Clomiphene citrate effect on testosterone level and semen parameters in 18 infertile men with low testosterone level and normal/low gonadotropines level.

OBJECTIVE: To determine the effect of a 3-month course of clomiphene citrate (CC) on plasma testosterone (T) level and on semen parameters in 18 infertile men with low T level and normal or low gonadotropines level. STUDY DESIGN: A retrospective study was conducted by reviewing the medical records of men referred to a university fertility medicine unit for infertility management between January 2010 and March 2015. Men treated with CC for at least 3 months were included if they presented with: RESULTS: 18 patients met the inclusion criteria. CC was prescribed for 3 months at the dose of 50 mg every 48 h. Plasma T level was assessed at baseline and after 1 month of CC administration. Semen parameters were assessed at baseline and after 3 months of CC administration. The median pre-treatment T level was 9.1 nmol/l; after 1 month of CC treatment the median post-treatment T level increased to 20.2 nmol/l (p = <0.001). Median baseline sperm concentration was 7 millions/ml with a median progressive motility of 18%. After 3 months of CC, the median post-treatment sperm concentration was 17.5 millions/ml (p = 0.024) and the median post-treatment progressive sperm motility was 18% (p = 0.40). Three natural pregnancies occurred during the treatment period. CONCLUSION: CC is an effective and inexpensive treatment to increase plasma T level in infertile men with low T level and normal or low gonadotropines level. Our study suggests that CC could increase sperm concentration even in oligospermic infertile men, without, however, a significant effect on progressive sperm motility. More powered randomized controlled trials are needed to definitively assess CC effect on sperm parameters and on natural pregnancy rates.

[Fertility preservation techniques in women of reproductive age ]. / Techniques de préservation de la fertilité chez la femme en âge de procréer.

As a result of advances in oncologic treatment, a growing number of women diagnosed with cancer may envisage cure. Young women diagnosed with cancer often have a desire to fall pregnant in the future or may even be diagnosed with cancer in the process of family planning. The potential gonadotoxic effect of certain chemotherapeutic agents is well described. Therefore, it is essential that all women concerned about their fertility receive counselling from a reproductive medicine specialist to discuss the fertility preservation options. Currently, ovarian stimulation with cryopreservation of oocytes or fertilized oocytes is the treatment of choice. However, other options such as in vitro maturation or ovarian tissue cryopreservation should be discussed if ovarian stimulation is contraindicated.

A European multicentre prospective randomized study to assess the use of assisted hatching with a diode laser and the benefit of an immunosuppressive/antibiotic treatment in different patient populations.

BACKGROUND: Assisted hatching (AH) techniques, designed for facilitating the embryo escape out of the zona pellucida (ZP) have been used in IVF centres since 1992. The initial indications for AH were patient's age, ZP thickness, high basal FSH and repeated IVF failures. Several retrospective and prospective studies assessing AH in these indications have given disparate results. Our aims were to evaluate the benefits of AH and immunosuppressive/antibiotic treatment (IA) in patients with either a poor prognosis of success, previous implantation failures or transfers of cryopreserved embryos. METHODS: Four IVF centres allocated 426 patients, randomized for AH and IA, into four groups of AH indications between 1997 and 1999. AH was performed with a diode laser. ZP thickness, opening size and embryo score were recorded. Outcome measures were implantation and delivery rates. RESULTS: Patients coming for a first or third transfer of cryopreserved embryos and poor prognosis patients admitted for a first trial did not benefit from AH. Even patients with repeated implantation failures of fresh embryos did not gain significantly from AH. CONCLUSIONS: Among AH indications, absence of implantation after several transfers of good quality embryos remains the strongest patient selection criterion. Prescription of an immunosuppressive/antibiotic treatment is essential.

Racecadotril demonstrates intestinal antisecretory activity in vivo.

BACKGROUND: Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. METHODS: A 1 m, jejunal, Thiry-Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5-6 h after commencement of a 2-h infusion of cholera toxin (0.4 microgram/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). RESULTS: Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 +/- 0.15 to 0.37 +/- 0.13 mL/min; from 125.0 +/- 16.1 to 14.7 +/- 9.5 microMol/min; and from 3.41 +/- 0.66 to 1.66 +/- 0.61 microMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. CONCLUSIONS: This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.

Neuronal death in the central nervous system during development.

