth muscle. Applications of SP and NKA produced depolarizing and contractile responses in a concentration-dependent fashion. The EJP and contraction were almost abolished by the non-specific tachykininergic antagonist, spantide (3 μM). Application of SP antagonist, L-732,138, (1 μM) markedly inhibited EJP (82.5%) and contraction (68.9%) and completely blocked excitatory responses produced by exogenous application of SP. While application of NKA antagonist, SR48968 (1 μM) completely blocked the depolarising and contractile responses to NKA, it only slightly inhibited those to EFS (17.2% and 31.4% respectively).These results provide evidence that, in the circular muscle of hamster ileum, endogenous tachykinins are the main NANC excitatory neurotransmitters and their action is mediated by both NK1 and NK2 receptors.

Stereoselective transformation of pyrazinones into substituted analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol

Various analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol have been prepared via Diels–Alder reaction of substituted pyrazinones with ethene followed by acid methanolysis of the bridged lactam adducts. Further reduction of the resulting methyl 2-piperidinecarboxylate ester compounds led to the corresponding 2-piperidinemethanol products that were converted into potential SP antagonists.

Upregulation of neurokinin-1 receptor expression in rat spinal cord by an N-terminal metabolite of substance P.

Chronic inflammatory conditions are associated with an upregulation of both substance P (SP) and neurokinin-1 (NK-1) receptors in the dorsal spinal cord. These receptors have been implicated in hyperalgesia as well as stress-induced analgesia. On the basis of the release of SP during chronic pain, and its rapid metabolism, we tested the hypothesis that SP metabolites regulate the synthesis of either SP or NK-1 receptors in the spinal cord. We measured expression of preprotachykinin mRNA and NK-1 receptor mRNA following intrathecally administered substance P(1-7) (SP1-7), the major metabolite of SP in rat, and following capsaicin, a compound known to induce release of endogenous SP. SP(1-7) and capsaicin each increased NK-1 receptor mRNA in the spinal cord (6 h) followed by an increase in NK-1 receptor-immunoreactivity (24 h and 1 week). D-SP(1-7), a D-isomer and antagonist of SP(1-7), did not mimic the effect of SP(1-7), indicating stereoselectivity. Instead, D-SP(1-7) prevented the upregulation of NK-1 receptor immunoreactivity that was induced by capsaicin injected intrathecally, suggesting that the effect of capsaicin is also mediated by SP N-terminal metabolites. In contrast, the decrease in SP synthesis produced by capsaicin was not dependent on SP metabolites as SP(1-7) failed to decrease either preprotachykinin mRNA content in dorsal root ganglia (6 h) or SP immunoreactivity in the lumbar spinal cord (24 h and 1 week). In addition, the effects of capsaicin on SP synthesis were not prevented by D-SP(1-7). Thus, SP metabolites, at times and doses that are antinociceptive, appear to enhance SP-mediated signal transduction by upregulating NK-1 receptor expression without affecting SP synthesis.

A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes

Substance P (SP), a potent modulator of neuroimmunoregulation, exerts its activity by binding to the neurokinin-1 receptor (NK-1R). The SP–NK-1R interaction is important in inflammation and viral infections, including HIV infection of human immune cells. We recently demonstrated that SP modulates HIV replication and that a non-peptide SP antagonist CP-96,345 inhibits HIV replication in human monocyte-derived macrophages (MDM) by affecting the SP–NK-1R interaction. In order to examine the effect of the SP antagonist on SP mRNA expression, MDM was incubated with or without CP-96,345 in the presence or absence of HIV infection. SP mRNA expression in these cells was then determined by real-time PCR technology. The effect of CP-96,345 on chemokine gene expression was also investigated by using a cDNA array assay. CP-96,345 down-regulated SP mRNA expression and antagonized exogenous SP-enhanced SP expression at the mRNA level, suggesting that SP autocrine regulation was interrupted by CP-96,345. CP-96,345 inhibited HIV replication in MDM, associated with down-regulated SP mRNA expression in comparison to HIV infection controls. In parallel with down-regulated SP and CCR5 mRNA expression, cDNA array assays indicated that CP-96,345 treatment also inhibited IL-8 gene expression, while enhancing expression of fractalkine and monocyte chemotactic protein-3 (MCP-3). Since SP plays an important role in inflammation and viral infections, these studies may have potential applications for therapeutic intervention of inflammation and viral infection of immune cells.

