RESUMO
Of the two corticotropin releasing factor receptors known, corticotrophin releasing factor 2 receptor (CRF2R) is expressed in skeletal muscle. The function of this receptor in skeletal muscle is at present unknown. In order to better understand the role of the CRF2R in skeletal muscle, we treated rats with CRF2R agonists and evaluated the effect of these agents on normal and denervated muscle mass. Rats treated with the non-selective CRFR agonist, sauvagine, did not demonstrate any significant and consistent change in non-denervated and denervated fast twitch [tibialis anterior (TA) or extensor digitorum longus (EDL)] or slow/mixed twitch [medial gastrocnemius (MG) or soleus] fiber muscle mass. In adrenalectomized rats, sauvagine treatment resulted in no significant and consistent change in non-denervated fast or slow/mixed twitch fiber muscles but did cause a significant and consistent increase in denervated fast twitch (TA and EDL) but not slow/mixed twitch muscle mass. Interestingly adrenalectomy had no effect on the degree of muscle atrophy. Rats treated with the CRF2R selective agonist urocortin 2 demonstrated an increase in non-denervated and denervated fast and slow/mix twitch fiber muscle mass. The urocortin 2 induced increase in muscle mass was accompanied by an increase in muscle fiber cross-sectional area and muscle absolute force. These studies demonstrated that activation of the CRF2R decreased the level of skeletal muscle mass, force, and myocyte cross-sectional area loss resulting from sciatic nerve damage and increased the mass, force and myocyte cross-sectional area of normal (non-atrophying) skeletal muscle. In addition, we also observed that removal of the adrenals increased the effectiveness of the non-selective CRFR agonists sauvagine, presumably via the removal of the pro-atrophy influence of adrenal produced corticosteroids. These results demonstrate that pharmacological modulation of the CRF2R may be a viable method to treat skeletal muscle atrophy.
Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Músculo Esquelético/fisiologia , Peptídeos/farmacologia , Receptores de Hormônio Liberador da Corticotropina/agonistas , Proteínas de Anfíbios , Animais , AMP Cíclico/química , Feminino , Células Musculares/efeitos dos fármacos , Células Musculares/fisiologia , Denervação Muscular , Músculo Esquelético/efeitos dos fármacos , Hormônios Peptídicos , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/fisiologia , UrocortinasRESUMO
BACKGROUND: The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA). OBJECTIVE: The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats. METHODS: Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor. RESULTS: Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl. CONCLUSIONS: The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity.
Assuntos
Obesidade/tratamento farmacológico , alfa-MSH/análogos & derivados , alfa-MSH/efeitos adversos , Animais , Aprendizagem da Esquiva , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos , Ratos , Distúrbios do Paladar/induzido quimicamente , alfa-MSH/administração & dosagemRESUMO
We show that magnetic resonance imaging (MRI) can be used to quantify the amount of muscle in the lower legs of adult rats and to noninvasively monitor the onset and progression of denervation-induced atrophy. Muscle cross-sectional areas determined from 2D gradient-echo MR images allow longitudinal quantification of the protective effects of a beta(2)-adrenergic agonist clenbuterol. We also show that the estimation of clenbuterol's efficacy is improved by computation of the muscle volume. Rapid animal throughput and the ability to accurately estimate efficacy make MRI an attractive technology for studying skeletal muscle atrophy and hypertrophy, allowing the evaluation of potential therapies in longitudinal studies.
Assuntos
Clembuterol/farmacologia , Imageamento por Ressonância Magnética , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Simpatomiméticos/farmacologia , Animais , Feminino , Denervação Muscular , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Atrofia Muscular/prevenção & controle , Ratos , Ratos Sprague-Dawley , Nervo IsquiáticoRESUMO
A proteomic analysis was performed comparing normal rat soleus muscle to denervated soleus muscle at 0.5, 1, 2, 4, 6, 8 and 10 days post denervation. Muscle mass measurements demonstrated that the times of major mass changes occurred between 2 and 4 days post denervation. Proteomic analysis of the denervated soleus muscle during the atrophy process demonstrated statistically significant (at the p < 0.01 level) changes in 73 soleus proteins, including coordinated changes in select groups of proteins. Sequence analysis of ten differentially regulated proteins identified metabolic proteins, chaperone and contractile apparatus proteins. Together these data indicate that coordinated temporally regulated changes in the proteome occur during denervation-induced soleus muscle atrophy, including changes in muscle metabolism and contractile apparatus proteins.