About half the neurons in the brain die at the time when their connections are being formed. This neuronal death is regulated by anterograde and retrograde signals that reflect both electrical activity and the uptake of trophic factors. Our recent data on the isthmo-optic projection indicate that there are in fact two different retrograde signals: a slow-acting survival signal mediated by a neurotrophin, and a fast-acting death signal mediated by calcium entry due to electrical activity in the presynaptic terminals. The developmental roles of the cell death are not well understood, but they appear to include the elimination of aberrant connections. The intracellular mechanisms of the cell death may not always correspond to the apoptotic ones so thoroughly investigated in vitro, because only one of the three morphological types occurring regularly in vivo resembles apoptosis. However, our experiments on retinal ganglion cells indicate that several apoptotic mechanisms apply in this particular in vivo situation: these include an involvement of oxygenated free radicals and glutathione, cell cycle-related events, and probably the synthesis of proteins promoting neuroprotection or cell death.

Presynaptic initiation by action potentials of retrograde signals in developing neurons.

Until recently, the only means by which electrical activity was believed to initiate retrograde signals was via postsynaptic events: modulated synthesis or release of trophic factors. We have evidence in chick embryos for a presynaptic initiation of retrograde signals from the retina to the isthmo-optic nucleus, which is known to undergo 55% neuron death between embryonic days 12 and 17 and to become laminated during this period. Intraocular injections of saxitoxin just before embryonic day 14 reduce neuron death and prevent lamination in the isthmo-optic nucleus within as few as 6 hr. We show that these rapid effects are attributable to the direct action of saxitoxin on the isthmo-optic terminals. Alternative possibilities, such as an indirect effect via the target cells, are ruled out by control experiments. Normally, action potentials may lead to a chain of second messenger events in the axon terminal that is signaled retrogradely via the transport of a long-lived second messenger.

Early retrograde effects of blocking axoplasmic transport in the axons of developing neurons.

Depriving developing neurons of retrograde trophic support may disrupt their development and often causes them to die. We here report the effects, in chick embryos, of eliminating retrograde support in the isthmo-optic projection by blocking axoplasmic transport in the terminal parts of the axons, which is known ultimately to kill the isthmo-optic neurons. Within only 9 h, this had perturbed the process of cellular reorganisation that eventually leads to the laminated appearance of the mature isthmo-optic nucleus. Neuron survival in the isthmo-optic nucleus was affected even more quickly, but the earliest change, occurring in as little as 3 h, was not an increase in the number of dying neurons, but a decrease below control values. This novel effect was still present at 6 and 9 h after the injection, but at longer survival times the number of dying neurons increased well above control values as expected. Our interpretation of the transient decrease in neuronal death is that retrograde trophic signals include both death-promoting and life-promoting components, and that the former act faster in this system.

Retrograde neurotrophin-mediated control of neurone survival in the developing central nervous system.

Neuronal death in vertebrate development is widely believed to be regulated by retrograde survival signals from the axonal target territory, and these signals are assumed to be initiated by the binding of trophic molecules to the axon terminal. However, direct evidence for the retrograde transmission of such survival signals along developing axons is only available in the peripheral nervous system. We show here in a central projection, the isthmo-optic projection of chick embryos, that a neurotrophin, brain-derived neurotrophic factor, can indeed initiate retrograde survival signals from the target territory. A related molecule, neurotrophin-3, is ineffective.

Origins of motility patterns in isolated arterially perfused rat intestine.

BACKGROUND/AIMS: Assessment of the neuromuscular control of small intestinal motility and movement of luminal contents is hampered in vivo by measurement techniques and in vitro by tissue viability. The aim of this study was to establish the structural and functional integrity of an isolated segment of rat ileum and characterize its motility. METHODS: Segments of rat ileum were perfused arterially with oxygenated fluorocarbon and luminally with saline. Oral and aboral pressures were correlated with conformational changes detected by concurrent video imaging. RESULTS: Light and electron microscopy showed no neuromuscular abnormalities after experiments, and acetylcholine-induced pressure amplitudes were unchanged during experiments. Under basal conditions, low-frequency contractions showing constant frequency (0.27/min) and amplitudes (oral, 17 hPa; aboral, 15 hPa) corresponded to luminally occlusive aborally propagated contractions, which were eliminated by tetrodotoxin. High-frequency contractions with a constant frequency (27/min) were also seen; their basal amplitude (0.3 hPa) increased immediately before and after low-frequency contractions and after tetrodotoxin. Tetrodotoxin also increased basal intestinal tone. CONCLUSIONS: An isolated, arterially perfused segment of rat ileum retains structural and functional integrity. It shows low-frequency propulsive contractions, controlled by the enteric nervous system, and myogenic high-frequency contractions, probably subject to tonic neural inhibition.