Substance P in the descending cholinergic projection to REM sleep-induction regions of the rat pontine reticular formation: anatomical and electrophysiological analyses.

Release of acetylcholine within the pontine reticular formation (PRF) from the axon terminals of mesopontine cholinergic neurons has long been hypothesized to play an important role in rapid eye movement (REM) sleep generation. As some of these cholinergic neurons are known to contain substance P (SP), we used anatomical, electrophysiological and pharmacological techniques to characterize this projection in the rat. Double immunofluorescence demonstrated that 16% of all cholinergic neurons within the mesopontine tegmentum contained SP; this percentage increased to 27% in its caudal regions. When double immunofluorescence was combined with retrograde tracing techniques, it was observed that up to 11% of all SP-containing cholinergic neurons project to the PRF. Whole-cell patch-clamp recordings from in vitro brainstem slices revealed that SP administration depolarized or evoked an inward current in a dose-dependent manner in all PRF neurons examined, and that these effects were antagonized by a SP antagonist. The amplitude of the SP-induced inward current varied with changes in the Na+ concentration, did not reverse at the calculated K+ or Cl- equilibrium potentials, and was not attenuated in the presence of tetrodotoxin, low Ca2+ concentration or caesium ions. These data suggest that activation of a tetrodotoxin-insensitive cation channel(s) permeable to Na+ is responsible for a SP-induced inward current at resting membrane potentials. The depolarizing actions of SP appeared to be primarily due to activation of the adenylate cyclase pathway, and were additive with cholinergic receptor activation even at maximal concentrations. These data indicate that SP is colocalized in a subpopulation of mesopontine tegmental cholinergic neurons projecting to REM sleep-induction regions of the PRF, and that actions of these two neuroactive substances on PRF neurons are additive. If SP is coreleased with acetylcholine, the additive actions of the two neurotransmitters might heighten the excitability of postsynaptic PRF neurons and ensure the initiation and maintenance of REM sleep.

Capsaicin-Sensitive Nerve Fibres Induce Epithelial Cell Proliferation, Inflammatory Cell Immigration and Transforming Growth Factor-alpha Expression in the Rat Colonic Mucosa In Vivo

Background: Capsaicin-sensitive nerve fibres protect gastrointestinal mucosa in animal models of mucosal injury by modulation of mucosal blood flow and mucus secretion. The aim of our study was to evaluate the effects of capsaicin-sensitive nerve fibres in rat colonic mucosa on epithelial cell proliferation and transforming growth factor-alpha (TGF α ) expression, which is important in mucosal defence, protection and repair. Methods: Male Wistar rats received either a capsaicin enema with or without giving antagonists to calcitonin-gene-related-peptide (CGRP) or substance P (SP) i.v. immediately prior to the capsaicin enemas; a capsaicin enema after sensory desensitization as described previously; or a vehicle enema. In all experiments, animals received 50 mg/kg BrdU i.v. and were killed at 2, 4, 8, 12, 24 and 48 h after the various treatments. Colonic mucosal specimens were evaluated microscopically for mucosal damage, changes in the numbers of inflammatory cells and BrdU-immunoreactive epithelial cell nuclei. In the same specimens, TGF α -mRNA and-protein expression were evaluated by RT-PCR and Western blot analysis using standardized procedures. Results: A significant increase in the number of mucosal inflammatory cells and an increase in BrdU-immunoreactive nuclei were detected following mucosal exposure to capsaicin. A 2-fold increase of TGF α mRNA and a 10-fold increase of TGF α protein expression were obtained 2-12 h after capsaicin enemas. The effects on the invading number of inflammatory cells and on the increase in BrdU immunoreactive epithelial cell nuclei were significantly reduced by both CGRP and SP antagonists and were abolished in rats previously sensory-desensitized. Conclusion: Capsaicin-sensitive nerve fibres modulate epithelial cell proliferation and TGF α expression in colonic mucosa as well as a migration of inflammatory cells into the colonic mucosa. These effects are mediated by the neurotransmitters CGRP and SP.

