RESUMEN
The present study focused on the interactive pain regulation of endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) or endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on chimeric peptide MCRT (YPFPFRTic-NH2, based on YPFP-NH2 and PFRTic-NH2) at the supraspinal level in mice. Results demonstrated that the co-injection of nanomolar EKA/B and MCRT showed moderate regulation, whereas 30 pmol EKA/B had no effect on MCRT. The combination of EKC/D and MCRT produced enhanced antinociception, which was nearly equal to the sum of the mathematical values of single EKC/D and MCRT. Mechanism studies revealed that pre-injected naloxone attenuated the combination significantly compared with the equivalent analgesic effects of EKC/D alone, suggesting that EKC/D and MCRT might act on two totally independent pathways. Moreover, based on the above results and previous reports, we made two reasonable hypotheses to explain the cocktail-induced analgesia, which may potentially pave the way to explore the respective regulatory mechanisms of EKA/B, EKC/D, and MCRT and to better understand the complicated pain regulation of NK1 and µ opioid receptors, as follows: (1) MCRT and endomorphin-1 possibly activated different µ subtypes; and (2) picomolar EKA/B might motivate the endogenous NPFF system after NK1 activation.
Asunto(s)
Endorfinas/farmacología , Dimensión del Dolor/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Precursores de Proteínas/farmacología , Taquicininas/farmacología , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Endorfinas/administración & dosificación , Endorfinas/antagonistas & inhibidores , Infusiones Intraventriculares , Masculino , Ratones , Naloxona/farmacología , Fragmentos de Péptidos/administración & dosificación , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/antagonistas & inhibidores , Taquicininas/administración & dosificación , Taquicininas/antagonistas & inhibidoresRESUMEN
There is increasing focus on the involvement of tachykinins in immune and inflammatory responses. Hemokinin-1 (HK-1) is a recently identified tachykinin that originates primarily from immune cells, and has structural similarities to substance P (SP), found mainly in neurons. However, there are species differences in HK-1, and the role of HK-1 in humans, particularly the intestine, has received minimal attention. The aim of this study was to investigate the inflammatory role of human HK-1 in the human colon. The effects of HK-1 and SP were compared on the production of multiple inflammatory cytokines and chemokines from human colonic mucosal explants. Data generated by Procarta multiplex assay and QuantiGene assay demonstrated that 4 h incubation with HK-1 (0.1 µM) significantly stimulated transcript expression and release of MCP-1, MIP-1α and ß, RANTES, TNF-α, IL-1ß and IL-6 from the mucosa. SP (0.1 µM) had comparable actions, but had no effect on MCP-1 or RANTES. These effects were inhibited separately by tachykinin NK1 and NK2 receptor antagonists SR140333 and SR48968 (both 0.1 µM), suggesting that these responses were mediated by both NK1 and NK2 receptors. In conclusion, these data support a novel inflammatory role for HK-1 in human colon, signaling via NK1 and NK2 receptors (and possibly other tachykinin-preferring receptors) to regulate the release of a broad spectrum of proinflammatory mediators. The study suggests that along with SP, HK-1 is also a proinflammatory mediator, likely involved in colonic inflammation, including inflammatory bowel disease (IBD).
Asunto(s)
Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-2/metabolismo , Sustancia P/metabolismo , Taquicininas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Quimiocinas/metabolismo , Citocinas/metabolismo , Femenino , Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/efectos de los fármacos , Masculino , Persona de Mediana Edad , Sustancia P/administración & dosificación , Taquicininas/administración & dosificaciónRESUMEN
Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.
Asunto(s)
Dolor/prevención & control , Fragmentos de Péptidos/farmacología , Taquicininas/farmacología , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Benzamidas/farmacología , Bicuculina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas del GABA/farmacología , Humanos , Inyecciones Intraventriculares , Masculino , Ratones , Naloxona/análogos & derivados , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Dolor/fisiopatología , Dimensión del Dolor/métodos , Fragmentos de Péptidos/administración & dosificación , Piperidinas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Taquicininas/administración & dosificación , Taquicininas/química , Tropanos/farmacologíaRESUMEN
Desensitization is induced by the repeated administration of high doses of substance P (SP) or hemokinin-1 (HK-1). However, little information is available about the mechanisms involved in the induction of desensitization by these peptides. Thus, to characterize this desensitization, we examined the dose-dependent effect of these peptides, the effect of pretreatment with neurokinin 1(NK1) receptor antagonists, and the effect of pretreatment with inhibitors of protein kinases such as protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin kinase II (CaMKII) and mitogen-activated protein kinase kinase (MEK). The number of scratchings induced by 10(-3)M SP or HK-1 decreased following pretreatment with 10(-11)-10(-3)M SP or HK-1 with a marked reduction at 10(-3) and 10(-6)M SP or HK-1. The effect of NK1 receptor antagonists on desensitization induced by pretreatment with 10(-6)M SP was marked, whereas there was little effect of pretreatment with these antagonists on 10(-6)M HK-1-induced desensitization. Additionally, 10(-6)M SP- and HK-1-induced desensitization was attenuated by pretreatment with PKA, PKC and MEK inhibitors, except a CaMKII inhibitor that inhibited SP-induced desensitization. These results indicate that the receptor and kinases involved in HK-1-induced desensitization are partially different from those of SP.
