Biomedical subjects

N N Abumrad

Publications and source records attributed to N N Abumrad.

At least 19 recordsLinked to original sources

PubMed2001

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine.

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7-8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by approximately 60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.

Animals↗

PubMed2001

Contribution of excitatory amino acids to hypoglycemic counter-regulation.

We determined the contribution of central N-methyl-D-aspartate (NMDA) receptor activation to the neuro-endocrine counter-regulatory response to insulin-induced hypoglycemia. Glucose kinetics, gluconeogenic substrate balance and counter-regulatory hormonal responses were determined in two groups of conscious dogs fitted with chronic vascular catheters and intracerebroventricular (i.c.v.) cannula. Peripheral insulin infusion (5 mU/kg per min for 3 h) decreased plasma glucose levels 40% and increased the rate of glucose appearance (R(a)) 2-fold. This was associated with significant increases in net hepatic uptake of glycerol and lactate, without any change in the net hepatic uptake of alanine. i.c.v. pretreatment with MK-801, an NMDA receptor antagonist, blunted (50%) the rise in glucose R(a) as well as the increase in the net hepatic uptake of glycerol and lactate. Hypoglycemia increased plasma cortisol (3-fold to 14.3+/-1 mg/dl) and epinephrine levels (14-fold to 3811+/-172 pg/ml), and this stress response was attenuated (30% and 60%, respectively) by MK-801 pretreatment. In controls, MK-801 did not alter the increase in norepinephrine or glucagon elicited by hypoglycemia. These results indicate that during hypoglycemia, central excitatory amino acids contribute to the modulation of the glucoregulatory response through activation of NMDA receptors, resulting in stimulation of the sympathoadrenal and hypothalamic-pituitary adrenal axis. This mechanism appears to play an important role in the sustained elevation in hepatic glucose production during hypoglycemia.

Animals↗

PubMed2000

Differential effects of hemorrhage and LPS on tissue TNF-alpha, IL-1 and associate neuro-hormonal and opioid alterations.

LPS administration and hemorrhage are frequently used models for the in vivo study of the stress response. Both challenges stimulate cytokine production as well as activate opiate and neuro-endocrine pathways; which in turn modulate the inflammatory process. Differences in the magnitude and tissue specificity of the proinflammatory cytokine and neuro-hormonal responses to these stressors are not well established. We contrasted the tissue specificity and magnitude of the increase in circulating and tissue cytokine (TNF-alpha, IL-1alpha and IL-1beta) content in response to either fixed-pressure hemorrhage (approximately 40 mm Hg) followed by fluid resuscitation (HEM) or lipopolysaccharide (LPS; 100 microg/100 g BW) administration. LPS and HEM elevated circulating levels of TNF-alpha, while neither stress altered circulating IL-1-alpha and IL-beta. LPS-induced increases in TNF-alpha content were greater than those elicited by HEM in all tissues studied except for the lung, where both stressors produced similar increases. Tissue (lung, spleen and heart) content of IL-1alpha was increased by HEM but was not affected by LPS. Tissue (lung, spleen, and heart) content of IL-1beta was increased by LPS but was not affected by HEM. HEM produced greater increases than LPS in epinephrine (16- vs. 4-fold) and norepinephrine (4-fold vs. 60%) levels and similar elevations in beta-endorphin. LPS produced greater elevation in corticosterone levels (2-fold) than HEM (50%). These results suggest differential tissue cytokine modulation to HEM and LPS, both with respect to target tissue and cytokine type. The hormonal milieu to HEM is characterized by marked catecholaminergic and moderate glucocorticoid while that of LPS is characterized by marked glucocorticoid with moderate catecholaminergic influence.

Animals↗

PubMed1999

HMG-1 as a late mediator of endotoxin lethality in mice.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Animals↗

PubMed1999

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.

Adult↗

PubMed1999

Clinical experience over 48 years with pheochromocytoma.