PACAP 1–38 as neurotransmitter in the porcine antrum

The concentration of PACAP 1–38 in porcine antrum amounted to 15.4±7.9 and 20.3±8 pmol/g tissue in the mucosal and muscular layers. PACAP immunoreactive (IR) fibres innervated the muscular (co-localised with VIP) and submucosal/mucosal layers (some co-storing VIP and CGRP) including myenteric and submucosal plexus and blood vessels. Only myenteric nerve cell bodies contained PACAP-IR (co-storing VIP). In isolated perfused antrum, vagus nerve stimulation (8 Hz) and capsaicin (10 −5 M) increased PACAP 1–38 release. PACAP 1–38 (10 −9 M) increased substance P (SP), gastrin releasing peptide (GRP) and VIP release. PACAP 1–38 (10 −8 M) inhibited gastrin secretion and stimulated somatostatin secretion and motility dose-dependently. PACAP-induced motility was strongly inhibited by the antagonist PACAP 6–38 but also by atropine and substance P-antagonists (CP99994/SR48968) but PACAP 6–38 had no effect on vagus-induced secretion or motility. Conclusion: PACAP 1–38 may be involved in antral motility and secretion by interacting with cholinergic, SP-ergic, GRP-ergic and/or VIP-ergic neurones, and may also be involved in afferent reflex pathways.

Substance P Plays a Critical Role in Photic Resetting of the Circadian Pacemaker in the Rat Hypothalamus

Glutamate is considered to be the primary neurotransmitter in the retinohypothalamic tract (RHT), which delivers photic information from the retina to the suprachiasmatic nucleus (SCN), the locus of the mammalian circadian pacemaker. However, substance P (SP) also has been suggested to play a role in retinohypothalamic transmission. In this study, we sought evidence that SP from the RHT contributes to photic resetting of the circadian pacemaker and further explored the possible interaction of SP with glutamate in this process. In rat hypothalamic slices cut parasagittally, electrical stimulation of the optic nerve in early and late subjective night produced a phase delay (2.4 +/- 0.5 hr; mean +/- SEM) and advance (2.6 +/- 0.3 hr) of the circadian rhythm of SCN neuronal firing activity, respectively. The SP antagonist L-703,606 (10 microm) applied to the slices during the nerve stimulation completely blocked the phase shifts. Likewise, a cocktail of NMDA (2-amino-5-phosphonopentanoic acid, 50 microm) and non-NMDA (6,7-dinitroquinoxaline-2,3-dione, 10 microm) antagonists completely blocked the shifts. Exogenous application of SP (1 microm) or glutamate (100 microm) to the slices in early subjective night produced a phase delay ( approximately 3 hr) of the circadian firing activity rhythm of SCN neurons. Coapplication of the NMDA and non-NMDA antagonist cocktail (as well as L-703,606) resulted in a complete blockade of the SP-induced phase delay, whereas L-703,606 (10 microm) had no effect on the glutamate-induced delay. These results suggest that SP, as well as glutamate, has a critical role in photic resetting. Furthermore, the results suggest that the two agonists act in series, SP working upstream of glutamate.

Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes.

Substance P (SP) is a potent modulator of neuroimmunoregulation. We recently reported that human immune cells express SP and its receptor. We have now investigated the possible role that SP and its receptor plays in HIV infection of human mononuclear phagocytes. SP enhanced HIV replication in human blood-isolated mononuclear phagocytes, whereas the nonpeptide SP antagonist (CP-96,345) potently inhibited HIV infectivity of these cells in a concentration-dependent fashion. CP-96,345 prevented the formation of typical giant syncytia induced by HIV Bal strain replication in these cells. This inhibitory effect of CP-96,345 was because of the antagonism of neurokinin-1 receptor, a primary SP receptor. Both CP-96,345 and anti-SP antibody inhibited SP-enhanced HIV replication in monocyte-derived macrophages (MDM). Among HIV strains tested (both prototype and primary isolates), only the R5 strains (Bal, ADA, BL-6, and CSF-6) that use the CCR5 coreceptor for entry into MDM were significantly inhibited by CP-96,345; in contrast, the X4 strain (UG024), which uses CXCR4 as its coreceptor, was not inhibited. In addition, the M-tropic ADA (CCR5-dependent)-pseudotyped HIV infection of MDM was markedly inhibited by CP-96,345, whereas murine leukemia virus-pseudotyped HIV was not affected, indicating that the major effect of CP-96,345 is regulated by Env-determined early events in HIV infection of MDM. CP-96,345 significantly down-regulated CCR5 expression in MDM at both protein and mRNA levels. Thus, SP-neurokinin-1 receptor interaction may play an important role in the regulation of CCR5 expression in MDM, affecting the R5 HIV strain infection of MDM.