Assuntos
Músculo Esquelético/metabolismo , Proteoma , Animais , Denervação , Eletroforese em Gel Bidimensional , Feminino , Proteínas Musculares/metabolismo , Músculo Esquelético/inervação , Mapeamento de Peptídeos , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
The effects of bombesin (BBS) on ion transport in the mouse isolated jejunum were studied in full thickness (intact) or serosal stripped (mucosal) sheets of jejunum mounted in Ussing chambers. Although serosal BBS (0.1-30 nM) induced a concentration-related increase in transmural potential difference (PD) and short-circuit current (Isc) without altering conductance in both preparations, the peptide was more potent and efficacious in mucosal than in intact tissues. In all preparations, pretreatment with BBS abolished the effects of a subsequent administration of BBS showing the rapid development of desensitization. In intact tissues, serosal pretreatment with either chlorisondamine (3 microM) or tetrodotoxin (0.1 microM) decreased, but did not abolish BBS action. Meanwhile, atropine pretreatment (3 microM) did not affect the BBS response. In these tissues, previous blockade of NaCl cotransport by furosemide (300 microM) decreased BBS (30 nM) stimulation of PD or Isc. In mucosal preparations, tetrodotoxin pretreatment (0.1 microM) similarly reduced but did not eliminate BBS (3 nM) stimulation of PD or Isc, whereas atropine pretreatment (1 microM) again had no effect on BBS action. In contrast in these mucosal tissues, furosemide pretreatment (300 microM) did not modify the BBS response. Furthermore, carbachol pretreatment (10 microM) prevented completely the tetrodotoxin-resistant action of BBS. These findings in vitro suggest that the increase of PD and Isc following BBS administration in isolated mouse jejunum is associated with three different levels of action of this peptide: BBS may act on noncholinergic nerves, at pre- and post-ganglionic levels, as well as directly on the enterocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bombesina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Animais , Bombesina/antagonistas & inibidores , Carbacol/farmacologia , Relação Dose-Resposta a Droga , Furosemida/farmacologia , Técnicas In Vitro , Canais Iônicos/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
Central and peripheral sites of opioid action on net basal fluid transport were studied in loops of jejunum in urethane-anesthetized mice. Intracerebroventricular administration of morphine, [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO), D-Pen2, D-Pen5] enkephalin (DPDPE) or U50,488H produced dose-related increases in net basal intestinal absorption. Intracerebroventricular DAMGO was approximately 2.6, 1278 and 2674 times more potent than morphine, DPDPE and U50,488H, respectively. The increase in net basal fluid absorption mediated by i.c.v. administration of all these compounds, except DPDPE, was antagonized in a dose-related manner by coadministration of i.c.v. naloxone, an opioid antagonist which did not produce any effects when given alone. Neither the increase in net basal fluid absorption produced by DPDPE nor the fluid transport effects produced by the other agonists tested was antagonized by the delta antagonist, N,N-diallyl-Tyr-alpha-aminoisobutyric acid [( Aib]-Aib-Phe-Leu-OH) and no effects were observed with this delta antagonist alone. Intracerebroventricular administration of beta-funaltrexamine (18.8 nmol, 4 hr before testing) blocked the i.c.v. effects of DAMGO, but not those of U50,488H. In contrast to the effects seen following i.c.v. administration of these agonists, no changes in net basal fluid transport were obtained by the i.p. route for DAMGO, DPDPE, [D-Ala2,D-Leu5]enkephalin, [D-Ala2, Met5]enkephalinamide or U50,488H; of the compounds tested, only morphine produced an increase in net basal fluid absorption after i.p. administration. The effects of i.c.v. or i.p. morphine were blocked by i.c.v. SR 58002C, a quaternary opioid antagonist which had no effects alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Analgésicos/farmacologia , Líquidos Corporais/metabolismo , Encefalinas/farmacologia , Intestinos/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina , D-Penicilina (2,5)-Encefalina , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacologia , Leucina Encefalina-2-Alanina , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Levalorfano/análogos & derivados , Levalorfano/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