OBJECTIVE: To analyze the presentation, localization, surgical management, pathology, and long-term outcome of a large series of patients with pheochromocytomas. SUMMARY BACKGROUND DATA: There are several areas of controversy pertaining to pheochromocytomas. Although many studies report a higher rate of malignancy for extraadrenal pheochromocytomas than for adrenal pheochromocytomas, the number of patients with the former tumor are small and statistical analysis is lacking. There has also been recent debate as to whether microscopic features of the tumor may be predictive of future behavior. METHODS: From 1950 to 1998, the authors observed 108 pheochromocytomas in 104 patients. The outcome of these patients has been followed prospectively. The medical records of these patients were reviewed for data on the presentation, localization, surgical management, pathology, and outcome. Patient survival was analyzed using Kaplan-Meier survival distributions. RESULTS: This study included 66 female patients and 38 male patients. The average age at surgery was 42.3 years. Sporadic cases accounted for 84% of the patients; the other 16% had multiple endocrine neoplasia type 2, von Recklinghausen's disease, von Hippel-Lindau disease, or Carney's syndrome. Of 64 adrenal tumors, 55 were initially considered benign, 6 had microscopic malignant features, and 3 had malignant disease. Mean patient follow-up was 12.6 years. To date, in five additional patients (none with microscopic disease) malignant disease developed (13% overall rate of malignancy). Recurrence occurred as late as 15 years after resection. Of 26 extraadrenal pheochromocytomas, 14 were initially considered benign, 8 had microscopic malignant features, and 4 had malignant disease. Thus, 46% of patients had either malignant disease or tumors with malignant features. Mean patient follow-up was 11.5 years. In one patient with benign disease and in one patient with malignant features, malignant disease developed (23% overall rate of malignancy). The difference in the rate of malignancy was not statistically significant between adrenal and extraadrenal pheochromocytomas. Patients with adrenal and extraadrenal pheochromocytomas also had similar rates of survival (p = NS). CONCLUSIONS: The data suggest that patients with extraadrenal pheochromocytomas have the same risk of malignancy and the same overall survival as patients with adrenal pheochromocytomas. Lifelong follow-up of these patients is mandatory.

Adolescent↗

PubMed1999

Mammalian opiate alkaloid synthesis: lessons derived from plant biochemistry.

The presence of opiate receptors in mammalian tissues has stimulated the search for endogenous ligands to these receptors and has led to the discovery and characterization of endogenous opioid peptides. However, recent studies have provided evidence for the presence of opiate alkaloids in mammalian tissues and for their endogenous synthesis. The study of their origin and synthetic pathway has been significantly influenced by the early classical biochemical studies performed in plants. This review is a historical account of the use and abuse of opiates, the elucidation of morphine's synthetic pathway in the poppy plant, and the subsequent characterization of its presence in mammalian tissues. Clearly, our understanding of its synthetic pathway and regulation is a reflection of observations originally made in plant biochemistry.

Alkaloids↗

PubMed1998

Differential responses of brain, liver, and muscle glycogen to opiates and surgical stress.

We examined the effects of intracerebroventricular (ICV) cannula implantation followed by the administration of morphine sulfate (MOR) and its metabolite, morphine-6-glucuronide (M6G), on the glycogen content of the brain, liver, and muscle. ICV cannulation resulted in nearly a 30% reduction in brain glycogen, and ICV MOR resulted in a 36% reduction in liver glycogen content compared to time-matched controls, but it had no additional effect on either the brain or muscle glycogen content. ICV M6G showed a more significant reduction, to 50% of liver glycogen, but it had no effect on either brain or muscle glycogen. Neither IV MOR nor M6G produced any significant alteration in tissue glycogen content. These results indicate that the stress response associated with neurosurgery, especially the placement of the ICV cannula, is associated with a decrement in brain glycogen. The activation of opioid receptors in the brain results in enhanced hepatic glycogenolysis but has no additional effect on the brain glycogen content.

Analgesics, Opioid↗

PubMed1998

CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS.

The increased production of pro-inflammatory cytokines and nitric oxide have been postulated to contribute to the deleterious sequella of LPS administration. To date, clinical strategies to control these responses using individual specific inhibitors have been disappointing. The aim of the present study was to determine whether a tetravalent guanylhydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected intravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCl) 60 min prior to the injection of LPS (100 microg/100 g body weight). LPS produced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-alpha levels as well as in tissue content of TNF-alpha, IL-1beta, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidase (MPO) activities as well as with an increase in lung and spleen nitric oxide end products (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-alpha levels. CNI-1493 attenuated the LPS-induced increase in tissue cytokine (TNF-alpha, IL-1beta, and IL-6) content in lung and spleen but did not alter that of liver or gut. CNI-1493 pretreatment protected both lung and gut from LPS-induced apoptosis and in addition attenuated the rise in MPO activity in the gut. These results suggest diverse effects of CNI-1493 that are tissue specific and that confer protection against the hemodynamic and inflammatory responses to LPS.