Asunto(s)
Desensibilización Inmunológica , Prurito/tratamiento farmacológico , Prurito/psicología , Taquicininas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Inyecciones Espinales , Modelos Lineales , Masculino , Antagonistas del Receptor de Neuroquinina-1 , Inhibidores de Proteínas Quinasas/farmacología , Quinuclidinas/farmacología , Ratas , Ratas Sprague-Dawley , Taquicininas/administración & dosificaciónRESUMEN
The central mechanisms that mediate neuropeptide K (NPK) associated anorexia are poorly understood in any species, and information in this area of avian biology is totally lacking. Thus, the effects of intracerebroventricular NPK treatment were studied in Cobb-500 chicks (Gallus gallus). In Experiment 1, NPK caused decreased feed intake, but did not affect water intake or whole blood glucose concentration. In Experiment 2, NPK-treated chicks had increased c-Fos immunoreactivity in the parvicellular division of the paraventricular nucleus and arcuate nucleus. The lateral hypothalamus, ventromedial hypothalamus, dorsomedial hypothalamus, periventricular nucleus, magnocellular division of the paraventricular nucleus, and the superchiasmatic nucleus were not affected by NPK treatment. In Experiment 3, the number of feed pecks, exploratory pecks, jumps, escape attempts, and distance moved were decreased, while time spent standing was increased. None of the NPK-treated chicks sat or entered deep rest. In Experiment 4, blockage of corticotrophin releasing factor receptors did not affect NPK-induced anorexia. Thus, we conclude that NPK is a regulator of chick appetite and the effects may be mediated directly in the arcuate nucleus and parvicellular division of the paraventricular nucleus.
Asunto(s)
Pollos/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/fisiología , Taquicininas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Glucemia/efectos de los fármacos , Hormona Liberadora de Corticotropina/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Inyecciones Intraventriculares , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Distribución Aleatoria , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Taquicininas/administración & dosificaciónRESUMEN
We have recently reported that rat/mouse hemokinin-1 (r/m HK-1), a mammalian tachykinin, produced dose- and time-related antinociceptive effects at the supraspinal level via activating NK(1) receptors. Moreover, r/m HK-1 remarkably enhanced both the antinociceptive extent and duration of morphine administered at the peripheral and supraspinal level through a convergence of pharmacological effects of opioid-responsive neurons. Pethidine hydrochloride is an important narcotic analgesic, which acts as an opiate agonist and has pharmacological effects similar to morphine. To improve our knowledge of the pharmacology of pethidine, the aim of the present study was to investigate the relationship between the nociception of r/m HK and pethidine by comparing it with that of r/m HK-1 and morphine. Our data showed that r/m HK-1 remarkably enhanced the antinociceptive extent of pethidine administered at the peripheral level, but not at the supraspinal level. These antinociceptive effects were blocked by prior treatment with the classical opioid receptor antagonist naloxone, indicating that the potentiated analgesic effect is mediated by opioid-responsive neurons. Differences in the antinociceptive activity of pethidine and morphine in combination with r/m HK-1, arise because there are differences in the physicochemical and pharmacokinetic properties of pethidine and morphine, particularly their lipophilicity. Our results may pave the way for a new strategy for the control of pain and may provide a clinical strategy to enable selection of either opioid as a priority.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Meperidina/administración & dosificación , Dolor/tratamiento farmacológico , Taquicininas/administración & dosificación , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Inyecciones Intraventriculares/métodos , Masculino , Ratones , Ratones Endogámicos , Dimensión del Dolor/métodos , Tiempo de Reacción/efectos de los fármacos , Factores de TiempoRESUMEN
Some novel tachykinin peptides exhibiting homology with known members of the tachykinin family have been recently reported; however, little is known about the function of these peptides. Repeated intrathecal administration of substance P (SP) causes desensitization by binding SP to neurokinin 1 (NK1) receptor. Thus, to clarify the characteristics of the receptors involved in these novel peptides, we investigated whether desensitization is induced by intrathecal administration of these peptides in rats since desensitization is induced by binding these peptides to the receptor. Intrathecal administration of 10(-3) M hemokinin-1 (HK-1) and 10(-3) M decapeptide common in the carboxyl-terminal region of endokinin A and endokinin B (EKA/B) as well as SP evoked scratching behavior. When each peptide was administered twice with an interval of 15 min, remarkable desensitization of scratching behavior was produced. Furthermore, the first administration of EKA/B or SP produced clear cross-desensitization to SP, EKA/B and HK-1, whereas the first administration of HK-1 demonstrated weak cross-desensitization to EKA/B and SP. These results suggest that EKA/B and SP may bind to both the NK1 receptor and HK-1-preferred receptor, and HK-1 may preferentially bind to its preferred receptor.