Bombesin changes excitability of rat brain stem neurons sensitive to gastric distension.

The responses of single neurons in the dorsal vagal complex to physiological gastric distension were investigated in anesthetized control and capsaicin-treated rats. In both groups, the responses of brain stem neurons to close arterial injection of the regulatory peptide bombesin (BBS) were studied. These experiments observed whether selective chemical deafferentation by capsaicin caused any significant change in the central representation of responses to gastric distension and peripheral BBS administration. In 43 animals a total of 49 neurons was studied, 21 of which were in rats pretreated with capsaicin. In normal animals, the majority of neurons (89%, n = 28) responded in the same manner (increase or decrease in firing rate) to gastric distension and peripheral BBS administration. Of the 21 neurons studied in capsaicin-treated rats, 76% responded in the same direction to gastric distension and BBS. Two neurons responsive to gastric distension failed to respond to BBS. There was no significant difference between the proportion of neurons responding both to gastric distension and BBS in normal and capsaicin-treated rats. Responses to both gastric distension and BBS were abolished by bilateral cervical vagotomy in both groups of rats. In these experiments, BBS apparently acted on peripheral receptors near the stomach to produce, via the vagus nerve, effects on neuronal excitability in the dorsal vagal complex. Almost all of these neurons were also responsive to activation of gastric mechanoreceptors. The responses of dorsal vagal complex neurons to gastric distension and peripheral BBS were capsaicin insensitive, which is in contrast to the action of cholecystokinin under the same conditions.

Central mu, delta- and kappa-opioid influences on intestinal water and electrolyte transport in dogs.

The effects of intracerebroventricular (i.c.v.) administration of opioid peptides with mu-(DAGO), mu- and delta-(DALAMIDE, DADLE) and kappa-(dynorphin) properties on normal and stimulated (cholera toxin) net fluxes of water, Na+ and K+ through a jejunal Thiry-Vella loop were investigated in conscious dogs. Basal net water absorption was slightly, but significantly (P less than 0.05) increased during i.c.v. infusion of DALAMIDE or DAGO (0.5 ng/kg/min) but not DADLE and dynorphin-(1-13) at the same rate; DALAMIDE and DAGO also markedly reduced (by 72.3 and 79.5% respectively) the secretory effects of cholera toxin (0.4 micrograms/ml). Similar effects were obtained with DALAMIDE and DAGO when injected i.c.v. as a bolus (100 ng/kg) prior to cholera toxin infusion; they were suppressed after i.v. pretreatment with naltrexone (0.3 mg/kg) but also with propranolol (0.2 mg/kg). In contrast, i.v. phentolamine (0.2 mg/kg) and bilateral truncal vagotomy, were unable to block their effects. These results suggest that Met-enkephalin can act centrally to affect intestinal transport of (i) water and (ii) electrolytes in dogs. They act probably at central mu-receptors which are involved in the regulation of intestinal secretion mediated through a central or peripheral beta-adrenergic pathway.

Influence of centrally administered somatostatin and two related peptides on intestinal absorption of water and electrolytes in conscious dogs.

The effects of intracerebroventricular (ICV) administration of somatostatin (SRIF) and two related peptides, anti SRIF and SMS 201-995, on jejunal fluxes of water, Na+ and K+ were investigated in dogs prepared with a Thiry-Vella (TV) loop. Intestinal transport in the TV loop and concomitant transit time were also measured during infusion (2 mg/min) of an isotonic electrolyte solution and phenol-red bolus injections. Basal net water absorption was reduced significantly (p less than 0.01) over periods of 2 to 5 hr and in a dose-related manner, with ICV administrations of SRIF (5 to 100 ng/kg); doses of SRIF, 5 to 25 times higher but administered IV, were inactive. Similar reductions in the net fluxes of water, Na+ and K+ were observed over 2 to 5 hr following ICV administration of a putative somatostatin antagonist and SMS 201-995 at doses of 100 ng/kg. Neither metoclopramide (1 mg/kg), phentolamine (0.1 mg/kg) nor methysergide (0.2 mg/kg) given IV were able to antagonize the effects of centrally administered SRIF (100 ng/kg) on intestinal fluxes. In contrast, the effects of SRIF were abolished completely by naloxone (0.2 mg/kg) but not methyl-naloxone (0.3 mg/kg) given systemically. It is concluded that somatostatin and the two related peptides act centrally to reduce jejunal absorption of water and electrolytes. The effects of SRIF appear to be related to opiate receptors, possible involving central nerve pathways which utilize opiate-like transmitters.

