Potent inhibition of gastric acid secretion by intravenous interleukin-1 beta and -1 alpha in rats.

The influence of human and rat recombinant interleukin-1 (hIL-1 beta and -1 alpha and rIL-1 beta) on acid secretion was investigated in conscious pylorus-ligated rats. Intravenous injection of either hIL-1 beta, hIL-1 alpha or rIL-1 beta dose dependently inhibited gastric acid output with an ED50 of 0.05 microgram, 0.5 microgram and 2.2 micrograms, respectively. The antisecretory action of IL-1 beta was associated with an increase in circulating levels of gastrin. hIL-1 beta-induced inhibition of acid secretion was dose dependently reversed by peripheral injection of the IL-1 receptor antagonist, IL-RA, with a dose ratio of 1:10(3) for complete reversal. The inhibitory effect of hIL-1 beta was blocked by indomethacin and was not modified by IV injections of the CRF receptor antagonist, alpha-helical CRF(9-41), or the monoclonal somatostatin antibody CURE.S6, or by systemic capsaicin pretreatment. These results show that systemic hIL-1 beta-induced inhibition of gastric acid secretion is mediated through IL-1 receptors and prostaglandin pathways, and does not involves CRF receptors, afferent fibers, or changes in circulating gastrin or somatostatin levels.     

Involvement of endogenous CRF in carbon tetrachloride-induced acute liver injury in rats

Central neuropeptides play important roles in many physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Central injection of corticotropin-releasing factor (CRF) aggravates carbon tetrachloride (CCl4)-induced acute liver injury through the sympathetic nervous pathway in rats. However, still nothing is known about a role of endogenous neuropeptides in the brain in hepatic pathophysiological regulations. Involvement of endogenous CRF in the brain in CCl4-induced acute liver injury was investigated by centrally injecting a CRF receptor antagonist in rats. Male fasted Wistar rats were injected with CRF receptor antagonist alpha-helical CRF-(9-41) (0.125-5 microg) intracisternally just before and 6 h after CCl4 (2 ml/kg) administration, and blood samples were obtained before and 24 h after CCl4 injection for measurement of hepatic enzymes. The liver sample was removed 24 h after CCl4 injection, and histological changes were examined. Intracisternal alpha-helical CRF-(9-41) dose dependently (0.25-2 microg) reduced the elevation of alanine aminotransferase and aspartate aminotransferase levels induced by CCl4. Intracisternal alpha-helical CRF-(9-41) reduced CCl4-induced liver histological changes, such as centrilobular necrosis. The effect of central CRF receptor antagonist on CCl4-induced liver injury was abolished by sympathectomy and 6-hydroxydopamine pretreatment but not by hepatic branch vagotomy or atropine pretreatment. These findings suggest the regulatory role of endogenous CRF in the brain in experimental liver injury in rats.     

Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

N-acetyl-GRP(20-26)-O-CH3 reverses intracisternal bombesin-induced inhibition of gastric acid secretion in rats

Intracisternal injection of 19 pmoles of bombesin in light-ether-anesthetized rats, five minutes after intracisternal vehicle, produced a 75% and 63% inhibition in gastric acid output and concentration, respectively, in 2-hour pylorus-ligated rats. Pretreatment of rats with the characterized peripheral bombesin antagonist N-acetyl-GRP(20-26)-O-CH3 (1 nmole) reversed the inhibitory effect of bombesin on gastric acid output and concentration. In contrast, the related bombesin antagonist N-acetyl-GRP-O-CH2-CH3 (1 nmole) was ineffective in this system. In urethane-anesthetized, acute gastric fistula rats infused with pentagastrin, intracisternal N-acetyl-GRP(20-26)-O-CH3 protected against the inhibition in gastric acid output produced by intracisternal bombesin (19 pmoles). Thus the recently characterized peripheral bombesin antagonist N-acetyl-GRP(20-26)-O-CH3 also appears to be effective in antagonizing central bombesin-induced inhibition in gastric acid secretion in two models. This represents a first report of a synthetic bombesin antagonist effective in reversing central bombesin-induced effects on gastric function.     