Asunto(s)
Conducta Animal/efectos de los fármacos , Péptidos/administración & dosificación , Taquicininas/administración & dosificación , Taquicininas/química , Análisis de Varianza , Animales , Interacciones Farmacológicas , Inyecciones Espinales/métodos , Masculino , Estructura Terciaria de Proteína/fisiología , Ratas , Ratas Sprague-Dawley , Sustancia P/administración & dosificación , Factores de TiempoRESUMEN
Rat/mouse hemokinin 1 (r/m HK-1) is a mammalian tachykinin peptide whose biological functions are not fully understood. Our recent report showed that i.c.v. administration of r/m HK-1 could produce dose- and time-related antinociceptive effect at nanomole concentration, and naloxone significantly antagonized this effect. Thus, we provide indirect evidence favoring a role of NK1 supraspinal receptors in the inhibitory control of descending pain pathways, a role that seems to partially involve the activation of the endogenous opioid systems. Based on this report, the present study was conducted to further investigate the direct functional interaction between supraspinal tachykinin (r/m HK-1) and opioid systems. The results demonstrate that i.c.v. administration of r/m HK-1 (5 nmol/kg) could significantly potentiate the antinociceptive effects of morphine which was injected at peripheral and supraspinal level. These antinociceptive effects were blocked by prior treatment with the classical opioid receptors antagonist naloxone, indicating that the potentiated analgesic response is mediated by opioid-responsive neurons. Consistent with previous biochemical data, a likely mechanism underlying the peptide-mediated enhancement of opioid analgesia may center on the ability of r/m HK-1 to release endogenous opioid peptides. We suggest that there may be a cascade amplification mechanism in pain modulation when the two agents were co-administrated. The synergistic analgesic relationship of morphine and r/m HK-1 established here supports the hypothesis that supraspinal tachykinin and peripheral and central opioid systems have a direct functional interaction in the modulation of local nociceptive responses.
Asunto(s)
Inyecciones Intraventriculares , Inyecciones Subcutáneas , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Precursores de Proteínas/administración & dosificación , Taquicininas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Sinergismo Farmacológico , Inyecciones Intraventriculares/métodos , Inyecciones Subcutáneas/métodos , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/métodos , Tiempo de Reacción/efectos de los fármacos , Factores de TiempoRESUMEN
Hemokinin-1 (HK-1) is a new peptide described as a member of the tachykinin family. HK-1 has biological effects similar to substance P (SP), a representative of the tachykinin family, following central administration. However, the biological function of HK-1 at the spinal level has not been well characterized. Thus, we investigated the effect of intrathecal administration of HK-1 by comparing it with that of SP. Intrathecal administration of HK-1 as well as SP at 10(-3) M caused pain-related behavior such as scratching. The scratching by HK-1 administration was inhibited by pretreatment with an antagonist of substance P receptor. In addition, SP (10(-8)-10(-6) M) decreased the latency of the withdrawal response of the hind paw to noxious thermal stimulation 20-30 min after intrathecal administration, whereas administration of HK-1 had little effect on this response. These results suggest that there may exist a proper receptor related to HK-1.
Asunto(s)
Miembro Posterior , Dolor/psicología , Fragmentos de Péptidos/administración & dosificación , Taquicininas/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Interacciones Farmacológicas , Miembro Posterior/efectos de los fármacos , Miembro Posterior/fisiopatología , Miembro Posterior/efectos de la radiación , Calor/efectos adversos , Masculino , Dimensión del Dolor/efectos de los fármacos , Quinuclidinas/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Sustancia P/administración & dosificación , Factores de TiempoRESUMEN
The tachykinins are a group of structurally related peptides found in the rat hypothalamus and anterior pituitary. We have evaluated the effects of four tachykinins on LH release in male rats. In intact male rats, intracerebroventricular (icv) injection of neurokinin A (NKA), neuropeptide K (NPK), and neuropeptide-gamma (NP gamma) elicited dose-related, transient increases in plasma LH. Substance P (SP) was ineffective under these conditions. A further examination showed that in vitro incubation with either NPK or NP gamma of hemipituitaries from intact but not castrated male rats promoted release of LH into the medium, thereby revealing that the excitatory effects of tachykinins in intact male rats may, in part, be a result of stimulation of LH release directly from the anterior pituitary. On the other hand, the effects of these four tachykinins on LH release were different in castrated rats. Intracerebroventricular injection of NPK, NKA, and NP gamma as well as SP, which was ineffective in intact male rats, evoked a long-lasting suppression of LH release. Comparatively, NPK was the most effective tachykinin in eliciting LH responses in both of these tests involving different endocrine environments. We next evaluated the possibility that the inhibitory effects of tachykinins (NPK) may be mediated by activation of inhibitory endogenous opioid peptides. The results showed that iv infusion of the opiate receptor antagonist naloxone, to block the possible inhibitory effects of endogenous opioid peptides, only partially counteracted the suppressive effects of icv NPK on plasma LH levels. Thus, in addition to revealing the diverse effects of structurally related tachykinins on LH release, the results of these investigations showed specifically that the NK-2 receptor agonists NPK, NP gamma, and NKA stimulated LH release in intact rats, in part, by a direct action at the level of the pituitary, whereas the NK-1 receptor agonist SP was inactive under these conditions. These findings imply a paracrine/autocrine mode of excitatory action on LH release involving pituitary NK-2 receptor subtypes. On the other hand, in castrated rats, all four tachykinins readily suppressed LH release by a central action involving, in part, an activation of hypothalamic opioid systems.