The present investigation examined the effects of centrally and peripherally administered corticotropin-releasing factor on gastric emptying and gastrointestinal transit in mice. Corticotropin-releasing factor, given either intracerebroventricularly or intrathecally, caused a dose-dependent inhibition of gastric emptyping and gastrointestinal transit. Intravenous or intraperitoneal administration of corticotropin-releasing factor, while 5- to 7-fold less potent than after central injection, produced an equivalent level of effect. alpha-Helical corticotropin-releasing factor, a corticotropin-releasing factor receptor antagonist, blocked the effects of intracerebroventricularly administered corticotropin-releasing factor when the antagonist was given concurrently by the intracerebroventricular, but not by the intraperitoneal, route. Conversely, corticotropin-releasing factor, when given peripherally, was antagonized equally well by intracerebroventricular or intraperitoneal administration of the antagonist. The inhibition of gastric emptying induced by corticotropin-releasing factor was reduced by pretreatment with the ganglionic blocking agent, chlorisondamine, and in adrenalectomized mice, but this effect was not antagonized by naloxone. These findings provide evidence for an action of corticotropin-releasing factor within the central nervous system, as well as a peripheral site of action, to inhibit gastric emptying in the mouse. The gastrointestinal motor effects of corticotropin-releasing factor are not mediated through opioid mechanisms although their full expression may require intact autonomic innervation and adrenal function.
Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Adrenalectomia , Animais , Clorisondamina/farmacologia , Hormônio Liberador da Corticotropina/administração & dosagem , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Injeções Intravenosas , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naloxona/farmacologia , Fragmentos de Peptídeos/farmacologiaRESUMO
Opioid control of mucosal ion transport was examined in intact, full thickness preparations of mouse jejunum in vitro, using standard Ussing chamber techniques. DPDPE and DAMGO were used as selective agonists for delta and mu subtypes of opioid receptors, respectively, whereas U50,488H [trans-(+-)-3,4-dichloro-N-Me-N-[2-(1-pyrrolidinyl]-benzene-acedamid+ ++ e- methanesulfonate] and U69,593 [(5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidiny)-1- oxa-spiro-(4,5)-dec-8-yl]-benzeaneacetamide] were used as selective agonists at the kappa-opioid receptor. When added to the serosal medium of intact tissues, DPDPE, DAMGO, U50,488H and morphine, but not U69,593, produced a concentration-dependent reduction of basal transmural potential difference and short-circuit current (Isc), and an increase in tissue conductance. DPDPE was 41-, 341- and 476-fold more potent than DAMGO, U50,488H and morphine, respectively, in producing these effects, although all these compounds were equiefficacious. DPDPE, but not DAMGO, U50,488H or U69,593, caused a similar effect on basal Isc when added to the mucosal medium. Naloxone produced a rightward shift in the concentration-effect curve for DAMGO and DPDPE, yielding distinct Ke values for naloxone of 9.7 +/- 0.5 and 42.9 +/- 7.9 nM, respectively. In contrast, ICI 174,864, a delta-selective antagonist, blocked the Isc response induced by DPDPE but not DAMGO. The Isc response of U50,488H, however, was neither blocked nor reversed by naloxone or ICI 174,864, nor blocked by norbinaltorphimine, suggesting that the response was not mediated via opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Eletrólitos/metabolismo , Encefalinas/farmacologia , Mucosa Intestinal/metabolismo , Pirrolidinas/farmacologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida , Animais , Transporte Biológico/efeitos dos fármacos , Cloretos/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina , D-Penicilina (2,5)-Encefalina , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacologia , Técnicas In Vitro , Jejuno/metabolismo , Camundongos , Morfina/farmacologia , Sódio/metabolismoRESUMO