Intracisternal injection of TRH precursor, TRH-glycine, stimulates gastric acid secretion in rats

Intracisternal injection of thyrotropin-releasing hormone (TRH)-Gly (pGlu-His-Pro-Gly) produced a dose-dependent (1-100 micrograms) stimulation of gastric acid secretion in urethane-anesthetized rats implanted acutely with a gastric fistula. The peak response occurred 20-30 min after intracisternal injection and lasted for more than 2 h. Intravenous injection of TRH-Gly (100 micrograms) did not modify gastric acid secretion. Following intracisternal injection of TRH-Gly, a peak elevation of both TRH-Gly and TRH levels is observed in the cerebrospinal fluid (CSF) within 15 min. Thereafter, TRH values are returned to basal levels at 75 min after the injection, whereas TRH-Gly concentrations remain significantly elevated throughout the 2-h period of measurement. Compartmental analysis revealed that CSF conversion of TRH-Gly to TRH was only 0.0072%/min. Medullary coronal sections containing the dorsal vagal complex and the raphé nucleus revealed increased content of TRH-Gly, but not TRH, 40 min after administration of TRH-Gly at an intracisternal dose effective in stimulating gastric acid secretion (100 micrograms). In addition, TRH but not TRH-Gly (10(-7)-10(-5) M) displaced [3H]MeTRH binding from rat medullary blocks containing the dorsal vagal complex. These data suggest that the intracisternal TRH-Gly-induced stimulation of gastric acid secretion is not related to its conversion to TRH in the CSF, or direct activation of TRH receptors in the medulla. The acid secretory response of TRH-Gly may be due to the formation of TRH at the active brain sites, or alternatively to activation of its own specific receptors.     

Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats

Intracisternal injection of TRH (1 microgram) under light ether anesthesia induced within 4 hr gastric lesions in 24-hr fasted rats maintained unrestrained at room temperature. Saline, ovine corticotropin-releasing factor (oCRF, 10 micrograms), or human pancreatic growth hormone-releasing factor [hpGRF(1-40), 10 micrograms] tested under the same conditions did not modify the integrity of the gastric mucosa. TRH injected intravenously (100 micrograms/kg) proved to be ineffective. The production of gastric erosions elicited by intracisternal TRH (0.1-1 microgram) or by a stabilized TRH analog, RX 77368 [pGlu-His-(3,3'-dimethyl)-ProNH2, (0.01-0.1 microgram)] was dose-dependent. RX 77368 shows an enhanced potency over TRH. TRH action on gastric mucosa was reversed by atropine, omeprazole and cimetidine. These results demonstrate that TRH, unlike the other hypothalamic releasing factors CRF or GRF, is able to act within the brain to cause the formation of gastric erosions probably through mechanisms involving changes in gastric acid secretion. Intracisternal injection of TRH or its potent analog RX 77368 appears also as a new, simple method to produce centrally mediated experimental gastric erosions in 24 hr-fasted rats.     

Potent central nervous system action of p-Glu-His-(3,3'-dimethyl)-Pro NH2, a stabilized analog of TRH, to stimulate gastric secretion in rats

Intracisternal injection of the TRH analog RX 77368 (p-Glu-His-(3,3'-dimethyl)-Pro NH2) increased gastric acid and pepsin output in conscious pylorus-ligated rats. In urethane-anesthetized, gastric fistula rats, intracisternal RX 77368 or TRH induced stimulation of gastric acid output which was rapid in onset, long lasting, and dose-dependent, in doses ranging from 3 to 100 ng/rat for RX 77368, and 0.1 to 1 micrograms/rat for TRH. Vagotomy or atropine pretreatment reversed RX 77368 gastric secretory response. The analog was less effective when infused intravenously (1-10 micrograms X kg-1 X h-1) and 22 times more potent than TRH when given intracisternally. These results demonstrated the ability of RX 77368 to act within the rat brain to enhance gastric secretion (acid and pepsin) through vagus cholinergic dependent mechanisms. The enhanced potency and extended duration of action of RX 77368 over TRH, could make intracisternal injection of this peptide a useful test to induce centrally mediated vagal dependent stimulation of gastric secretion in rats.     