Effects of centrally administered naloxone on gastrointestinal myoelectrical activity in morphine-dependent rats.

The gastrointestinal myoelectrical alterations associated with morphine tolerance and subsequent withdrawal with naloxone were studied before and after treatment with adrenergic blockers, atropine, indomethacin and methysergide administered either i.c.v. or s.c. The rats were prepared chronically with electrodes implanted on the stomach, duodeno-jejunum and colon and two small polyethylene catheters were inserted into the lateral ventricles of the brain. They were rendered physically dependent on morphine by the s.c. administration of a slow-release emulsion containing morphine (75 mg over 48 hr). Morphine treatment was associated with an immediate (15-30 min) inhibition of gastric and colonic spiking activity and intestinal migrating myoelectric complex lasting 6 to 8 hr, followed by a partial recovery of gastric spiking activity while a permanent disorganized motility pattern persisted on the intestine. After 48 hr of morphine treatment the i.c.v. and s.c. administrations of naloxone at doses of 0.03 and 3 mg X kg-1, respectively, promoted typical electrical activity lasting 2 to 3 hr, characterized by the presence of five to seven grouped spike bursts and termed "minute rhythm." Previous central but not peripheral administration of either tolazoline or phentolamine at a dose of 0.3 mg X kg-1 inhibited the i.c.v. naloxone precipitated withdrawal. Neither atropine i.c.v. (30 micrograms X kg-1) nor methysergide i.c.v. (20 micrograms X kg-1) and s.c. (0.2 mg X kg-1) nor indomethacin s.c. (4 mg X kg-1) were found to have any effect on i.c.v. naloxone induced minute rhythm pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous system influence of prostaglandin E2 on jejunal water and electrolyte transport in conscious dogs.

The effects of intracerebroventricular (i.c.v.) vs. i.v. administration of prostaglandin E2 (PGE2) on net fluxes of water, Na+, and K+ through a jejunal Thiry-Vella loop were investigated before or after previous treatment with adrenergic blockers, indomethacin, and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB8) in conscious dogs. Administered intracerebroventricularly at doses of 20-100 ng/kg, PGE2 significantly reduced (p less than 0.01), in a dose-related manner, the net fluxes of water, Na+, and K+, which were reversed from an absorption to a secretion. Intravenously administered PGE2 at a five times higher dosage failed to significantly alter net water and electrolyte fluxes. Phentolamine (0.2 mg/kg body wt) and tolazoline (2 mg/kg body wt) administered intravenously abolished the secretory effects of centrally administered PGE2 (50 ng/kg). However, 10 times lower dosages of phentolamine and tolazoline administered intracerebroventricularly did not prevent the PGE2-induced secretion of water and electrolytes. Intracerebroventricular administration of indomethacin (10 micrograms/kg body wt) and TMB8 (1 microgram/kg body wt), did not modify the effect of i.c.v.-administered PGE2; however, indomethacin administered intracerebroventricularly alone stimulated water and electrolyte absorption. None of these treatments results in a significant (p greater than 0.05) change in mean transit time through the Thiry-Vella loop. We conclude that centrally administered PGE2 influences jejunal water, Na+, and K+ absorption, through a mechanism related to adrenergic innervation and/or involving at least alpha 2-adrenoceptors. The results also suggest that PGE2 in the central nervous system controls jejunal water and ion transport in the dog.

Central regulation of intestinal basal and stimulated water and ion transport by endogenous opiates in dogs.