It is now well established that compounds classified as kappa opioids can, in circumstances where they produce no measurable agonist effects, antagonize the actions of mu opioids. Largely on the basis of studies in vitro, beta-funaltrexamine (beta-FNA) has been classified as a reversible kappa agonist and long acting mu antagonist. The present study investigated the possibility that the mu antagonist profile of this compound could be related to its kappa agonist actions. We used two tests of analgesia (the acetic acid writhing test and the hot-water tail-flick test) and selective kappa agonists and antagonists given at supraspinal and spinal sites in mice. Intrathecal (i.t.) administration of beta-FNA, but not the selective kappa agonist U50,488H, produced long-lasting and dose-related analgesia in the writhing test for periods up to 48 hr after a single dose. In contrast, i.t. beta-FNA had no agonist actions in the tail-flick test. The kappa antagonist, nor-binaltorphimine (nor-BNI) produced no agonist effects in either analgesic test when given i.t. In the writhing test, nor-BNI produced a rightward displacement of the beta-FNA dose-response line regardless of whether beta-FNA was given 10 min or 4 hr before testing, indicating that i.t. beta-FNA was acting as a kappa agonist in this test. As both i.t. morphine and beta-FNA are active in the writhing test, the antagonist actions of i.t. beta-FNA could be evaluated only in the tail-flick test. beta-FNA, but not nor-BNI, blocked the effects of i.t. morphine in the tail-flick test.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Analgesia , Analgésicos/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Pirrolidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida , Analgésicos/administração & dosagem , Animais , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfina/farmacologia , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Pirrolidinas/administração & dosagem , Receptores Opioides kappa , Receptores Opioides muRESUMO
Veratrum alkaloids were used to examine the effect of neural stimulation on intestinal ion transport in full-thickness (intact) and serosally stripped (mucosal) preparations of mouse jejunum. When applied to the serosal media of mucosal preparations, veratrine or veratridine evoked a biphasic increase in transmural potential difference and short-circuit current, consisting of phasic and tonic increases of both bioelectric parameters without a change of tissue conductance; these responses were blocked by pretreatment with tetrodotoxin, but unaffected by pretreatment with atropine, naloxone or yohimbine. In ion flux experiments, neural stimulation of mucosal tissues produced changes of unidirectional fluxes that corresponded with an increase in net Cl- secretion and a reduction of net Na+ absorption, supporting a net secretory role for neurons that were associated with the intestinal mucosa. In intact jejunal preparations, neural stimulation by veratrine or veratridine caused a tetrodotoxin-sensitive reduction of basal transmural potential difference and short-circuit current and a significant increase of tissue conductance. Flux studies on intact tissues failed to reveal the ionic basis for the effects of nerve stimulation by veratridine in these tissues. Nonetheless, the neurally evoked reduction of short-circuit current was attenuated by yohimbine pretreatment, but unaffected by naloxone or atropine, suggesting an involvement of alpha-2 adrenoceptors in the mediation of this effect. These findings demonstrate the existence of endogenous neurotransmitter systems that play opposing roles in the regulation of mucosal ion transport in the small intestine of the mouse.
