Cardiorespiratory action of opioid/tachykinin agonist peptide hybrid in anaesthetized rats: Transduction pathways.

AWL3106 composed of opioid (dermorphin) and tachykinin (substance P7-11) pharmacophores is a new compound with high analgesic potency and markedly reduced ability to induce tolerance and dependence. The present study aimed to determine the respiratory and cardiovascular responses evoked by this peptide in urethane-chloralose anaesthetized, spontaneously breathing rats in the presence or absence of vagal connection. Intravenous injection of AWL3106 at a dose of 0.3µmol/kg in intact rats resulted in apnoea lasting 5.1 ± 0.7s. Breathing that followed was of diminished frequency (F) and augmented tidal volume (VT) with no significant impact on minute ventilation. AWL3106-challenge induced biphasic fall in arterial blood pressure with no effect on heart rate. Midcervical and supranodosal sectioning the vagal nerves prevented the occurrence of the apnoea and abrogated the post-AWL3106 reduction in F but failed to eliminate the increase in VT. Hypotensive response appeared to be less profound following supranodose vagotomy. NaloxoneHCl abolished solely the occurrence of apnoea. However additional blockade of tachykinin NK1 receptors with SR140333 was required to abolish VT increase, deceleration of breathing and to markedly suppress AWL3106-induced hypotension. The present study shows that extravagally controlled stimulation of VT maintains fairly regular ventilation by levelling the bradypnoeic effects. Although the peptide showed no cardiac effects, hypotension occurring beyond the vagal loop may limit future therapeutic benefits of this chimeric compound.

The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction.

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r(-/-) mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.

Molecular recognition of tachykinin receptor selective agonists: insights from structural studies.

This Review deals essentially with the elucidation of structural features of Tachykinin family of neuropeptides, which are known to interact through three distinct GPCR subtypes, namely NK1 (Neurokinin 1), NK2 (Neurokinin 2) and NK3 (Neurokinin 3) receptors. In mammals, Tachykinins have been shown to elicit a wide array of activities such as powerful vasodilatation, hypertensive action and stimulation of extravascular smooth muscle and are known to be involved in a variety of clinical conditions including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma. This broad spectrum of action of Tachykinins is attributed to the lack of selectivity of tachykinins to their receptors. All tachykinins interact with all the three-receptor subtypes with SP preferring NK1, NKA preferring NK2 and NKB preferring NK3. This lack of specificity can be accounted for by the conformational flexibility of these short, linear peptides. Hence, identification of structural features of the agonists important for receptor binding and biological activity is of great significance in unraveling the molecular mechanisms involved in tachykinin receptor activation and also in rational design of novel therapeutic agents. Understanding structure of the ligand-receptor complex and analysis of topography of the binding pocket of the tachykinin receptor is also crucial in rational design of drugs.

GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats.

Kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn) are coexpressed within KNDy neurons that project from the hypothalamic arcuate nucleus (ARC) to GnRH neurons and numerous other hypothalamic targets. Each of the KNDy neuropeptides has been implicated in regulating pulsatile GnRH/LH secretion. In isolation, kisspeptin is generally known to stimulate, and Dyn to inhibit LH secretion. However, the NKB analog, senktide, has variously been reported to inhibit, stimulate or have no effect on LH secretion. In prepubertal mice, rats and monkeys, senktide stimulates LH secretion. Furthermore, in the monkey this effect is dependent on kisspeptin signaling through its receptor, GPR54. The present study tested the hypotheses that the stimulatory effects of NKB on LH secretion in intact rats are mediated by kisspeptin/GPR54 signaling and are independent of a Dyn tone. To test this, ovarian-intact prepubertal rats were subjected to frequent automated blood sampling before and after intracerebroventricular injections of KNDy neuropeptide analogs. Senktide robustly induced single LH pulses, while neither the GPR54 antagonist, Kp-234, nor the Dyn agonist and antagonist (U50488 and nor-BNI, respectively) had an effect on basal LH levels. However, Kp-234 potently blocked the senktide-induced LH pulses. Modulation of the Dyn tone by U50488 or nor-BNI did not affect the senktide-induced LH pulses. These data demonstrate that the stimulatory effect of NKB on LH secretion in intact female rats is dependent upon kisspeptin/GPR54 signaling, but not on Dyn signaling.

