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Biomedical subjects

C M Kuhn

Publications and source records attributed to C M Kuhn.

At least 37 records · Page 2Linked to original sources
PubMed1996

mu-Opioid agonists stimulate growth hormone secretion in immature rats.

The purpose of the present study was to evaluate the opioid receptor subtype mediating opioid modulation of growth hormone (GH) secretion during ontogeny. The mu-agonist morphine and the kappa agonist U50,488 caused a stimulation and inhibition of GH secretion, respectively, on postnatal day 10. Studies on postnatal days 2, 5, 10, 15 and 20 showed that kappa-inhibition could be observed as early as day 2, but substantial mu-stimulation was not observed until postnatal day 10. Intracerebroventricular (i.c.v.) administration of the mu-selective peptide [D-Ala2-NMe-Phe4-Gly-ol]-enkephalin (DAMGO) elicited a marked rise in GH secretion, while administration of the delta-agonists [D-pen2D-pen5]-enkephalin (DPDPE) or deltorphin II caused only a minor and non-dose-related rise in GH secretion in neonatal rats. The relative importance of mu- and delta-receptors in stimulating GH secretion was also studied in older pups (day 20). i.c.v. administration of DAMGO stimulated GH secretion, while neither DPDPE nor deltorphin II consistently increased GH secretion. Furthermore, peripheral administration of either morphine or the highly selective mu-agonist sufentanil elicited marked GH secretion on postnatal day 20, but only combined administration of the mu-antagonist beta-funaltrexamine (beta-FNA) and the delta-antagonist naltrindole substantially diminished these responses. These results suggest that both mu- and kappa-opioid receptors are involved in the regulation of GH secretion in neonatal rats. While delta-receptors do not play a prominent independent role in this response, they may act synergistically with mu-receptors in producing stimulation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

Adrenocorticotropic Hormone↗
PubMed1995

Glipizide stimulates sympathetic outflow in diabetes-prone mice.

The purpose of the present study was to determine if the oral hypoglycemic agent glipizide influenced sympathetic outflow in diabetes-prone mice. C57BL/6 (diabetes-prone) and diabetes-resistant (A/J) were treated with saline or glipizide, and sympathetic outflow determined by the fall in organ norepinephrine content after synthesis inhibition with alpha-methyl-para-tyrosine. Sympathetic outflow to the liver and pancreas were slower in Bl/6 mice than in control A/J. Glipizide increased sympathetic outflow to the pancreas in both strains of mice, but did not influence outflow to other organs significantly. The results of this study suggest that glipizide can influence central glucoregulatory mechanisms after peripheral administration.

Animals↗
PubMed1995

Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice.

We have previously demonstrated that the C57BL/6J (B/6J) mouse will develop severe obesity, hyperglycemia, and hyperinsulinemia if weaned onto a high-fat, high-sucrose (HH) diet. In the present study, we compared the effects of fat and sucrose separately and in combination on diabetes- and obesity-prone B/6J and diabetes- and obesity-resistant A/J mice. After 4 months, the feed efficiency ([FE] weight gained divided by calories consumed) did not differ across diets in A/J mice, but B/6J mice showed a significantly increased FE for fat. That is, B/6J mice gained more weight on high-fat diets without consuming more calories than A/J mice. The increase in FE was related to adipocyte hyperplasia in B/6J mice on high-fat diets. Fat-induced obesity in B/6J mice was unrelated to adrenal cortical activity. In the absence of fat, sucrose produced a decreased in FE in both strains. Animals fed a low-fat, high-sucrose (LH) diet were actually leaner than animals fed a high-complex-carbohydrate diet. Fat was also found to be the critical stimulus for hyperglycemia and hyperinsulinemia in B/6J mice. In the absence of fat, sucrose had no effect on plasma glucose or insulin. These data clearly show that across these two strains of mice, genetic differences in the metabolic response to fat are more important in the development of obesity and diabetes than the increased caloric content of a high-fat diet.

Adipose Tissue↗
PubMed1995

Impaired second phase insulin response of diabetes-prone C57BL/6J mouse islets.

The C57BL/6J mouse develops obesity and diabetes in response to a high-fat, high-simple carbohydrate diet. To determine the dynamics of glucose-induced insulin release in this animal model of NIDDM, we studied the acute insulin response to glucose of perifused islets in C57BL/6J (diabetes-prone) and A/J (diabetes-resistant) mice fed a normal control diet and of others fed a diabetogenic diet. The insulin response of normal C57BL/6J islets was almost monophasic, with a deficiency in the second phase during high glucose stimulation when compared to that of A/J control islets. The defect in C57BL/6J mice was exaggerated in animals fed a diabetogenic diet. It is suggested that a latent deficiency of second phase insulin release may contribute to the development of the diet-induced syndrome in this model.