Animals↗

PubMed1998

Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia.

The contribution of gluconeogenic precursors to renal glucose production (RGP) during insulin-induced hypoglycemia was assessed in conscious dogs. Ten days after surgical placement of sampling catheters in the right and left renal veins and femoral artery and an infusion catheter in the left renal artery, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [6-3H]glucose and [2-13C]glycerol. Renal blood flow was determined with a flowprobe, and the renal balance of lactate, alanine, and glycerol was calculated by arteriovenous difference. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine, from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine, from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon, from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). RGP increased from 1.7 +/- 0.4 to 3.0 +/- 0.5 (left) and from 0.6 +/- 0.2 to 3.2 +/- 0.2 (right) micromol x kg(-1) x min(-1) (P < 0.01). Whole-body glycerol appearance increased from 6.0 +/- 0.5 to 7.7 +/- 0.7 micromol x kg(-1) x min(-1)(P < 0.01); renal conversion of glycerol to glucose increased from 0.13 +/- 0.04 to 0.30 +/- 0.10 (left) and from 0.11 +/- 0.03 to 0.25 +/- 0.05 (right) micromol x kg(-1) x min(-1), (P < 0.05). Net renal gluconeogenic precursor uptake increased from 1.5 +/- 0.4 to 5.0 +/- 0.4 (left) and from 0.9 +/- 0.2 to 3.8 +/- 0.4 (right) micromol x kg(-1) x min(-1) (P < 0.01). Renal lactate uptake could account for approximately 40% of postabsorptive RGP and for 60% of RGP during hypoglycemia. These results indicate that gluconeogenic precursor extraction by the kidney, particularly lactate, is stimulated by counterregulatory hormones and accounts for a significant fraction of the enhanced gluconeogenesis induced by hypoglycemia.

Alanine↗

PubMed1998

Energy metabolism and fuel mobilization: from the perioperative period to recovery.

To determine the metabolic responses to surgical trauma, we assessed the rates of whole body (WB) proteolysis and glucose turnover using established isotopic techniques in combination with interorgan amino acid and substrate balances (using arteriovenous differences times flow) after laparotomy. Circulating levels of hormones and mediators known to affect these parameters were also examined. Mongrel dogs (n = 5-8 per group) were studied postoperatively under general anesthesia (immediate postoperative period) and at 3 days postoperatively (3 dPO) and 2 weeks later. Our results show that the immediate postoperative period is characterized by significant hyperglycemia, secondary to decreased glucose clearance (without any alterations in the rates of hepatic glucose production) and significant increase in gut proteolysis, with a mild increase in WB proteolysis. The gut proteolysis accounted for nearly 40% of WB proteolysis. At 3 dPO, blood glucose levels returned to normal, whereas the rate of WB proteolysis was maximally increased. Gut proteolysis was mildly elevated and accounted for nearly 8% of WB proteolysis. All metabolic parameters were back to near basal at 2 weeks postoperatively. These metabolic changes were accompanied by significant elevations in the plasma levels of endogenous morphine and cortisol and lower glucagon and insulin growth factor-I levels in the immediate postoperative period and at 3 dPO. These studies underscore the importance of the gut as a reservoir of amino acids during the immediate postoperative period, accounting for more than one-third of WB proteolysis. At 3 dPO, when maximal stimulation of WB proteolysis and amino acid oxidation are observed, the contribution from the gut is negligible and is most likely replaced by breakdown from skeletal muscle.

Adrenocorticotropic Hormone↗

PubMed1997

Relationship between subjective effects of cocaine and dopamine transporter occupancy.

Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the brain. Although this concept is central to current cocaine research and to treatment development, a direct relationship between DAT blockade and the subjective effects of cocaine has not been demonstrated in humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in human volunteers who regularly abuse cocaine. We report here that intravenous cocaine at doses commonly abused by humans (0.3-0.6 mg kg(-1)) blocked between 60 and 77% of DAT sites in these subjects. The magnitude of the self-reported high was correlated with the degree of DAT occupancy, and at least 47% of the transporters had to be blocked for subjects to perceive cocaine's effects. Furthermore, the time course for the high paralleled that of cocaine concentration within the striatum, a brain region implicated in the control of motivation and reward. This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine. Although these findings provide justification to target the DAT for medication development they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost complete DAT occupancy.