Role of tachykinin receptors in the modulation of colonic peristaltic activity in mice.

Tachykinins are important mediators of neuroneuronal and neuromuscular transmission in the gastrointestinal tract, however their contribution to colonic peristalsis in mice remains unclear. Therefore, our aim was to characterise the functional role of tachykinins in mediating peristalsis by evaluating the effect of selective tachykinin NK(1), NK(2) and NK(3) receptor agonists and antagonists on in vitro colonic peristaltic activity in mice. Using a modified Trendelenburg set-up, gradual distension of proximal and distal colonic segments evoked rhythmic, aborally migrating contractions. Peristaltic activity was assessed by quantifying the amplitude and interval of the corresponding pressure waves. Stimulation of NK(1) receptors showed regional differences as both the pressure amplitude and interval were enhanced in the distal colon without affecting peristalsis proximally. Blockade of NK(1) receptors reduced the peristaltic pressure amplitude in the proximal and distal colon while the interval was not significantly altered. NK(2) receptor stimulation resulted in a modest enhancement of the amplitude in proximal and distal segments and a slightly prolonged interval distally. Blockade of NK(2) receptors reduced the peristaltic pressure amplitude and interval in the distal colon. NK(3) receptor stimulation significantly augmented the amplitude in both segments and prolonged the interval distally. However, NK(3) receptor blockade had no effect on peristaltic activity. In conclusion, tachykinins contribute to colonic peristalsis in mice by acting mainly on NK(1) and NK(2) receptors and their effects show a proximal-to-distal gradient. NK(3) receptors might play a role in conditions of excess tachykinin release but appear not to be involved under the conditions of the present study.

The broad-spectrum antitumor action of cyclosporin A is due to its tachykinin receptor antagonist pharmacological profile.

Cyclosporin A (CsA) is an immunosuppressive drug. In human cancer cells substance P (SP) and neurokinin-1 (NK-1) receptor antagonists, respectively, induce cell proliferation and inhibition. CsA is a tachykinin receptor antagonist that showed selectivity for both NK-1 and NK-2 receptors. CsA exerts antitumor action against gastric (AGS) and colon (HT29) carcinoma cell lines. However, the mechanisms involved in this action remain unknown, and it is unknown whether CsA exerts an antitumor action on other human cancer cell lines or not. To demonstrate that CsA exerts a broad-spectrum antitumor action, we carried out an in vitro study of the growth-inhibitory capacity of CsA against seven human cancer cell lines, namely GAMG glioma, SKN-BE(2) neuroblastoma, WERI-Rb-1 retinoblastoma, HEp-2 larynx carcinoma, CAPAN pancreas carcinoma, 23132/87 gastric carcinoma, and SW-403 colon carcinoma. A Coulter counter was used to determine viable cell numbers followed by application of the MTS colorimetric method. Micromolar concentrations of CsA inhibited the growth of these tumor cells, both with and without previous administration of nanomolar concentrations of SP; the inhibition occurred in a dose-dependent manner. Moreover, CsA blocks SP-induced mitogen stimulation of tumor cells, suggesting that the NK-1 receptor is involved in such action. Following administration of CsA apoptosis was observed in the above seven tumor cell lines. These findings suggest that the antitumor action of CsA is at least due to its NK-1 receptor antagonist pharmacological profile, since the involvement of NK-2 receptors in the mentioned action must not be discarded, and that CsA has a broad-spectrum antitumor action.

Role of neurokinin receptors and ionic mechanisms within the respiratory network of the lamprey.