Assuntos
Eletrólitos/metabolismo , Jejuno/metabolismo , Alcaloides de Veratrum/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Cloretos/metabolismo , Estimulação Elétrica , Técnicas In Vitro , Jejuno/inervação , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sódio/metabolismo , Tetrodotoxina/farmacologiaRESUMO
The possibility that the delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE) and the putative endogenous kappa agonist, dynorphin A-(1-17) could differentially modulate the effects of a group of chemically diverse mu agonists was evaluated using inhibition of volume-induced contractions of the rat urinary bladder as a model of central nervous system opioid receptor function in vivo. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), [N-MePhe3, D-Pro4]enkephalin (PL017), morphine, normorphine, sufentanil, etorphine, phenazocine, meperidine and methadone inhibited spontaneous bladder contractions for approximately 20 to 30 min. Low doses of DPDPE or dynorphin A-(1-17) failed to affect spontaneous bladder contractions; higher doses of DPDPE (greater than 15.5 nmol) and dynorphin A-(1-17) (i.e., greater than 3.7 nmol), inhibited bladder contractions. When coadministered i.c.v., DPDPE displaced the morphine dose-response line to the left and also potentiated the effects of normorphine and etorphine. In contrast, DPDPE failed to alter the actions of equieffective doses of DAGO, PL017, meperidine, methadone, phenazocine or sufentanil. The potentiation of the effects of morphine by DPDPE were prevented by i.c.v. coadministration of the delta antagonist, ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH); at the dose tested, the delta antagonist had no agonist effects alone and did not antagonize the effects of morphine directly. Furthermore, the agonist effects of morphine were potentiated by several different doses of DPDPE. Administration of i.c.v. dynorphin A-(1-17) produced a rightward displacement of the morphine dose-response line and also antagonized the effects of normorphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Analgésicos/farmacologia , Dinorfinas/farmacologia , Encefalinas/farmacologia , Contração Muscular/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Sinergismo Farmacológico , D-Penicilina (2,5)-Encefalina , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacologia , Feminino , Morfina/farmacologia , Ratos , Ratos Endogâmicos , Receptores Opioides delta , Receptores Opioides kappa , Receptores Opioides mu , Reflexo/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
Neural regulation of electrolyte transport in mouse jejunum was investigated in vitro using: 1) a full-thickness intestinal segment (intact preparation) and 2) a mucosal preparation, consisting of only mucosa, basement membrane and muscularis mucosa. In Ussing chambers, intact tissues exhibited high- and low-frequency oscillations of basal transmural potential difference (PD) and short-circuit current (Isc), whereas mucosal tissues exhibited only low-frequency oscillation of these parameters. High-frequency oscillations of PD and Isc were found to originate from muscle activity. Under basal conditions, intact tissues exhibited net Na+ absorption and net Cl- secretion, whereas mucosal tissues displayed greater net Na+ absorption and net Cl- absorption. When applied to the serosal medium of intact tissues, tetrodotoxin, a neurotoxin, and chlorisondamine, a ganglionic blocking agent, caused a concentration-dependent reduction of basal PD and Isc, whereas atropine produced no significant effect; these agents were without effect in mucosal tissues. Furthermore, in intact tissues, tetrodotoxin caused significant increases in net Na+ absorption and net residual flux, attaining values that were comparable to those seen in mucosal tissues. Carbachol, a muscarinic agonist, and 1,1-dimethyl-4-phenylpiperizinium, a ganglionic stimulant, elicited concentration-dependent, transient increases of basal PD and Isc when applied to the serosal medium of intact tissues; in mucosal preparations, carbachol elicited greater changes of basal PD and Isc, whereas 1,1-dimethyl-4-phenylpiperizinium produced no significant effect. In intact tissues, Isc responses elicited by carbachol were antagonized by atropine, but not tetrodotoxin or chlorisondamine; Isc responses induced by 1,1-dimethyl-4-phenylpiperizinium, however, were blocked by tetrodotoxin or chlorisondamine, but not atropine. These results support the existence of a multisynaptic, and tonically active neural pathway which serves to limit intestinal Na+ transport at some point below the maximal absorptive capacity of the mucosa. Furthermore, cholinergic muscarinic and nicotinic receptors are present in distinct neural pathways that influence intestinal electrolyte transport in the small intestine of the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Eletrólitos/metabolismo , Jejuno/metabolismo , Plexo Mientérico/fisiologia , Potenciais de Ação , Animais , Atropina/farmacologia , Transporte Biológico , Carbacol/farmacologia , Iodeto de Dimetilfenilpiperazina/farmacologia , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contração Muscular/efeitos dos fármacos , Nifedipino/farmacologia , Tetrodotoxina/farmacologia , Teofilina/farmacologiaAssuntos