Adult↗

PubMed1997

Concentration and occupancy of dopamine transporters in cocaine abusers with [11C]cocaine and PET.

The concentration (Bmax) of the dopamine transporter (DAT) and the maximum and effective occupancies by cocaine doses of 0.1 mg/kg or 0.05 mg/kg were measured in the striatum of cocaine abusers (n = 12) by using [11C]cocaine as a radiotracer for the DAT and positron emission tomography (PET). Two methods based on a three-compartment model with one binding site (the nonlinear least squares (NLSQ) and the Farde pseudoequilibrium method) were used to estimate Bmax. Effective occupancies and maximum occupancies were calculated from the distribution volume ratios (DVR) and a three-compartment model, respectively. The NLSQ and Farde methods gave similar values of Bmax (average, 650 +/- 350 pmol/ml and 776 +/- 400 pmol/ml, respectively), but the individual estimates of Bmax were found to be very sensitive to small variations in other model parameters and were not correlated with the parameter Bmax/Kd (r = .07). The average maximum (and effective) occupancies were found to be 67% (50%) and 52% (39%) for the 0.1-mg/kg and the 0.05-mg/kg studies, respectively. The ED50 based on the effective occupancy corresponds to 0.1 mg/kg, which is significantly smaller than the ED50 of 3 mg/kg calculated from studies in which [123]beta-CIT is displaced by cocaine. The effect on the Bmax estimate of two binding sites with different Kd's is also considered by simulation. We conclude (1) that the lack of robustness in the Bmax estimate limits the usefulness of any one subject's Bmax and suggests that the combination parameter Bmax/Kd (or the DVR), which has been used extensively, is a more stable measure of free receptor/transporter concentration. The average Bmax may, however, provide an estimate of the expected concentration in humans. (2) The DVR can be used as a measure of DAT occupancy without applying an explicit model.

Adult↗

PubMed1997

Cocaine abusers do not show loss of dopamine transporters with age.

Cocaine blocks dopamine transporters (DAT) and this effect is crucial to its reinforcing properties. To assess the effects of chronic cocaine on DAT we evaluated 20 current cocaine abusers and 20 age matched controls using PET and [C-11]cocaine as a DAT ligand. Though there were no differences in DAT availability between groups, current cocaine abusers (and 12 detoxified cocaine abusers studied previously) did not show the typical age-related decline in DAT seen in controls. Though further studies are required to rule out sampling effects and to control for confounding variables (i.e. smoking), one could speculate that chronic DAT blockade by cocaine has a protective effect on the loss of DAT with age.

Adult↗

PubMed1997

Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal.

Dopamine may play a role in opiate withdrawal and dependence. We measured dopamine D2 receptor availability in 11 opiate-dependent subjects using PFT and [11C]raclopride at baseline and during naloxone-precipitated withdrawal. Because [11C]raclopride is sensitive to endogenous dopamine, this strategy enabled us to test whether we could document in humans the DA reductions reported in animal models of opiate withdrawal. Results were compared with values from 11 controls, two of which also received naloxone. The ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1) was used as model parameter for D2 receptor availability. Baseline measures for Bmax/Kd were lower in opiate-dependent subjects (2.44 +/- 0.4) than in controls (2.97 +/- 0.45 P < or = .009). Naloxone precipitated an intense withdrawal in the abusers but did not change the Bmax/Kd ratio. This study documents decreases in D2 receptors in opiate-dependent subjects but does not document significant changes in striatal DA concentration during acute withdrawal.

Adult↗

PubMed1997

Role of the kidney in plasma glucose regulation during hyperglycemia.