Asunto(s)
Ventrículos Cerebrales/fisiología , Hormona Luteinizante/metabolismo , Neuroquinina A/farmacología , Neuroquinina B/farmacología , Neuropéptidos/farmacología , Fragmentos de Péptidos/farmacología , Sustancia P/farmacología , Taquicininas/farmacología , Animales , Ventrículos Cerebrales/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Hormona Luteinizante/sangre , Masculino , Neuroquinina A/administración & dosificación , Neuroquinina B/administración & dosificación , Orquiectomía , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Endogámicas , Valores de Referencia , Sustancia P/administración & dosificación , Taquicininas/administración & dosificaciónRESUMEN
Tachykinins, a family of biologically active related peptides, are found in variable amounts in the rat hypothalamus. We assessed the effects of five tachykinins, substance P (SP), neurokinin A (NKA), neuropeptide K (NPK), neuropeptide gamma (NP gamma), and neurokinin B (NKB), on LH release in different experimental model systems in ovariectomized rats. In the first series of experiments rats were ovariectomized and implanted with permanent cannulae in the third cerebroventricle of the rat brain. Two weeks later, the effects of intracerebroventricular injection of 0.5 or 1.25 nm various tachykinins on LH release were studied. The results showed that whereas SP, NKA, and NKB were ineffective, and NP gamma was marginally effective, NPK produced a long-lasting suppression of LH release. NPK decreased LH release in a dose- and time-related fashion. Similarly, in the second series of experiments, whereas SP and NKA were inactive, NPK completely suppressed the LH surge induced by progesterone in estrogen-primed ovariectomized rats. In the third series of experiments we observed that NK-2 receptor agonist [Nle10]NKA4-10, and not NK-1 receptor agonist [Sar9,Met(O2)11]SP, suppressed both the release of LH in vivo and basal and KCl-induced hypothalamic LHRH release in vitro. These results show that NPK is the most effective tachykinin in suppressing LH release, and the inhibitory response is mediated by hypothalamic NK-2 receptors. These findings are in accord with the hypothesis that NPK may serve as a hypothalamic inhibitory neurotransmitter/neuromodulator of LHRH secretion.
Asunto(s)
Hormona Luteinizante/sangre , Neuropéptidos/farmacología , Taquicininas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Estradiol/análogos & derivados , Estradiol/farmacología , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Inyecciones Intraventriculares , Neuroquinina A/farmacología , Ovariectomía , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Potasio/farmacología , Progesterona/farmacología , Radioinmunoensayo , Ratas , Sustancia P/farmacología , Taquicininas/administración & dosificación , Factores de TiempoRESUMEN
Hemokinin-1 (HK-1) is a recently described mouse tachykinin peptide whose biological functions are not fully understood. To date, a unique receptor for HK-1 has not been identified. Recent studies suggest HK-1 may have a role in immunological functions, but there has been little characterization of HK-1's effects in the central nervous system (CNS). In the present studies, we confirm that HK-1 is an endogenous agonist at all of the known tachykinin receptors, and is selective for the NK1 receptor over the NK2 and NK3 subtypes. CHO cells transfected with the human NK1 receptor released intracellular calcium in response to HK-1. In addition, HK-1 competed with substance P (SP) for binding to mouse NK1 and human NK1 receptors. In vivo central administration of HK-1 to gerbils and mice induced foot-tapping and scratching behaviors, respectively, similar to those observed following central administration of SP or the NK1 receptor agonist, GR-73632. Furthermore, these behavioral effects were blocked by the selective NK1 receptor antagonist, MK-869. Finally, a comprehensive expression analysis of HK-1 demonstrated that HK-1 mRNA is much more broadly expressed than previously reported with expression observed in many brain regions. Together these data demonstrate that HK-1 is a functional agonist at NK1 receptors and suggest that HK-1 may function both centrally and peripherally.