The influence of intracerebroventricular (ICV) vs intravenous (IV) administration of (D-Ala2, Met5) enkephalinamide (Dalamide) on normal and stimulated (cholera toxin) jejunal fluxes of water, Na+, and K+ were investigated in dogs prepared with a Thiry-Vella (TV) loop. Intestinal transport in the TV loop and concomitant transit time were measured during an infusion (2 ml/min) of an isotonic electrolyte solution alone, or containing 0.4 micrograms/ml of cholera toxin (CT). Basal net water absorption was slightly, but significantly (P less than 0.05), increased during an ICV infusion of Dalamide at 0.5 ng/kg/min, while the secretory effects of cholera toxin were markedly reduced by nearly 75%. Similar effects were observed for Na+ and K+ movement. In contrast, Dalamide infused intravenously at a five times higher dose, ie, 2.5 ng/kg/min did not affect the control and CT-stimulated water and electrolyte movements. The jejunal loop transit times were halved during CT infusion. Similar values were observed under Dalamide ICV administration as well as during a five times higher dose of Dalamide administered intravenously. It was concluded that (1) Dalamide administered into the CNS, but not peripherally, increased the absorption of water, Na+, and K+, causing a net reduction in their secretion induced by cholera toxin; and (2) these effects did not result from changes in transit time. These results also suggest that Met-enkephalin can act in the brain to affect the intestinal transport of water and electrolytes in dogs.

Centrally mediated stimulation of jejunal water and electrolyte secretion by calcitonin in dogs.

The effects of intracerebroventricular versus intravenous injection of salmon calcitonin (sCT) at a dose of 0.2 IU X kg-1 on jejunal fluxes of water, Na+, and K+ were investigated before and after vagotomy or an intravenous treatment with indomethacin (1 mg X kg-1) in dogs prepared with a jejunal Thiry-Vella loop. Intestinal transport in the Thiry-Vella loop and concomitant mean transit time were measured during an infusion (2 ml X min-1) of an isotonic electrolyte solution and phenol red bolus injections. Basal net water absorption was significantly (P less than 0.01) reduced by 51.7% from 2 to 3 h after intracerebroventricular administration of sCT, Na+ absorption was reduced by 62.6%, and net flux of K+ was reversed from absorption to secretion. A similar intravenous dose had no effect. Previous treatment with indomethacin or bilateral thoracic vagotomy did not reduce the water, Na+, and K+ secretory effects of centrally administered sCT, whereas indomethacin per se appeared to reduce water and electrolyte absorption. A significant (P less than or equal to 0.05) increase in mean transit time was observed after intracerebroventricular but not intravenous calcitonin (0.2 IU X kg-1), and this effect was abolished after vagotomy. These results suggest that calcitonin may be involved in the central control of intestinal secretion in dog, inasmuch as these effects were mediated by different structures from those affecting intestinal motility.

Central control of intestinal motility by prostaglandins: a mediator of the actions of several peptides in rats and dogs.

The effect of intracerebroventricular and intravenous administrations of prostaglandin E2 on gastrointestinal motility were investigated in conscious rats and dogs using electrodes and strain gauges, respectively. Injections were performed during the fed state and the motor changes were compared with those after intracerebroventricular administration of calcitonin, neurotensin, and (D-Ala2, Met5) enkephalinamide. Intracerebroventricular administration of prostaglandin E2 (0.5 micrograms) to fed rats restored the migrating myoelectric complex for 67 +/- 16 min. A migrating myoelectric complex-restoring effect was also observed after intracerebroventricular administration of calcitonin (0.02 U) and neurotensin (80 ng). This effect was blocked by previous intracerebroventricular administration of indomethacin (0.25 mg). Administered centrally to dogs but not intravenously at a 10-fold greater dose, prostaglandin E2 (0.1 microgram/kg) reduced (52.8%) the duration of the jejunal postprandial motor state similarly to that observed after intracerebroventricular administration of calcitonin (0.1 U/kg), neurotensin (0.1 microgram/kg), and (D-Ala2, Met5) enkephalinamide (0.1 microgram/kg). These effects of calcitonin and neurotensin were abolished 4 h after an intramuscular injection of indomethacin (2 mg/kg), whereas those of (D-Ala2, Met5) enkephalinamide persisted. These results suggest that (a) prostaglandins act centrally to control the pattern of intestinal motility in both rats and dogs and (b) calcitonin and neurotensin when injected intracerebroventricularly affect the intestinal motor profile probably by stimulating prostaglandin release within the brain.

Central effects of growth hormone-releasing factor (GRF) on intestinal motility in dogs: involvement of dopaminergic receptors.