Is somatostatin or a somatostatin-like peptide involved in central nervous system control of gastric secretion?

Intracisternal injection of octapeptide analogs of somatostatin (SS), Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys (des-AA1,2,4,5,12,13-[D-Trp8]SS (ODT8-SS)) and Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Cys, increased the volume and the acid output of gastric secretion in rats. ODT8-SS given intravenously did not affect basal gastric secretion. The gastrosecretory effect of ODT8-SS, administered intracisternally is dose-dependent (0.01-1 micrograms), long acting, reversible, specific, and abolished by vagotomy, or systemic injection of atropine or SS. SS (5-10 micrograms) or [D-Trp8]SS (1 microgram) had no effect on gastric secretion when given intracisternally. These results demonstrate that some octapeptide SS analogs, unlike SS or other SS analogs, have the capability to act in the brain to induce a vagal dependent stimulation of gastric secretion.     

Urocortin 2 acts centrally to delay gastric emptying through sympathetic pathways while CRF and urocortin 1 inhibitory actions are vagal dependent in rats

We characterized the influence of the selective corticotropin-releasing factor 2 (CRF(2)) receptor agonist human urocortin 2 (Ucn 2), injected intracisternally, on gastric emptying and its mechanism of action compared with intracisternal CRF or urocortin (Ucn 1) in conscious rats. The methylcellulose phenol red solution was gavaged 20 min after peptide injection, and gastric emptying was measured 20 min later. The intracisternal injection of Ucn 2 (0.1 and 1 microg) and Ucn 1 (1 microg) decreased gastric emptying to 37.8 +/- 6.9%, 23.1 +/- 8.6%, and 21.6 +/- 5.9%, respectively, compared with 58.4 +/- 3.8% after intracisternal vehicle. At lower doses, Ucn 2 (0.03 microg) and Ucn 1 (0.1 microg) had no effect. The CRF(2) antagonist astressin(2)-B (3 microg ic) antagonized intracisternal Ucn 2 (0.1 microg) and CRF (0.3 microg)-induced inhibition of gastric emptying. Vagotomy enhanced intracisternal Ucn 2 (0.1 or 1 microg)-induced inhibition of gastric emptying compared with sham-operated group, whereas it blocked intracisternal CRF (1 microg) inhibitory action (45.5 +/- 8.4% vs. 9.7 +/- 9.7%). Sympathetic blockade by bretylium prevented intracisternal and intracerebroventricular Ucn 2-induced delayed gastric emptying, whereas it did not influence intravenous Ucn 2-, intracisternal CRF-, and intracisternal Ucn 1-induced inhibition of gastric emptying. Prazosin abolished the intracisternal Ucn 2 inhibitory effect, whereas yohimbine and propranolol did not. None of the pretreatments modified basal gastric emptying. These data indicate that intracisternal Ucn 2 induced a central CRF(2)-mediated inhibition of gastric emptying involving sympathetic alpha(1)-adrenergic mechanisms independent from the vagus contrasting with the vagal-dependent inhibitory actions of CRF and Ucn 1.     

Fluoxetine pretreatment potentiates intracisternal TRH analogue-stimulated gastric acid secretion in rats.

Central injection of TRH or its metabolically stable analogue RX 77368 has been demonstrated to produce a vagal-dependent stimulation in gastric acid secretion. Accumulating evidence exists regarding the interaction of serotonin (5HT) with TRH containing neuronal systems. This study was performed to assess the effect of pretreatment with the 5HT uptake inhibitor fluoxetine on the TRH analogue-induced gastric acid secretory response. Systemic fluoxetine (30 mumol/kg, i.v.) produced a 43-85% increase in the intracisternal RX 77368 (78-780 pmol)-induced gastric acid output, while not affecting the basal acid response. The acid response to a lower dose of RX 77368 (26 pmol) was not altered. In addition, intracisternal fluoxetine (180 nmol) produced a 71% augmentation of the acid secretory response of i.c. RX 77368 (260 pmol). Intracisternal injection of lower doses (60, 120 nmol), or intravenous injection of 180 nmol of fluoxetine was ineffective in altering the intracisternal RX 77368-induced acid response. Pretreatment with the noradrenergic or dopaminergic uptake inhibitor desipramine or GBR 12909 did not alter the RX 77368-stimulated gastric acid secretory response. The results show that fluoxetine pretreatment potentiates the effect of intracisternal RX 77368 on acid secretion. The effect appears to be impulse dependent, and central sites of action are involved. The data suggest an interaction of synaptic serotonin with a RX 77368-elicited event (activation of TRH receptors, second messenger systems and/or firing of the motor vagus) results in potentiation of the RX 77368-induced gastric response.     