Little is known about the role of the kidney in plasma glucose regulation during hyperglycemia. We studied 12 overnight-fasted conscious dogs after either intrarenal (IR, n = 6) or peripheral (PH, n = 6) dextrose infusion to maintain hyperglycemia without glycosuria. Systemic and renal glucose kinetics were measured with [6-3H]glucose, lactate balance was measured by arteriovenous difference, and glycogen content was assayed in the kidneys. Plasma glucose (approximately 5.5 vs. approximately 6.3 mM), insulin (approximately 70 vs. approximately 110 pM), and glucose appearance (approximately 14 vs. approximately 16 mumol.kg-1.min-1 increased comparably in both groups (P < 0.05). In IR, fractional extraction of glucose (FEGlc) increased from 4.1 +/- 0.2 to 16.1 +/- 0.5% (P < 0.001) and lactate balance reversed to renal output (+1.3 +/- 0.2 vs. -0.9 +/- 0.2 mumol.kg-1.min-1, P < 0.01). Glycogen content was twofold higher in the left (127 +/- 33 micrograms/g tissue) than in the right kidney (56 +/- 11 micrograms/g tissue, P < 0.01). In PH, FEGlc decreased from 4.9 +/- 0.6 to 2.2 +/- 0.3% (P < 0.05), renal glucose utilization did not change (approximately 1.3 mumol.kg-1.min-1); and glycogen content was equal in both kidneys (approximately 45 micrograms/g tissue). We conclude that, although the kidney plays a minor role in plasma glucose disposal in physiological hyperglycemia, increased glucose uptake, glycogen storage, and lactate formation precede glycosuria and may represent important mechanisms by which the kidney contributes to normalization of plasma glucose in diabetes.

Animals↗

PubMed1997

Histaminergic contribution to the metabolic effects of neuroglucopenia.

We examined the contribution of central histamine receptor (H1 and H2) blockade to the glucoregulatory responses to intracerebroventricular 2-deoxy-D-glucose (2-DG) in conscious dogs. Intracerebroventricular 2-DG (2.5 mg.kg-1.min-1 for 15 min) increased plasma glucose (2-fold), blood lactate (4-fold), and glycerol (2-fold) levels. The rate of hepatic glucose production (Ra), determined isotopically, was increased two-fold. Significant increases over basal were also noted in plasma epinephrine, norepinephrine, insulin, glucagon, and cortisol. Pretreatment with cyproheptadine and cimetidine (100 micrograms each icv 15 min before 2-DG) attenuated the 2-DG-induced hyperglycemia by approximately 50% and delayed and attenuated the increase in glucose Ra (approximately 85% vs. 2-fold in group 1). Pretreatment with H1 and H2 antagonists inhibited the increases in epinephrine, norepinephrine, and glucagon in response to neuroglucopenia but did not affect the cortisol response. These findings suggest that some of the metabolic effects of neuroglucopenia, particularly the hyperglycemic response, the increased hepatic uptake of gluconeogenic precursors, and the enhanced glucose Ra, are partly mediated through central histaminergic receptor activation. This appears to be through effects of histaminergic activation on the autonomic and hormonal responses to central neuroglucopenia.

Alanine↗

PubMed1997

Central opiate mu-receptor-mediated suppression of tissue protein synthesis.

We determined the dose-dependent effects of central mu-opioid receptor stimulation on rates of tissue protein synthesis. Chronically catheterized conscious rats received an intracerebroventricular injection of [D-Ala2, N-Me-Phe4,Gly5-ol]enkephalin (DAGO, 0.5, 2, or 8 nmol/rat) or water (5 microliters) 45 min before determination of protein synthesis by the flooding dose technique. DAGO produced a significant decrease in tissue protein synthesis in liver (57%), spleen (54%), gut mucosa (36%), gut serosa (23%), kidney (48%), gastrocnemius (33%), and plantaris muscle (27%), but it did not alter rates of protein synthesis in the brain, heart, and soleus muscle. DAGO produced an acute dose-dependent respiratory depression 30 min after intracerebroventricular injection; this depression resulted in acidosis, hypoxia, and hypercapnia (pH 7.19 +/- 0.04, arterial partial O2, pressure 44.2 +/- 3.4 Torr, arterial O2 saturation 65.3 +/- 5.5%, and PCO2 66.3 +/- 4.4 Torr). Intracerebroventricular DAGO increased circulating levels of catecholamines, corticosterone, and growth hormone but did not alter those of insulin and insulin-like growth factor I. Significant positive correlations between protein synthesis and pH were observed in the tissues studied (i.e., liver protein synthesis vs. pH, P < 0.0001, r = 0.902; gastrocnemius protein synthesis vs. pH, P < 0.0001, r = 0.830). Our results indicate that mu-receptor stimulation inhibits tissue protein synthesis, and this effect appears to be secondary to respiratory depression and the resulting acidosis and/or hypoxia. Furthermore, our findings suggest differential sensitivity in tissue response to alterations in pH, hypoxia, and stress hormone elevation.

Adenosine Triphosphate↗