The effects of intracerebroventricular (ICV) and intravenous (IV) administration of human pancreatic growth hormone-releasing factor (hpGRF) on gastro-intestinal motility were examined in fasted and fed conscious dogs equipped with chronically implanted strain-gauges on the antrum and the jejunum. During the fasted state, hpGRF injected ICV at 0.1 micrograms . kg-1 or IV at 0.5 micrograms . kg-1 did not affect the cyclic occurrence of the migrating motor complex (MMC). This pattern was normally disrupted for 8-10 hours by a daily standard meal. Injected ventricularly (0.1 micrograms . kg-1) but not intravenously (0.5 micrograms . kg-1) 10-15 min after the daily meal, hpGRF significantly reduced (p less than 0.01) the duration of the jejunal fed pattern (2.0 +/- 1.4 vs. 8.4 +/- 1.1 hours for control) but not that of the stomach. This effect persisted when hpGRF (0.1 micrograms . kg-1 ICV) was administered after indomethacin (2 mg . kg-1 IM), naltrexone (0.1 mg . kg-1 IV) or domperidone (1 mg . kg-1 IV) but was abolished by a previous IV injection of metoclopramide (1 mg . kg-1). It was concluded that hpGRF is able to act centrally to control the pattern of jejunal motility in fed but not in fasted dog, its effect being probably mediated through dopaminergic pathways.

Central and peripheral control of gastrointestinal and colonic motility by endogenous opiates in conscious dogs.

The effects of two enkephalin analogues, (D-Ala2, Met5) and (D-Ala2, D-Leu5) enkephalinamide, on gastrointestinal and colonic motility were investigated in conscious fasted and fed dogs using chronically implanted strain gauges. The drugs, abbreviated here with the names DALAMIDE and DADLE, respectively, were administered by using both the intracerebroventricular and intravenous routes at increasing doses. In fasted dogs when administered via the intracerebroventricular route at a dose of 20 ng X kg-1, DALAMIDE disrupted the migrating myoelectric complex pattern. A similar effect was obtained only with a dose 25 times higher (500 ng X kg-1) administered intravenously; at this dosage DALAMIDE administered intravenously also reduced the colonic motility index by 66%. When intracerebroventricularly administered in fed dogs, 2 h after a meal, DALAMIDE (20 ng X kg-1) inhibited gastric motility but restored the jejunal migrating myoelectric complex pattern as "ectopic" complexes for 4-6 h. This effect however was not reproduced by intravenous treatment even at the highest dose used (500 ng X kg-1). Both intracerebroventricular and intravenous administration of DADLE, at doses as high as 100 and 500 ng X kg-1, respectively, affected neither the motility pattern nor the motility index of the antrum and proximal jejunum in the fasted or fed state. However, intracerebroventricular, but not intravenous, administration produced a short (10-15 min) increase of colonic motility. These results suggest that (a) Met-enkephalin influences the gastrointestinal motility predominately by a central action, manifested as a migrating myoelectric complex "reorganizing" effect in fed dogs; (b) Leu-enkephalin exerts a predominately centrally mediated stimulation of colonic motility, whereas Met-enkephalin inhibits it probably by a peripheral mechanism.

Neurotensin: a central neuromodulator of gastrointestinal motility in the dog.

The effects of intracerebroventricular and intravenous injection of neurotensin on gastrointestinal and colonic motility were examined in fasted and fed conscious, intact, and vagotomized dogs. When administered intracerebroventricularly at 20 ng X kg-1 or higher doses in the fasted state, neurotensin reduced the duration of the periods of gastric motility for 3-4 h. During this time the jejunal migrating motor complex was replaced by isolated phases of regular activity occurring at a rhythm of 2-3/h, while colonic motility was unaffected. These effects were abolished after vagotomy and were not observed for 25 times higher doses when administered intravenously. Injected intracerebroventricularly at a dose of 100 ng X kg-1 30 min after a meal, neurotensin significantly reduced (P less than 0.01) the duration of the fed pattern (2.7 +/- 0.7 vs. 8.7 +/- 1.2 h for control); this effect was not observed when neurotensin was administered intracerebroventricularly 20 min before or 120 min after a meal or when injected intravenously. Systemic administration of neurotensin at a dose of 500 ng X kg-1 significantly increased (P less than 0.05) during 2 h the colonic motility indexes in both fasted and fed dogs before and after vagotomy. It is concluded that neurotensin can act i) centrally to control the pattern of antral and jejunal motility in the fasted and fed dogs, these effects being mediated by the vagus; and ii) peripherally to control the pattern of colonic motility, this response being unaffected by vagotomy.