Central nervous system action of TRH to stimulate gastric emptying in rats

The effects of intracisternal injection of TRH on gastric emptying of a liquid meal was investigated in 24 h fasted rats using the phenol red method. Intracisternal injection of TRH, RX 77368, or [N-Val2]-TRH, an analog devoid of TSH-releasing activity, 5 min prior to a meal, stimulated gastric emptying measured 20 min later. TRH action was dose dependent (1-100 ng), and rapid in onset. The calculated time for emptying half of the meal was decreased from 16 +/- 3 min (control group) to 4 +/- 1 min (TRH 30 ng). The stable analog, RX 77368, unlike TRH, stimulated gastric emptying when the meal was given 60 min after peptide injection. Intravenous injection of atropine (2.5 micrograms) inhibited and that of carbachol (1 microgram) stimulated gastric emptying whereas i.v. injection of TRH (0.1-1 microgram) had no effect. Vagotomy but not adrenalectomy reversed the increase in gastric emptying induced by intracisternal TRH. Atropine blocked the stimulatory effect of TRH and carbachol. These results demonstrate that TRH acts within the brain to stimulate gastric emptying through vagus-dependent and cholinergic pathways whereas alterations of adrenal and pituitary-thyroid secretion do not play an important role.     

Effect of hypophysectomy, adrenalectomy, pituitary hormone secretion and gastric acid secretion on neurotensin induced gastric protection against stress gastric lesions

In previous studies we have established that intracisternal (i.c.) but not peripheral (intravenous) administration of neurotensin (NT), a brain and gastrointestinal tridecapeptide, totally prevents the development of gastric lesions produced by cold-restraint stress (CRS) with food-deprived rats. In this investigation, removal of the pituitary and adrenal gland, anterior pituitary hormone secretion and gastric acid secretion were evaluated independently as potential intermediates for NT's protective effect. NT (30 micrograms) produced a significant reduction of gastric lesions incidence and severity in intact and sham-operated controls. Adrenalectomy, but not hypophysectomy totally blocked the protective effect of i.c. NT. In addition, replacement therapy with s.c. prednisone (1 mg/kg) for 5 days following adrenalectomy did not restore the protective activity of central (i.c.) NT in adrenalectomized rats. A significant reduction of serum levels of TSH, PRL and GH following i.c. NT (30 micrograms) was observed after 2h of CRS. The gastrosecretory studies revealed that i.c. NT (30 micrograms) did not affect gastric acid secretion in pylorus ligated rats. However, blockade of peripheral (gut) cholinergic (muscarinic) receptors with i.p. atropine methylbromide (1 mg/kg) significantly raised gastric pH and reduced gastric acid concentration and output. In conclusion, the results of this study indicate that the acute protective effect of brain NT appears to be mediated, at least in part, by the sympathoadrenomedullary axis, and not by the pituitary gland or substances derived from the pituitary or by inhibition of gastric acid secretion.     