Effects of substance P and vasoactive intestinal peptide on interferon-gamma and interleukin-4 production in severe atopic dermatitis

Recent studies have demonstrated that two T cell-derived lymphokines, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), play a crucial role in the pathogenesis of atopic dermatitis (AD). It is known that neuropeptides, such as substance P (SP) and vasoactive intestinal peptide (VIP), have various immunomodulatory effects. Elevated levels of these neuropeptides and increased staining of SP positive nerve fibers have been reported in AD patients. The study was designed to examine the effects of SP and VIP on the production of IFN-gamma and IL-4. The aim of the study was to establish whether these neuropeptides acted to affect cytokine release in the peripheral blood mononuclear cells (PBMCs) of AD patients. The effects of SP and VIP on the production of IFN-gamma and IL-4 in phytohemagglutinin stimulated PBMC cultures over a 48-hour period were analyzed by enzyme-linked immunosorbent assay in 15 AD patients. Non-atopic individuals were used as a control group. Base cytokine profiles of AD patients showed significantly decreased IFN-gamma and increased IL-4 when weighed against non-atopic controls. Compared with controls, SP had a significant percentage enhancing effect on both IFN-gamma and IL-4 production at concentrations of 10(-8) M and 10(-6) M, however, this IFN-gamma up-regulatory effect of SP was reversed by spantide, a SP antagonist. The ratios of IFN-gamma: IL-4 production were significantly elevated in the SP treated AD group. Although VIP had no specific noticeable effects on the IFN-gamma and IL-4 production. Our data may suggest that SP has an influence on the immunomodulation of AD patient by regulating IFN-gamma production, either directly or indirectly. Vasoactive intestinal peptide, on the other hand, has no modulatory effects on the cytokine production of AD patients.

Substance P as prophylaxis for JP-8 jet fuel-induced immunotoxicity.

Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system that persisted for extended periods of time. It was found that administration of aerosolized substance P (SP) was able to protect exposed animals from JP-8-induced immune changes, whereas administration of SP antagonists compounded the deleterious effects ofjet fuel exposure. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure. In the current study, aerosolized SP was analyzed for its potential prophylactic ability to counteract JP-8-induced immunotoxicity. It was observed that concentrations as low as 1 nM were effective in ameliorating the effects of JP-8 exposure on the immune system. SP administered before JP-8 exposure could prophylactically protect both the spleen and thymus from significant organ weight loss, but could not completely restore immune cell numbers to normal, baseline levels. Furthermore, SP treatment could be delayed as long as 1 h postexposure and reverse the effects of jet fuel exposure on immune organ weight loss and immune cell recovery. Significantly, SP could be given 15 min pre-JP-8 exposure but neither 1 nor 6 h pre-JP-8 exposure, and prevent immune dysfunction as measured in mitogenesis assays. However, SP could be delayed up to 6 h post-JP-8 exposure and still almost completely restore immune function. Thus, SP appears able to both prevent and reverse the immunotoxicological effects associated with JP-8 exposure. These results also provide insight into the manner in which JP-8 jet fuel mediates its effects on the immune system.

Epidermal Growth Factor Receptor Transactivation Mediates Substance P-induced Mitogenic Responses in U-373 MG Cells

Ligand-induced activation of G protein-coupled receptors is emerging as an important pathway leading to the activation of certain receptors with intrinsic tyrosine kinase activity, such as the epidermal growth factor receptor (EGFR). Substance P (SP) exerts many effects via activation of its G protein-coupled receptor (neurokinin-1, NK-1). SP participates in acute inflammation and activates key proteins involved in mitogenic pathways, such mitogen-activated protein kinases (MAPKs), stimulating DNA synthesis. We tested the hypothesis that SP-induced MAPK activation and DNA synthesis require activation of the EGFR. In U-373 MG cells, which express functional NK-1, SP induced tyrosine phosphorylation of several proteins including EGFR. SP induced formation of an activated EGFR complex containing the adapter proteins SHC and Grb2, but not c-Src. SP activated the MAPK pathway as shown by increased Erk2 kinase activity. SP induced Erk2 activation, and DNA synthesis was inhibited in cells transfected with a dominant negative EGFR plasmid lacking kinase activity, as well as in cells treated with a specific EGFR inhibitor. In addition, pertussis toxin, an inhibitor of Galpha(iota) protein subunits, prevented SP-induced EGFR transactivation and subsequent DNA synthesis. Our results implicate EGFR as an essential regulator in SP/NK-1-induced activation of the MAPK pathway and cell proliferation in U-373 MG cells, and these events are mediated by a pertussis toxin-sensitive Galpha protein. We suggest that this mechanism by which SP controls cell proliferation is an important pathway in tissue restoration and healing.