Bombesina/farmacologia , Mucosa Intestinal/metabolismo , Canais Iônicos/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Técnicas In Vitro , Mucosa Intestinal/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , CamundongosRESUMO
The role of central (supraspinal and spinal) and peripheral alpha-adrenoceptors in the regulation of gastrointestinal propulsion in the mouse was studied using clonidine, an alpha 2-adrenoceptor agonist. Clonidine produced a dose-dependent inhibition of propulsion when given intracerebroventricularly, intrathecally, or subcutaneously, but was most potent when given intracerebroventricularly. The antitransit effects of centrally given clonidine were antagonized by intracerebroventricular (i.c.v.) yohimbine, but higher doses were required when this antagonist was given peripherally. Whereas i.c.v. and s.c. administration of clonidine were effective in inhibiting gut transit in spinally transected mice, intrathecal (i.th.) administration of this agonist was not. A supraspinal site of clonidine action is suggested based upon (a) the higher central to peripheral potency of clonidine; (b) the greater potency of i.c.v., compared with s.c., administration of yohimbine in blocking i.c.v. clonidine; (c) the lack of effect of i.th. administration of clonidine in spinally transected mice; and (d) the reduced potency of i.c.v., but not s.c., administration of clonidine in spinally transected mice. Additionally, a peripheral site of clonidine action is suggested by (a) the lower potency of i.c.v. yohimbine in blocking s.c., compared with i.c.v., clonidine; (b) the lower potency of i.c.v. yohimbine in blocking i.c.v. clonidine in transected mice (compared with normal mice); (c) the equal potency of s.c. clonidine in slowing propulsion in normal and spinally transected mice; and (d) the equal potency of i.c.v. yohimbine in blocking s.c. clonidine in normal and spinally transected mice. These data in mice would thus support the concept that normal (peripheral) therapeutic administration of clonidine would affect gut motor function by interactions within the brain and directly at the level of the gut.
Assuntos
Clonidina/administração & dosagem , Trânsito Gastrointestinal/efeitos dos fármacos , Medula Espinal/fisiologia , Animais , Clonidina/farmacologia , Injeções Intravenosas , Injeções Intraventriculares , Injeções Espinhais , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Prazosina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Medula Espinal/cirurgia , Ioimbina/farmacologiaRESUMO
Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of administration, dose-response relationships, and time to effect.
Assuntos
Reativadores da Colinesterase/farmacologia , Soman/toxicidade , Acetilcolina/biossíntese , Animais , Atropina/farmacologia , Hemicolínio 3/análogos & derivados , Hemicolínio 3/farmacologia , Cinética , Dose Letal Mediana , Masculino , Compostos de Pralidoxima/farmacologia , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
The mu antagonist property of the kappa agonist U50,488H was studied at the spinal level, using motility of the rat urinary bladder as an endpoint in vivo. Intrathecal (i.th.) administration of the mu agonists [D-Ala2,NMePhe4,Gly-ol]enkephalin (DAGO), [N-MePhe3,D-Pro4]enkephalin (PL017), morphine and normorphine, as well as the delta agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), resulted in an equieffective inhibition of volume-initiated contractions of the urinary bladder. In contrast, i.th. administration of U50,488H, a highly selective kappa agonist, had no effect on bladder motility. Pretreatment of rats with i.th. U50,488H prior to agonist administration, blocked the suppression of spontaneous bladder activity induced by equieffective i.th. does of morphine and normorphine, but failed to alter the inhibitory effect of the mu agonists DAGO and PL017, or that of the delta agonist DPDPE. The finding that U50,488H differentially antagonized the identical bladder effects of several mu agonists suggests the presence of mu receptor subtypes (mu isoreceptors) in the rat spinal cord, which may be involved in the regulation of bladder function.