Asunto(s)
Conducta Animal/efectos de los fármacos , Precursores de Proteínas/administración & dosificación , Receptores de Neuroquinina-1/agonistas , Sustancia P/farmacología , Taquicininas/administración & dosificación , Animales , Conducta Animal/fisiología , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Femenino , Gerbillinae , Humanos , Masculino , Ratones , Antagonistas del Receptor de Neuroquinina-1 , Precursores de Proteínas/biosíntesis , Receptores de Neuroquinina-1/metabolismo , Sustancia P/biosíntesis , Taquicininas/biosíntesisRESUMEN
1. The effects on micturition of RP 67,580, a selective NK1 receptor antagonist, and SR 48,968, a highly, potent antagonist at NK2 receptor sites, given intrathecally (i.t.) or intra-arterially (i.a.) near the bladder, were investigated in unanaesthetized rats with and without bladder outlet obstruction. 2. In normal rats, RP 67,580, given i.t. in doses of 2 and 20 nmol per rat, decreased micturition pressure, but did not change other cystometric parameters. After 20 nmol of RP 67,580, dribbling incontinence due to retention was observed in 1 out of 7 animals. This effect was reversible. I.t. RP 67,580 in a dose of 2 nmol, had no effect on hyperactivity induced by intravesically instilled capsaicin. 3. In animals with bladder hypertrophy secondary to outflow obstruction, RP 67,580, given i.t. in a dose of 2 nmol per rat, decreased the micturition pressure, but had no effect on other cystometric parameters. After 20 nmol, dribbling incontinence due to retention was observed in 5 out of 7 animals. 4. RP 67,580, given i.a. in a dose of 4 nmol, had little effect on the cystometric parameters investigated, both in normal animals and rats with bladder hypertrophy. 5. SR 48,968, given i.t. in doses of 2 and 20 nmol per rat, had no clear-cut effects on the micturition pattern in normal rats, or rats with bladder hypertrophy. However, the drug reduced capsaicin-induced bladder hyperactivity. When given i.a. in a dose of 4 nmol, SR 48,968 had no effect on cystometric parameters in normal rats or rats with bladder hypertrophy. 6. The effects of both RP 67,580 and SR 48,968 were stereoselective, their enantiomers (RP 68,651 and SR 48,965) being inactive.7. These results thus suggest that at the spinal level there is a tachykinin involvement (via NK,receptors) in the micturition reflex induced by bladder filling, both in normal rats, and, more clearly, in animals with bladder hypertrophy secondary to outflow obstruction. The bladder response to filling was not influenced by blockade of vesical NKI and NK2 receptors. On the other hand, the bladder hyperactivity evoked by intravesical capsaicin seems to involve NK2 receptors both at the bladder and spinal levels.
Asunto(s)
Taquicininas/farmacología , Obstrucción del Cuello de la Vejiga Urinaria/patología , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacos , Analgésicos/farmacología , Animales , Benzamidas/farmacología , Cistoscopía , Femenino , Hipertrofia/patología , Indoles/farmacología , Inyecciones Intraarteriales , Inyecciones Espinales , Isoindoles , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-2/antagonistas & inhibidores , Taquicininas/administración & dosificación , Vejiga Urinaria/patología , Cateterismo UrinarioRESUMEN
1. Scald injury in Sv129+C57BL/6 mice induced a temperature and time dependent oedema formation as calculated by the extravascular accumulation of [(125)I]-albumin. Oedema formation was suppressed in NK(1) knockout mice compared to wildtypes at 10 (P<0.01) and 30 min (P<0.001). However, at 60 min a similar degree of extravasation was observed in the two groups. 2. Kinin B(1) (des-Arg(10) Hoe 140; 1 micromol kg(-1)) and B(2) (Hoe 140; 100 nmol kg(-1)) antagonists caused an inhibition of oedema in wildtype mice at 10 and 30 min (P<0.001), but not at 60 min or at 30 min in NK(1) receptor knockout mice. 3. The inhibition of thermic oedema by des-Arg(10) Hoe 140 was reversed by des-Arg(9) bradykinin (0.1 micromol kg(-1); P<0.01) and also observed with a second B(1) receptor antagonist (des-Arg(9) Leu(8) bradykinin; 3 micromol kg(-1); P<0.01). Furthermore des-Arg(10) Hoe 140 had no effect on capsaicin (200 microg ear(-1)) ear oedema, but this was significantly reduced with Hoe 140 (P<0.05). 4. Scalding induced a large neutrophil accumulation at 4 h, as assessed by myeloperoxidase assay (P<0.001). This was not suppressed by NK(1) receptor deletion or kinin antagonists. 5. These results confirm an essential role for the NK(1) receptor in mediating the early, but not the delayed phase of oedema formation or neutrophil accumulation in response to scalding. The results also demonstrate a pivotal link between the kinins and sensory nerves in the microvascular response to burn injury, and for the first time show a rapid involvement of the B(1) receptor in murine skin.