Asymmetric synthesis of the key intermediate of an SP antagonist RPR107880 using a base-catalyzed Diels–Alder reaction

An asymmetric synthesis of the key intermediate of RPR 107880, a substance P antagonist, using a base-catalyzed Diels–Alder reaction of 3-hydroxy-2-pyrone and N-benzylmaleimide is described.

Specific inhibition of glucocorticoid-induced thymocyte apoptosis by substance P.

Glucocorticoids (GC) are strong inducers of thymocyte apoptosis. In the present study we looked into the possibility that the neuropeptide substance P (SP) might serve as an antagonist to GC-induced apoptosis. Indeed, SP inhibited hydrocortisone (HC)-induced apoptosis of CD4+CD8+ thymocytes in mice, both in vivo and in vitro. It also inhibited HC-induced apoptosis in the T cell hybridoma line 2B4.11, which is sensitive to GC. The inhibitory effect was complete if SP was given with HC or within 1 h after it; partial inhibitory effect could be seen at 2 h and no effect at 3 h. The presence of the SP antagonist nullified SP effect. The effect was specific to both components of the system (i.e., HC as apoptosis inducer and SP as its inhibitor), as judged from comparison to three other apoptosis-inducing means (irradiation, thymic epithelial cells, or retinoic acid), and to two other neuropeptides (somatostatin and vasoactive intestinal peptide). SP/HC antagonism was further demonstrated in two relevant molecular events: 1) HC augmented GC receptor production in our cell system and this was inhibited by SP; and 2) HC reduced the expression of the transcription factor NF-kappaB, SP increased it and when both were present, SP effect dominated. On the other hand, the level of IkappaB (NF-kappaB inhibitory molecule) was decreased by SP, preserved at a relatively high level with HC, and when both SP and HC were present, SP effect dominated. The intensity of SP effect, both in vivo and in vitro, its specificity, its inhibition by SP antagonist, as well as the previously documented presence of SP and its receptor in the thymus suggest that SP might be a physiological antagonist of the potent thymocyte apoptosis induced by GC.

The effect of CP-96,345, a non-peptide substance-P antagonist, on thermoregulation and the development of endotoxin-fever in rats

1. Substance-P (SP) has been shown to induce a regulated rise in body temperature when injected into one of the lateral cerebral ventricles of rats. 2. The non-peptide antagonist of SP (CP-96,345) decreased the SP-induced rise in core temperature and, when given prior to an intravenous endotoxin injection, it also attenuated the febrile response to endotoxin.

The effects of substance P and vasoactive intestinal peptide on interleukin-6 synthesis in cultured human keratinocytes

Interleukin-6 (IL-6) is a cytokine implicated as a key mediator of immune and inflammatory responses in psoriasis. Recent studies have shown that neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), can modulate a production of IL-6 from cells, such as monocytes and astrocytes, participating in an immune reaction. The aim of this study was to assess the role of the neuropeptides on cytokine production of keratinocytes in physiologic or pathologic conditions. Cultured human keratinocytes derived from normal foreskin and psoriatic lesions were treated with various concentrations of SP or VIP, in the presence or absence of fetal bovine serum. The secretion of IL-6 by the treated keratinocytes was analyzed by enzyme-linked immunosorbent assay. Although neither SP nor VIP, by itself, was able to induce IL-6 synthesis in cultured human keratinocytes, we have found that SP, not VIP, significantly reduced 5% fetal bovine serum-induced IL-6 production in time- and dose-dependent fashion. This down-regulatory effect of SP was reversed by spantide, a SP antagonist. Lesional psoriatic keratinocytes showed a similar, but weaker, response when compared with normal keratinocytes. These data suggested that SP might modulate IL-6 synthesis of keratinocytes in either physiologic or pathologic conditions such as psoriasis.