Site of inhibitory action of CRE 9-41 on ACTH release from isolated rat pituitary cells

The corticotropin-releasing factor (CRF) analog CRF 9-41 inhibits CRF, but not forskolin or dibutyryl cyclic AMP, stimulated release of ACTH from isolated pituitary cells. CRF 9-41 also blocks CRF-stimulated accumulation of cyclic AMP in a parallel dose dependent fashion. CRF 9-41 has no effect on basal ACTH release or cAMP levels. This substantiates that the analog acts as a direct CRF antagonist and that the site of this inhibition is most likely at the level of binding of CRF to its receptor on the corticotrope. Various substances, including most prominently glucocorticoids, inhibit release of ACTH from the pituitary. In an effort to develop another class of inhibitors, Rivier et al recently synthesized analogs of corticotropin releasing factor (CRF). One among these, alpha-helical ovine CRF 9-41 blunts adrenalectomy and stress induced ACTH release in non-anesthetized rats. At micromolar concentrations, CRF 9-41, shifts rightward the dose response of isolated pituitary cells to ovine CRF. Thus, the authors suggested that CRF 9-41 acts as a competitive antagonist to CRF-induced ACTH secretion. CRF appears to act through stimulation of adenylate cyclase. To determine the potential site of action of CRF 9-41 in the activation sequence for adenylate cyclase, we studied its effects on pituitary cyclic AMP formation and ACTH secretion from dispersed anterior pituitary cells derived from normal adult rats, as well as, its interaction with cyclic nucleotide agonists.     

第三脑室注射组胺及其受体激动剂对五肽促胃液素诱导...

The present study shows the dual effects of intraventricularly injected histamine (0.25-2.0 micrograms/5 microliters) on pentagastrin-induced gastric acid secretion. Male Wistar rats weighing 200-300 g were anesthetized with intraperitoneal sodium pentobarbital. Gastric acid was continuously washed out with 37 degrees C saline solution by means of a perfusion pump. On the background of continuous intravenous infusion of pentagastrin [7.5 micrograms/(kg.h),] histamine (0.25 microgram/5 microliters) or 2-pyridylethylamine (PEA, 10 micrograms/5 microliters), a H1-receptor agonist, was injected into the third ventricle through a chronically implanted canula. The acid output decreased 10 min after injection and did not recover at 90 min. When the dose of histamine was increased to 1.0 micrograms or 2.0 micrograms, dual effects appeared. The acid output decreased respectively in 73% or 50% of the animals, while in the rest 27% and 50% of the animals, the acid output increased. H2-receptor agonist dimaprit (10 micrograms/5 microliters, i.c.v.) or impromidine (0.1 micrograms/5 microliters, i.c.v.) had no pronounced effect on pentagastrin-induced acid secretion. Pretreatment with diphenhydramine (16 micrograms/0.2 ml or 32 micrograms/0.2 ml, i.m.) abolished the inhibitory effect of histamine and PEA on acid secretion. These results suggest that histamine may be involved in the central regulation of gastric acid secretion, and the inhibitory effect may be mediated by H1-receptors in the brain. The mechanism underlying the production of the dual effects of histamine is unknown.     

Potent CNS action of calcitonin to inhibit cysteamine-induced duodenal ulcers in rat

Intracisternal injection of calcitonin (0.01-5 micrograms) dose dependently prevented the development of duodenal ulcers induced by cysteamine in female rats. By contrast, intravenous infusion of the peptide at a dose 50 times higher than an effective intracisternal dose, had no effect. Intracisternal injection of calcitonin increased by three fold the generation of 6-keto-PGF1 alpha, the stable hydrolysis product of PGI2, in the duodenal mucosa. These studies demonstrated that calcitonin acts within the brain to potently suppress duodenal ulcers induced by cysteamine. The mechanisms of the antiulcer effect may involve changes in prostaglandin generation along with alterations of gastrointestinal secretion and motility associated the central injection of calcitonin. Growing evidence suggests that salmon calcitonin may act as a neuromodulator or neurotransmitter in the central nervous system. Specific binding sites have been demonstrated for calcitonin in the hypothalamus, brain stem and dorsal horn of the spinal cord using homogenate and membrane preparations or in vitro autoradiography methods. The peptide injected into the cerebrospinal fluid (CSF) produces a wide spectrum of biological effects including analgesia, hyperthermia, changes in pituitary hormone release, decrease in food and water intake, locomotor activity, and blood pressure. Numerous studies also demonstrated that calcitonin acts within the brain to markedly influence gastrointestinal secretory and motor function in rats and dogs and gastric ulceration in rats. In particular, intracisternal injection of salmon calcitonin was found very potent to selectively inhibit gastric ulcers elicited by stress, aspirin and central thyrotropin-releasing factor but not by necrotizing agents. In the present study, we further investigated the antiulcer effect of salmon calcitonin using the well established cysteamine experimental model to induce duodenal ulcers in rats. Part of this work has been reported in abstract form.     

Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats

Although restraint stress accelerates colonic transit via a central corticotropin-releasing factor (CRF), the precise mechanism still remains unclear. We tested the hypothesis that restraint stress and central CRF stimulate colonic motility and transit via a vagal pathway and 5-HT(3) receptors of the proximal colon in rats. (51)Cr was injected via the catheter positioned in the proximal colon to measure colonic transit. The rats were subjected to a restraint stress for 90 min or received intracisternal injection of CRF. Ninety minutes after the administration of (51)Cr, the entire colon was removed, and the geometric center (GC) was calculated. Four force transducers were sutured on the proximal, mid, and distal colon to record colonic motility. Restraint stress accelerated colonic transit (GC of 6.7 +/- 0.4, n=6) compared with nonrestraint controls (GC of 5.1 +/- 0.2, n=6). Intracisternal injection of CRF (1.0 microg) also accelerated colonic transit (GC of 7.0 +/- 0.2, n=6) compared with saline-injected group (GC of 4.6 +/- 0.5, n=6). Restraint stress-induced acceleration of colonic transit was reduced by perivagal capsaicin treatment. Intracisternal injection of CRF antagonists (10 microg astressin) abolished restraint stress-induced acceleration of colonic transit. Stimulated colonic transit and motility induced by restraint stress and CRF were significantly reduced by the intraluminal administration of 5-HT(3) antagonist ondansetron (5 x 10(-6) M; 1 ml) into the proximal colon. Restraint stress and intracisternal injection of CRF significantly increased the luminal content of 5-HT of the proximal colon. It is suggested that restraint stress stimulates colonic motility via central CRF and peripheral 5-HT(3) receptors in conscious rats.     

Bombesin microinjected into the dorsal vagal complex inhibits vagally stimulated gastric acid secretion in the rat

Medullary sites of action for bombesin-induced inhibition of gastric acid secretion were investigated in urethane-anesthetized rats with gastric fistula. Unilateral microinjection of bombesin or vehicle into the dorsal vagal complex was performed using a glass micropipet and pressure ejection of 100 nl volume; gastric acid output was measured every 10 min by flushing the stomach. Microinjection of vehicle into the dorsal vagal complex did not alter gastric acid secretion (1.9 +/- mumol/10) from preinjection levels (2.9 +/- 0.8 mumol/10 min). Microinjection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, at a 77 pmol dose into the dorsal vagal complex stimulated gastric acid secretion for 100 min with a peak response at 40 min (24.1 +/- 3.2 mumol/10 min). Concomitant microinjection of RX 77368 (77 pmol) with bombesin (0.6-6.2 pmol) into the dorsal vagal complex dose dependently inhibited by 35-86% the gastric acid response to the TRH analog. Bombesin (6.2 pmol) microinjected into the dorsal vagal complex inhibited by 17% pentagastrin infusion-induced stimulation of gastric acid secretion (13.2 +/- 0.8 mumol/10 min) whereas intracisternal injection induced a 69% inhibition of the pentagastrin response. These results demonstrate that the dorsal motor complex is a sensitive site of action for bombesin-induced inhibition of vagally stimulated gastric secretion. However, other medullary sites must be involved in mediating the inhibitory effect of intracisternal bombesin on pentagastrin-stimulated gastric acid secretion.     