Asunto(s)
Bradiquinina/análogos & derivados , Dermatitis/etiología , Edema/etiología , Calor/efectos adversos , Receptores de Bradiquinina/fisiología , Receptores de Neuroquinina-1/fisiología , Administración Tópica , Animales , Bradiquinina/farmacología , Antagonistas de los Receptores de Bradiquinina , Quemaduras/etiología , Capsaicina/administración & dosificación , Capsaicina/farmacología , Movimiento Celular/inmunología , Dermatitis/inmunología , Edema/inducido químicamente , Edema/inmunología , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Piperidinas/farmacología , Quinuclidinas/farmacología , Receptor de Bradiquinina B1 , Receptor de Bradiquinina B2 , Receptores de Neuroquinina-1/genética , Taquicininas/administración & dosificación , Taquicininas/farmacología , Factores de TiempoRESUMEN
1. The cardiovascular and behavioural effects elicited by the intracerebroventricular (i.c.v.) administration of neuropeptide gamma (NP gamma) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for NK1 (RP 67,580), NK2 (SR 48,968) and NK3 (R 820) receptors. In addition, the central effects of NP gamma before and after desensitization of the NK1 and NK2 receptors with high doses of substance P (SP) and neurokinin A (NKA) were compared. 2. Intracerebroventricular injection of NP gamma (10-780 pmol) evoked dose- and time-dependent increases in mean arterial blood pressure (MAP), heart rate (HR), face washing, head scratching, grooming and wet-dog shake behaviours. Similar injection of vehicle or 1 pmol NP gamma had no significant effect on those parameters. 3. The cardiovascular and behavioural responses elicited by NP gamma (25 pmol) were significantly and dose-dependently reduced by pretreatment with 650 pmol and 6.5 nmol of SR 48,968. No inhibition of NP gamma responses was observed when 6.5 nmol of RP 67,580 was used in a similar study. Moreover, the prior co-administration of SR 48,968 (6.5 nmol) and RP 67,580 (6.5 nmol) with or without R 820 (6.5 nmol) did not reduce further the central effects of NP gamma and significant residual responses (30-50%) remained. 4. No tachyphylaxis to NP gamma-induced cardiovascular and behavioural changes was observed when two consecutive injections of 25 pmol NP gamma were given 24 h apart. 5. Simultaneous NK1 and NK2 receptor desensitization reduced significantly central effects mediated by 25 pmol NP gamma. However, significant residual responses persisted as seen after pretreatment with SR 48,968. 6. The results suggest that the central effects of NP gamma are mediated partly by NK2 receptors and by another putative tachykinin receptor subtype (NP gamma receptor?) that appears to be different from NK1 and NK3 receptors.
Asunto(s)
Neuropéptidos/farmacología , Fragmentos de Péptidos/farmacología , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismo , Taquicininas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Antagonistas del Receptor de Neuroquinina-1 , Neuropéptidos/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Wistar , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-3/antagonistas & inhibidores , Taquicininas/administración & dosificación , Taquicininas/antagonistas & inhibidoresRESUMEN
1. The effects of intrathecally (i.t.) injected substance P (SP), neurokinin A (NKA), [beta-Ala8]NKA (4-10) and [MePhe7]neurokinin B (NKB) at T13 thoracic spinal cord level were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. Antagonists selective for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820; 3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) receptors were used to characterize the spinal effect of SP on renal function. 2. Saline gavage (4.5% of the body weight) enhanced renal excretion of water, sodium and potassium over the subsequent hour of measurement. Whereas these renal responses were not affected by 0.65 nmol SP, the dose of 6.5 nmol SP blocked the natriuretic response (aCSF value 3.9 +/- 0.8; SP value 0.7 +/- 0.3 micromol min(-1), P<0.01) as well as the renal excretion of water (aCSF value 48.9 +/- 5.8; SP value 14.5 +/- 4.0 microl min(-1), P<0.01) and potassium (aCSF value 4.8 +/- 0.6; SP value 1.5 +/- 0.6 micromol min(-1), P<0.01) at 30 min post-injection. SP had no significant effect on urinary osmolality. The SP-induced renal inhibitory effects during the first 30 min were abolished in rats subjected to bilateral renal denervation 1 week earlier or in rats injected i.t. 5 min earlier with 6.5 nmol RP 67580. In contrast, the co-injection of SR 48968 and R 820 (6.5 nmol each) did not affect the inhibitory responses to SP. On their own, these antagonists had no direct effect on renal excretion function. Since SP induced only transient changes in mean arterial blood pressure (-18.8 +/- 3.8 mmHg at 1 min and +6.3 +/- 2.4 mmHg at 5 min post-injection), it is unlikely that the renal effects of SP are due to systemic haemodynamic changes. 3. NKA (6.5 nmol but not 0.65 nmol) produced a transient drop in renal excretion of water (aCSF value 31.2 +/- 5.1; NKA value 11.3 +/- 4.2 microl min(-1), P<0.05), sodium (aCSF value 1.7 +/- 0.8; NKA value 0.4 +/- 0.2 micromol min(-1), P<0.05) and potassium (aCSF value 4.1 +/- 0.7; NKA value 1.5 +/- 0.4 micromol min(-1), P<0.05) at 15 min post-injection. However, the same doses (6.5 nmol) of selective agonists for tachykinin NK2 ([beta-Ala8]NKA(4-10)) and NK3 ([MePhe7]NKB) receptors were devoid of renal effects. 4. This study provided functional evidence that tachykinins may be involved in the renal control of water and electrolyte excretion at the level of the rat spinal cord through the activation of NK1 receptors and the sympathetic renal nerve.