The importance of C-terminal residues of vertebrate and invertebrate tachykinins for their contractile activities in gut tissues

The C-terminal residues of mammalian tachykinins and urechistachykinins (Uru-TKs), tachykinin-related peptides of echiuroid worm origin, were substituted for each other. Their contractile effects were assayed on the cockroach hindgut and the guinea pig ileum. [Met 10] substitution of Uru-TKs caused a 1000 times lower activity on the hindgut, but a 1000 times higher activity on the ileum. In contrast, [Arg 11]substance P (SP) was 100 times more and 400 times less potent than SP on the hindgut and ileum, respectively. A SP antagonist blocked these Uru-TK activities on the hindgut. These results demonstrated that the C-terminal Met-NH 2 is necessary for ileum contraction and the Arg-NH 2 is required for hindgut contraction, which was caused by binding to the cockroach’s neurokinin-like receptor.

Mast cell production of TNF-α induced by substance P evidence for a modulatory role of substance P-antagonists

Unregulated increasing of Tumor necrosis factor-α (TNF-α) could be pathogenic in inflammatory diseases. The aim of this study was to investigate the anti-inflammatory role of the Substance P-antagonists (SPAs) through the inhibition of histamine release (HR) and TNF-α production from mast cell. Rat peritoneal mast cells (PMC) stimulated with Substance P (SP), in the presence of SPAs or not, were analyzed for HR and TNF-α protein production. Competitive Polymerase Chain Reaction, with an internal standard competing with target cDNA for the same primers, was used to determine the TNF-α mRNA expression. We show that the increase of either HR and TNF-α levels in peritoneal (PMC) after induction with SP was inhibited by pre-incubation with SPA or with the Peptide 101 (P101), while the [ d-Pro 2, d-Phe 7, d-Trp 9]-SP (dSP) had no effect. Neuraminidase treatment suggests that dSP, as well as SP, interacts with sialic acid residues on the cell surface. Moreover, SPA and P101 also inhibit the release of histamine and TNF-α induced by dSP suggesting that a receptor-independent mechanism is involved. These data could be useful to better understand the mechanisms involved in the mast cell activation and TNF-α production in the inflammatory diseases where SP is involved.

Electrophysiological evidence for the role of substance P in retinohypothalamic transmission in the rat

The retinohypothalamic tract (RHT) is a neural pathway through which photic time cues are delivered directly to the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN). Although the excitatory amino acid glutamate is the primary neurotransmitter in the RHT, other substances such as substance P (SP) also have been suggested to play a role. The present study tested the hypothesis that SP participates in retinohypothalamic transmission and selectively modulates either N-methyl-d-aspartate (NMDA) or non-NMDA receptor-mediated neurotransmission. The SP antagonist L-703,606 depressed the excitatory postsynaptic current (EPSC) evoked by optic nerve stimulation in SCN neurons in rat hypothalamic slices. The SP antagonist also had a similar depressive effect on the NMDA and non-NMDA receptor-mediated components of the EPSC. These results suggest that SP is an excitatory neuromodulator contributing to the expression of both the NMDA and non-NMDA receptor-mediated components of retinohypothalamic transmission.

Differential effects from parapyramidal region and rostral ventrolateral medulla mediated by substance P.

Rostral ventrolateral medulla (rVLM) and parapyramidal region (PPr) serve as important medullary control sites for sympathoexcitation. rVLM and PPr have direct projections to the intermediolateral cell column (IML) that are thought to be important in maintaining mean arterial blood pressure (MAP). Substance P (SP) is found in PPr neurons and in and near the subretrofacial area of the rVLM. At least some of these cells project to the IML. We investigated the involvement of SP at the IML in mediating rVLM- and PPr-evoked pressor responses in the chloralose-anesthetized cat. Pressor responses to electrical and chemical PPr and rVLM stimulation were altered after intrathecal injection, at the level of the T1-T3 spinal cord, of either SP antagonist [D-Pro(2), D-Phe(7), D-Trp(9)]-SP, SP antagonist CP 96,345, or SP antiserum. Although MAP and heart rate responses to PPr stimulation were attenuated by intrathecal SP antagonists or antiserum, MAP responses to rVLM stimulation were augmented. Previous studies have revealed differences in transmitters associated with these two areas, even though the general response of both areas is sympathoexcitatory. The present study implies that the identical substance may increase or decrease the MAP response depending on the pathway activated.