Corticotropin-releasing factor receptor antagonist: effects on the autonomic nervous system and cardiovascular function

The corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical [Glu27]-corticotropin-releasing factor 9-41 (CRF 9-41) has been assessed for its ability to modify plasma concentrations of epinephrine and norepinephrine, mean arterial pressure (MAP) and heart rate (HR). Basal concentrations of epinephrine and norepinephrine were not altered by lateral ventricular (icv) administration of CRF 9-41. However, this CRF antagonist, given icv, attenuated the rise of plasma epinephrine following 30% hemorrhage and insulin-induced hypoglycemia. CRF 9-41 did not alter the increased plasma concentrations of epinephrine or norepinephrine following icv administration of bombesin. Icv administration of CRF 9-41 blunted CRF-induced elevation of MAP and HR in normal animals. However, this CRF antagonist did not modify the MAP or HR in spontaneously hypertensive rats. Similarly, this CRF antagonist administered to Sprague-Dawley rats neither prevented the rise of MAP or HR following electrical stimulation of the central nucleus of the amygdala, nor did it affect nitroprusside-induced hypotension and tachycardia.     

Lack of effect of corticotropin releasing factor on hypothalamic dopamine and serotonin synthesis turnover rates in rats

Catecholamine and serotonin neurons in the hypothalamus regulate the secretion of corticotropin releasing factor (CRF). We considered the possibility that CRF might in turn affect the activity of these aminergic neurons. We examined the effect of intracisternal administration of synthetic CRF on the synthesis turnover rates of dopamine and serotonin in the hypothalamus of adult male rats using two different methods to assess turnover. In one study, we measured the accumulation of L-dihydroxyphenylalanine (L-DOPA) or 5-hydroxytryptophan (5-HTP) in mediobasal hypothalamus after L-aromatic amino acid decarboxylase inhibition with m-hydroxybenzylhydrazine 20 min before sacrifice, and in the second study we measured the accumulation of dopamine, norepinephrine, epinephrine and serotonin after monoamine oxidase inhibition with pargyline 20 min before sacrifice. The commercial CRF which we administered intraarterially increased plasma ACTH and corticosterone concentrations. Intracerebral CRF 5 to 20 micrograms 20 min before sacrifice or 20 micrograms 110 min before sacrifice did not alter the m-hydroxybenzylhydrazine-induced accumulation of L-DOPA or 5-HTP when compared with saline vehicle-injected controls. CRF 20 micrograms did not alter basal concentration or pargyline-induced accumulation of the catecholamines or serotonin in whole hypothalamus when compared with saline vehicle-injected controls. Thus, intracisternal administration of CRF did not alter hypothalamic dopamine or serotonin synthesis rates as assessed by two nonsteady state turnover methods. The data suggest that the release of CRF from neurons in hypothalamus does not alter the activity of catecholamine or serotonin neurons in the hypothalamus of normal adult male rats.     

Endogenous corticotropin-releasing factor modulates feeding induced by neuropeptide Y or a tail-pinch stressor.

Previous work has characterized an anorexic action for endogenous, central nervous system corticotropin-releasing factor (CRF). Central injection of CRF decreases food intake induced pharmacologically by various appetite stimulants and a CRF antagonist attenuates restraint stress anorexia. Also, stressful physiological stimuli that are relevant to ingestive regulation, such as glucoprivation and protein nutrient deficiency, activate CRF systems. The present experiments examined the effects of exogenously administered CRF and a CRF antagonist, alpha-helical CRF(9-41), on spontaneous feeding induced by neuropeptide Y (NPY) and by a tail-pinch stressor. Pretreatment with a low dose of the CRF antagonist (1 microgram ICV) enhanced the hyperphagia induced by NPY while reducing the latency to begin feeding and increasing the duration of eating during tail pinch. Higher doses of alpha-hel CRF (5 and 25 micrograms ICV) exhibited diminishing or opposite effects. In contrast, CRF pretreatment (0.02, 0.1, and 0.5 microgram ICV) blocked the acquisition of tail-pinch feeding. Hence, while CRF administration impairs intake in these and other feeding paradigms, alpha-hel CRF actually facilitated dose dependently the intensity of the feeding response to NPY and tail pinch. These results suggest that endogenous CRF systems may play a role in modulating excessive feeding under conditions of evoked appetite and that brain CRF systems regulate feeding when excessive intake threatens to compromise the performance of other noningestive behaviors.