We have suggested that in the lamprey, a medullary region called the paratrigeminal respiratory group (pTRG), is essential for respiratory rhythm generation and could correspond to the pre-Bötzinger complex (pre-BötC), the hypothesized kernel of the inspiratory rhythm-generating network in mammals. The present study was performed on in vitro brainstem preparations of adult lampreys to investigate whether some functional characteristics of the respiratory network are retained throughout evolution and to get further insights into the recent debated hypotheses on respiratory rhythmogenesis in mammals, such as for instance the "group-pacemaker" hypothesis. Thus, we tried to ascertain the presence and role of neurokinins (NKs) and burst-generating ion currents, such as the persistent Na(+) current (I(NaP)) and the Ca(2+)-activated non-specific cation current (I(CAN)), described in the pre-Bötzinger complex. Respiratory activity was monitored as vagal motor output. Substance P (SP) as well as NK1, NK2 and NK3 receptor agonists (400-800 nM) applied to the bath induced marked increases in respiratory frequency. Microinjections (0.5-1 nl) of SP as well as the other NK receptor agonists (1 microM) into the pTRG increased the frequency and amplitude of vagal bursts. Riluzole (RIL) and flufenamic acid (FFA) were used to block I(NaP) and I(CAN), respectively. Bath application of either RIL or FFA (20-50 microM) depressed, but did not suppress respiratory activity. Coapplication of RIL and FFA at 50 microM abolished the respiratory rhythm that, however, was restarted by SP microinjected into the pTRG. The results show that NKs may have a modulatory role in the lamprey respiratory network through an action on the pTRG and that I(NaP) and I(CAN) may contribute to vagal burst generation. We suggest that the "group-pacemaker" hypothesis is tenable for the lamprey respiratory rhythm generation since respiratory activity is abolished by blocking both I(NaP) and I(CAN), but is restored by enhancing network excitability.

Tachykinin receptor assays.

Described in this unit are methods for obtaining, preparing, and testing smooth muscle preparations bearing tachykinin receptors to study the agonist or antagonist properties of test compounds. Concentration-response curves to agonists are constructed to measure their ability to produce smooth muscle contractions and thus evaluate the potency and efficacy of the agonists. Antagonists are tested for their ability to shift the agonist concentration-response curve and to calculate their potency. Two different protocols are described for each of the three tachykinin receptors (NK(1), NK(2), and NK(3)). The NK(1) receptor assays use guinea pig ileum longitudinal muscle myenteric plexus (GPI) and rat urinary bladder (RUB), the NK(2) receptor assays use isolated endothelium-deprived rabbit pulmonary artery (RPA) and hamster trachea (HT), and the NK(3) receptor assays use GPI and rat portal vein (RPV).

Contractile responses induced by physalaemin, an analogue of substance P, in the rat esophagus.

We examined the effects of physalaemin, an agonist of tachykinin receptors, on mechanical responses in the rat esophagus to clarify possible regulatory roles of tachykinins in esophageal motility. Exogenous application of physalaemin caused tonic contractions in rat esophageal segments when tension was recorded in the longitudinal direction but not when tension was recorded in the circular direction. The physalaemin-evoked contractions were blocked by pretreatment with nifedipine, a blocker of L-type calcium channels in both striated and smooth muscle cells. However, tetrodotoxin, a blocker of voltage-dependent sodium channels in striated muscle cells and neurons, did not affect the physalaemin-induced contractions. These results indicate that physalaemin might induce contractile responses in longitudinal smooth muscle of the muscularis mucosa via direct actions on muscle cells but not on neurons. Although pretreatment with a tachykinin NK(1) receptor antagonist, N-acetyl-l-tryptophan 3,5-bis (trifluoromethyl) benzyl ester (L-732,138), did not significantly affect the physalaemin-evoked contractions in rat esophageal segments, a tachykinin NK(2) receptor antagonist, (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl] benzamide (SR48968), and a tachykinin NK(3) receptor antagonist, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide (SR142801), significantly inhibited the physalaemin-evoked contractions. These results suggest that tachykinins can activate longitudinal contraction of smooth muscle in the muscularis mucosa, mediated via tachykinin NK(2) and NK(3) receptors on muscle cells, in the rat esophagus.

Tachykinin receptor modulation of cyclooxygenase-2 expression in human polymorphonuclear leucocytes.