Asunto(s)
Riñón/efectos de los fármacos , Cloruro de Sodio/administración & dosificación , Taquicininas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Desnervación , Inyecciones Espinales , Riñón/inervación , Riñón/fisiología , Masculino , Natriuresis/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Taquicininas/efectos de los fármacos , Taquicininas/administración & dosificación , Taquicininas/líquido cefalorraquídeoRESUMEN
1. In the conscious rat, cardiovascular responses to intrathecally (i.t.) administered neuropeptide gamma (NP gamma) were studied prior to and after the i.t. pretreatment with selective antagonists at NK1 ((+/-)-CP 96345 and RP 67580), NK2 (SR 48968) and NK3 (R 486) receptors. Pretreatment with a mixture of peptidase inhibitors (phosphoramidon, captopril, bacitracin, phenanthroline) was also tested to ascertain whether or not the effect of NP gamma was mediated by a metabolite. The involvement of peripheral catecholamines was examined with intravenous injection of alpha-adrenoceptor (phentolamine) and beta-adrenoceptor (propranolol) antagonists. 2. NP gamma (0.078-78 nmol) induced dose-dependent increases in heart rate (HR) and mean arterial blood pressure (MAP). The highest dose of 78 nmol did not induce an increase of MAP greater than that with 7.8 nmol but was preceded by a transient decrease of MAP (1-3 min). No desensitization was observed when three injections of 7.8 nmol NP gamma were given at 90 min intervals. 3. Cardiovascular and behavioural (biting/scratching) effects evoked by 0.78 nmol NP gamma were significantly reduced by the NK1 antagonists, (+/-)-CP 96345 (65 nmol) or RP 67580 (7.8 and 78 nmol). However, cardiovascular responses to NP gamma were not affected by (+/-)-CP 96345 (6.5 nmol), SR 48968 (7.8 and 78 nmol) or R 486 (25 nmol). Pretreatment with peptidase inhibitors significantly enhanced the cardiovascular and behavioural responses to NP gamma. 4. The pressor response to 7.8 nmol NP gamma was converted to a vasodepressor response by pretreatment with phentolamine (2 mg kg-1, i.v.) while the chronotropic response was markedly reduced by propranolol (2 mg kg-1, i.v.). 5. These results suggest that the cardiovascular responses to i.t. NP gamma are mediated by NK1 receptors in the spinal cord leading to the peripheral release of catecholamines from sympathetic fibres or the adrenal medulla. It is unlikely that the spinal action of NP gamma results from its metabolic conversion into neurokinin A or another major metabolite.
Asunto(s)
Hemodinámica/efectos de los fármacos , Neuropéptidos/farmacología , Fragmentos de Péptidos/farmacología , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismo , Taquicininas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Espinales , Masculino , Antagonistas del Receptor de Neuroquinina-1 , Neuropéptidos/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Inhibidores de Proteasas/farmacología , Ratas , Ratas Wistar , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-3/antagonistas & inhibidores , Taquicininas/administración & dosificación , Taquicininas/antagonistas & inhibidoresRESUMEN
1. The effects of intracerebroventricular (i.c.v.) injection of selective and potent NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 486, [Trp7, beta-Ala8]NKA(4-10)) receptor antagonists were assessed on the cardiovascular and behavioural responses elicited by the i.c.v. injection of substance P (SP), neurokinin A (NKA) or [MePhe7]neurokinin B ([MePhe7]NKB) in the conscious freely moving rat. 2. SP, NKA and [MePhe7]NKB (5-650 pmol) evoked dose-dependent increases in mean arterial blood pressure (MAP) and heart rate (HR) with the rank order of potency SP > NKA > [MePhe7]NKB. The cardiovascular responses were accompanied by excessive face washing, grooming and wet dog shakes. 3. The cardiovascular effects and face washing behaviour induced by SP (25 pmol) were significantly reduced by the pre-injection (i.c.v., 5 min earlier) of RP 67580 (6.5 nmol). However, this antagonist failed to affect the central effects of 25 pmol NKA or [MePhe7]NKB. 4. The cardiovascular and behavioural responses (except for wet dog shakes) elicited by NKA (25 pmol) were significantly reduced by 6.5 nmol SR 48968. However, the latter antagonist had no effect on the SP or [MePhe7]NKB-mediated responses. 5. Both cardiovascular and behavioural effects produced by either SP or NKA (25 pmol) were completely abolished when rats were pretreated with a combination of RP 67580 (6.5 nmol) and SR 48968 (6.5 nmol), yet this combination of antagonists failed to modify the central effects of [MePhe7]NKB. 6. R 486 (6.5 nmol) inhibited the cardiovascular effects as well as wet dog shakes produced by [MePhe7]NKB, but it was inactive against the responses induced by either SP or NKA. 7. None of the tachykinin receptor antagonists or agonists caused motor impairment or respiratory distress. All antagonists blocked in a reversible manner and were devoid of intrinsic activity except R486 (6.5 nmol) which produced a transient increase of MAP and HR.8. These results suggest that the central effects of SP, NKA and [MePhe7]NKB are primarily mediated by central NK1, NK2 and NK3 receptors, respectively. However, a minor activation of NK2 receptors bySP and NK1 receptors by NKA was seen during blockade of both receptors. This study therefore supports the existence of functional NK1, NK2 and NK3 receptors in the adult rat brain.