BACKGROUND AND PURPOSE: We investigated the ability of natural and synthetic selective NK receptors agonists and antagonists to modulate cyclooxygenase-2 (COX-2) expression in human polymorphonuclear leucocytes (PMNs). EXPERIMENTAL APPROACH: The presence of all three tachykinin in PMNs was assessed by Western blot and PCR techniques. Natural and synthetic ligands selective for the tachykinin receptors were used to modulate COX-2 protein (measured with Western blotting) and activity [as prostaglandin E(2) (PGE(2)) output]. Effects of substance P (SP) on phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) activation were studied to analyse the signalling pathway involved in COX-2 up-regulation mediated by SP. KEY RESULTS: Stimulation of NK receptors with the natural ligands SP, neurokinin A (NKA) and neurokinin B, in the pmol.L(-1)-micromol.L(-1) concentration range, modulated COX-2 expression and PGE(2) release in a concentration- and time-dependent manner. Experiments with synthetic selective agonists [Sar(9), Met(O(2))(11)]SP, [beta-Ala(8)] NKA(4-10), senktide or selective antagonists L703,606, SR48,968 or SR142801, confirmed that COX-2 up-regulation was mediated by NK receptors. We found that mainly p38, p42 and p46 MAPKs were phosphorylated by SP and SB202190, PD98059 and SP600125, which are selective inhibitors of these kinases, blocked SP-induced COX-2 expression. SP also induced nuclear translocation of NF-kappaB concentration-dependently, with a maximum effect at 1 nmol.L(-1). CONCLUSIONS AND IMPLICATIONS: Human PMNs possess functional NK(1), NK(2) and NK(3) receptors, which mediate the induction of COX-2 expression and NF-kappaB activation by SP.

Action of tachykinins in the hippocampus: facilitation of inhibitory drive to GABAergic interneurons.

By acting on neurokinin 1 (NK1) receptors, neuropeptides of the tachykinin family can powerfully excite rat hippocampal GABAergic interneurons located in the CA1 region and by this way indirectly inhibit CA1 pyramidal neurons. In addition to contact pyramidal neurons, however, GABAergic hippocampal interneurons can also innervate other interneurons. We thus asked whether activation of tachykinin-sensitive interneurons could indirectly inhibit other interneurons. The study was performed in hippocampal slices of young adult rats. Synaptic events were recorded using the whole-cell patch clamp technique. We found that substance P enhanced GABAergic inhibitory postsynaptic currents in a majority of the interneurons tested. Miniature, action potential-independent inhibitory postsynaptic currents were unaffected by substance P, as were evoked inhibitory synaptic currents. This suggests that the peptide acted at the somatodendritic membrane of interneurons, rather than at their axon terminals. The effect of substance P was mimicked by a selective NK1 receptor agonist, but not by neurokinin 2 (NK2) or neurokinin 3 (NK3) receptor agonists, and was suppressed by a NK1 selective receptor antagonist. In contrast to substance P, oxytocin, another peptide capable of activating hippocampal interneurons, had no effect on the inhibitory synaptic drive onto interneurons. We conclude that tachykinins, by acting on NK1 receptors, can influence the hippocampal activity by indirectly inhibiting both pyramidal neurons and GABAergic interneurons. Depending on the precise balance between these effects, tachykinins may either activate or depress hippocampal network activity.

Neurokinins robustly activate the majority of septohippocampal cholinergic neurons.

In the brain, tachykinins acting via the three cloned neurokinin (NK) receptors are implicated in stress-related affective disorders. Hemokinin-1 is a novel tachykinin that reportedly prefers NK1 to NK2 or NK3 receptors. Although NK1 and NK3 receptors are abundantly expressed in the brain, NK2-receptor-mediated electrophysiological effects have rarely been described as NK2 receptors are expressed only in a few brain regions such as the nucleus of the medial septum/diagonal band. Medial septal/diagonal band neurons that control hippocampal mnemonic functions also colocalize NK1 and NK3 receptors. Functionally, intraseptal activation of all three NK receptors increases hippocampal acetylcholine release and NK2 receptors have specifically been implicated in stress-induced hippocampal acetylcholine release. Electrophysiological studies on the effects of NKs on septohippocampal cholinergic neurons are lacking and electrophysiological effects of hemokinin-1 have thus far not been reported in brain neurons. In the present study we examined the electrophysiological and pharmacological effects of multiple NKs on fluorescently tagged septohippocampal cholinergic neurons using whole-cell patch-clamp recordings in a rat brain slice preparation. We demonstrate that a vast majority of septohippocampal cholinergic cells are activated by NK1, NK2 and NK3 receptor agonists as well as by hemokinin-1 via direct post-synaptic mechanisms. Pharmacologically, hemokinin-1 recruits not only NK1 but also NK2 and NK3 receptors to activate septohippocampal cholinergic neurons that are the primary source of acetylcholine for the hippocampus.

Neurokinin receptors modulate the impact of uncontrollable stimulation on adaptive spinal plasticity.

Previous research has demonstrated that spinally transected rats can acquire a prolonged flexion response to prevent the delivery of shock. However, rats that receive shock irrespective of leg position cannot learn to maintain the same response. The present experiments examined the role of neurokinin receptors in this learning deficit. Results demonstrated that neurokinin (NK1 and NK2) antagonists blocked the induction of the learning deficit, whereas NK agonists induced a learning deficit. The study found that NK agonist administration did not substitute for uncontrollable shock exposure. Finally, administration of an NK1 agonist prior to uncontrollable shock prevented the induction of the deficit. These results provide additional evidence that engaging nociceptive plasticity undermines the capability of spinal neurons to support adaptive changes.

Identification, physiological actions, and distribution of TPSGFLGMRamide: a novel tachykinin-related peptide from the midgut and stomatogastric nervous system of Cancer crabs.

In most invertebrates, multiple species-specific isoforms of tachykinin-related peptide (TRP) are common. In contrast, only a single conserved TRP isoform, APSGFLGMRamide, has been documented in decapod crustaceans, leading to the hypothesis that it is the sole TRP present in this arthropod order. Previous studies of crustacean TRPs have focused on neuronal tissue, but the recent demonstration of TRPs in midgut epithelial cells in Cancer species led us to question whether other TRPs are present in the gut, as is the case in insects. Using direct tissue matrix assisted laser desorption/ionization Fourier transform mass spectrometry, in combination with sustained off-resonance irradiation collision-induced dissociation, we found that at least one additional TRP is present in Cancer irroratus, Cancer borealis, Cancer magister, and Cancer productus. The novel TRP isoform, TPSGFLGMRamide, was present not only in the midgut, but also in the stomatogastric nervous system (STNS). In addition, we identified an unprocessed TRP precursor APSGFLGMRG, which was detected in midgut tissues only. TRP immunohistochemistry, in combination with preadsorption studies, suggests that APSGFLGMRamide and TPSGFLGMRamide are co-localized in the stomatogastric ganglion (STG), which is contained within the STNS. Exogenous application of TPSGFLGMRamide to the STG elicited a pyloric motor pattern that was identical to that elicited by APSGFLGMRamide, whereas APSGFLGMRG did not alter the pyloric motor pattern.

Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.

Characterization of the gene structures, precursor processing and pharmacology of the endokinin peptides.

The endokinins represent several species-divergent and peripherally located mammalian tachykinins (hemokinin-1 in mouse and rat, endokinin-1 in rabbit and endokinins A and B in humans) and also the tachykinin gene-related peptides. These peptides are all encoded on the preprotachykinin 4 (TAC4) gene. Their complementary DNA sequences, gene structures and expression profiles have been determined from a number of different mammalian species. They are all flanked by adjacent upstream and downstream dibasic cleavage sites in their respective precursor proteins, except for human EKA/B that instead possesses a N-terminal monobasic cleavage site. Evidence for differential processing in the periphery at the N-terminal cleavage site of the tachykinins could explain why in humans the evolutionary pressure to maintain the N-terminal dibasic cleavage site of EKA/B has been lost. Furthermore, the TAC4 encoded tachykinins all exhibit a remarkable selectivity and potency for the highly species conserved tachykinin NK(1) receptor, similar to that of substance P. Particular consideration is also given to the potential interactions of the endokinins with the short NK(1) receptor isoform and to speculation of whether there could be an "endokinin-sensitive" NK(1) binding site.

Regulation of the stimulant actions of neurokinin a and human hemokinin-1 on the human uterus: a comparison with histamine.