Asunto(s)
Conducta Animal/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Receptores de Taquicininas/antagonistas & inhibidores , Taquicininas/farmacología , Animales , Benzamidas/farmacología , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Indoles/farmacología , Inyecciones Intraventriculares , Isoindoles , Masculino , Neuroquinina A/administración & dosificación , Neuroquinina A/antagonistas & inhibidores , Neuroquinina A/farmacología , Neuroquinina B/análogos & derivados , Neuroquinina B/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Oligopéptidos/farmacología , Piperidinas/farmacología , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-2/efectos de los fármacos , Receptores de Neuroquinina-3/antagonistas & inhibidores , Receptores de Neuroquinina-3/efectos de los fármacos , Sustancia P/administración & dosificación , Sustancia P/antagonistas & inhibidores , Sustancia P/farmacología , Taquicininas/administración & dosificaciónRESUMEN
The effects of lateral ventricular injections of succinyl-[Asp6, N-Me-Phe8]-substance P (SENK; 25, 100, 200 ng), a tachykinin NK3 receptor agonist, and [Sar9, Met(O2)11]-substance P (Sar Met; 100, 200 ng), an NK1 receptor agonist, on normal (gastric fistula closed) and sham drinking (gastric fistula open) of hypertonic NaCl by sodium-deficient rats were compared. Intraventricular injections of Sar Met had no effect on NaCl intake in either condition. Injections of 100 ng and 200 ng SENK caused an equal suppression of NaCl intake in the 2 fistula conditions. The latency to drink was not affected, but the initial lick rate was significantly lower and decayed more rapidly after 100 ng SENK than after saline or 25 ng SENK. The results show that (a) the tachykinin subtypes are not equally involved in the control of need-induced salt intake; (b) negative feedback from the stomach and distal gastrointestinal tract is not required for intraventricular injections of SENK to suppress sodium appetite; (c) the activation of NK3 receptors decreases the oral excitatory influence of hypertonic NaCl in sodium-deficient rats.
Asunto(s)
Apetito/fisiología , Conducta Alimentaria/fisiología , Ventrículos Laterales , Receptores de Neuroquinina-1/agonistas , Receptores de Neuroquinina-3/agonistas , Cloruro de Sodio Dietético/administración & dosificación , Sodio/deficiencia , Animales , Apetito/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Inyecciones Intraventriculares , Ventrículos Laterales/cirugía , Masculino , Ratas , Ratas Endogámicas , Sustancia P/administración & dosificación , Sustancia P/fisiología , Taquicininas/administración & dosificación , Taquicininas/fisiologíaRESUMEN
The central effects of tachykinins (substance P, neurokinin A, and neurokinin B) on the distribution of the motor activity to rib cage and abdominal expiratory muscles were studied in anesthetized tracheotomized spontaneously breathing dogs and cats. Intracisternal application of substance P (11 dogs) in doses of 10(-5) to 10(-4) M caused diaphragm electrical activity to change insignificantly from 19.3 +/- 1.9 to 24.8 +/- 3.2 units (P greater than 0.05), produced a moderate increase of triangularis sterni activity from 12.6 +/- 2.2 to 19.2 +/- 2.2 units (P less than 0.05), and stimulated a large increase of transversus abdominis activity from 9.4 +/- 2.7 to 28.5 +/- 2.6 units (P less than 0.01). Comparable effects were seen with similar doses of neurokinin A (8 dogs) and neurokinin B (3 dogs) administered intracisternally. Local application of substance P to the ventral medullary surface (5 dogs and 4 cats) also caused expiratory muscle activity to increase more than diaphragm activity, and in addition transversus abdominis activity increased to a larger extent than triangularis sterni activity. Furthermore, administration of the substance P antagonist [D-Pro2,D-Trp7,9]-SP to the ventral medullary surface decreased respiratory motor output, with expiratory muscles activity being attenuated to a greater extent than diaphragm activity. Application of neurotensin and N-methyl-D-asparate to the ventral surface of the medulla produced responses similar to those observed as a result of central administration of tachykinin peptides. The results suggest that 1) mammalian tachykinins are involved in the regulation of thoracic and abdominal expiratory muscle activity, 2) these muscles manifest substantial differences in their electrical responses to excitatory neuropeptides acting centrally, and 3) inputs from modulatory neurons located in this vicinity of the ventral medullary surface seem to be distributed unevenly to different expiratory premotor and/or motoneurons.