Regulation of the contractile effects of tachykinins and histamine on the human uterus was investigated with biopsy sections of the outer myometrial layer. The effects of neurokinin A (NKA) and human hemokinin-1 (hHK-1) in tissues from pregnant but not from nonpregnant women were enhanced by the inhibition of neprilysin. The effects of NKA and eledoisin were blocked by the NK2 receptor antagonist SR 48968 but not by the NK1 receptor antagonist SR 140333 in tissues from both groups of women. Human HK-1 acted as a partial agonist blocked by SR 48968 and, to a lesser extent, by SR 140333; endokinin D was inactive. In tissues from pregnant women, responses to high potassium-containing Krebs solution were 2-3-fold higher than those from nonpregnant women. Mepyramine-sensitive maximal responses to histamine were similarly enhanced. The absolute maximum responses to NKA and its stable NK2 receptor-selective analogue, [Lys5MeLeu9Nle10]NKA(4-10), were increased in pregnancy, but their efficacies relative to potassium responses were decreased. Tachykinin potencies were lower in tissues from pregnant women than in those from nonpregnant women. These data 1) show for the first time that hHK-1 is a uterine stimulant in the human, 2) confirm that the NK2 receptor is predominant in mediating tachykinin actions on the human myometrium, and 3) indicate that mammalian tachykinin effects are tightly regulated during pregnancy in a manner that would negate an inappropriate uterotonic effect. The potencies of these peptides in tissues from nonpregnant women undergoing hysterectomy are consistent with their possible role in menstrual and menopausal disorders.

Substance P selectively decreases paired pulse depression in the rat hippocampal slice.

BACKGROUND: Although being widespread in the hippocampus, the role tachykinins play in synaptic transmission is unclear. The effect of substance P on field potentials evoked by stimulation of the Schaffer collateral-commissural fibres and recorded from the CA1 region of the rat hippocampal slice were studied. RESULTS: Perfusion of substance P (8 microM) had no effect on the fEPSP or population spike. Substance P did however cause a selective reduction in the paired pulse depression of population spikes evoked by paired stimulation at interpulse intervals of 20-80 msec. A comparison of the actions of other tachykinin receptor agonists gave an order of potency of substance P > [beta-Ala8]-neurokinin A (4-10) > senktide. The effect of substance P was reduced by the neurokinin-1 receptor antagonist SR140333, but not by the neurokinin-2 or neurokinin-3 receptor antagonists, MDL 29,913 or [Trp7, beta-Ala8]-neurokinin A (4-10). CONCLUSION: The order of potency of the agonists, and the effects of the antagonists, both indicate that the effect of substance P on paired pulse depression is mediated by neurokinin-1 receptors.

Loperamide inhibits tachykinin NK3-receptor-triggered serotonin release without affecting NK2-receptor-triggered serotonin release from guinea pig colonic mucosa.

The effect of loperamide on tachykinin NK(2)- and NK(3)-receptor-mediated 5-HT outflow from guinea pig colonic mucosa was investigated in vitro. The selective tachykinin NK(2)-receptor agonist [beta-Ala(8)]-neurokinin A(4-10) (betaAla-NKA) or the selective NK(3)-receptor agonist senktide elicited an increase in 5-HT outflow from whole colonic strips, but not from mucosa-free muscle layer preparations. The enhancing effect of betaAla-NKA and senktide was prevented by the selective NK(2)-receptor antagonist GR94800 or the selective NK(3)-receptor antagonist SB222200. Loperamide concentration-dependently suppressed the senktide-evoked 5-HT outflow, but failed to affect the betaAla-NKA-evoked 5-HT outflow. The kappa-opioid receptor antagonist nor-binaltorphimine or the delta-opioid receptor antagonist naltrindole displaced the concentration-response curve for the suppressant action of loperamide to the right without significant depression of the maximum. However, the mu-opioid receptor antagonist CTOP did not affect the suppressant effect of loperamide. We concluded that the NK(3) receptor-triggered 5-HT release from colonic mucosa is suppressed by loperamide-sensitive mechanisms, whereas the NK(2)-receptor-triggered 5-HT release is loperamide-insensitive. Our data also suggest that the suppressant effect of loperamide is probably mediated by the activation of kappa- and delta-opioid receptors located on intrinsic neurons.