Animals↗
PubMed1995

Increased sensitivity to mu opiate antinociception in the neonatal rat despite weaker receptor-guanyl nucleotide binding protein coupling.

The developmental changes in mu opiate receptor-mediated antinociception and coupling to guanyl nucleotide binding proteins were studied in the rat. ED50 values for morphine- and sufentanil-induced antinociception were determined in the paw-lift assay on days 10 and 27. The ED50 for morphine analgesia in 10-day-old pups was 0.35 mg/kg and increased with age to 5.3 mg/kg on day 27. Similarly, sufentanil was more potent in pups than in weanlings, the ED50 increasing from 1.7 to 7.6 micrograms/kg. Serum and brain morphine levels after 5 mg/kg of morphine were higher in neonates (day 10) than weanlings (day 27), largely due to a more rapid redistribution phase in weanlings (T1/2 = 26 min.) than in pups (T1/2 = 2.5 hr). Additionally, a substantial (70%) antinociceptive response was achieved in neonates at brain morphine levels that were one-half those producing an equal effect in weanlings. Radioligand binding studies indicated that the number of mu receptors increased 2-fold without change in affinity between days 10 and 27, whereas the GTP analog guanylylimidophosphate was nearly twice as effective in shifting the mu receptors from high to low affinity on day 27 than on day 10. These data indicate that neonatal rats are more sensitive to mu opiate antinociception despite apparently weaker receptor-guanyl nucleotide binding protein coupling. This greater sensitivity is enhanced by the pharmacokinetic differences between neonates and weanlings which result in higher drug levels in pups after a similar dose.

Amino Acid Sequence↗
PubMed1995

The ontogeny of mu opiate tolerance and dependence in the rat: antinociceptive and biochemical studies.

The ontogeny of tolerance to mu opiate antinociception and the behavioral and endocrine profiles of the opiate withdrawal syndrome were studied in rats. Animals were treated with saline or an increasing dose regimen of morphine for 5 days (5-25 mg/kg b.i.d. s.c.) and were tested 36 hr later for morphine or sufentanil antinociception in the hot-plate paw-lift test, or withdrawal was precipitated with 5 mg/kg of naloxone 12 hr after the last chronic morphine dose. Twenty-seven-, 20- and 15-day-old rats all developed tolerance as indicated by a rightward shift of the dose-response curve after chronic morphine. Animals treated on days 4 to 8 and tested on day 10 did not develop tolerance to the same chronic dose regimen used in older animals. In contrast to the observed developmental difference in tolerance, both neonatal and weanling rats developed physical dependence after morphine treatment, as evidenced by the presence of withdrawal symptoms after naloxone administration. Withdrawal in weanling rats was characterized by ptosis, piloerection, abnormal posture, forepaw treading, vocalization on touch and mastication. In addition, both serum corticosterone and adrenocorticotropic hormone secretion were increased during passive withdrawal. The behaviors constituting the withdrawal syndrome precipitated in neonates were distinct from those in weanling rats. Spontaneous vocalization, wall climbing, tremor, mouthing and increased locomotion were all observed. As in the older animals, both serum corticosterone and adrenocorticotropic hormone secretion were elevated during passive withdrawal. Tremor also was induced in opiate naive neonates when naloxone (5 mg/kg) was administered 2 hr after a single 25-mg/kg morphine injection. Brain and serum morphine levels and the time course of antinociception were not altered by chronic morphine treatment at any age. Saturation binding assays in brain homogenates indicated that chronic morphine did not produce changes in receptor number or affinity for the antagonist. The shift induced by the guanine nucleotide Gpp(NH)p (10 microM) from high to low affinity on days 27 and 10, respectively, was not altered by chronic morphine treatment. These data indicate that 10-day-old rats are refractory to developing tolerance relative to older animals, and that changes in receptor number or coupling to guanine nucleotide proteins do not accompany tolerance to this regimen.

Animals↗
PubMed1994

Glycogen synthase: a putative locus for diet-induced hyperglycemia.

Inbred mouse strains fed a diabetogenic diet have different propensities to develop features analogous to type 2 diabetes mellitus. To define chromosomal locations that control these characteristics, recombinant inbred strains from diabetes-prone C57BL/6J (B/6J) and diabetes-resistant A/J strains were studied. Insulin levels and hyperglycemia correlated with two different regions of mouse chromosome 7 (two point LOD scores > 3.0). For insulin levels, 15 of 16 recombinant inbred strains were concordant with a region that contains the tubby mutation that results in hyperinsulinemia. For hyperglycemia, 19 of 23 strains were concordant with the D7Mit25 marker and 20 of 23 strains with the Gpi-1 locus on proximal mouse chromosome 7. Using more stringent criteria for hyperglycemia, 10 of 11 strains characterized as A/J or B/6J like were concordant with D7Mit25. This putative susceptibility locus is consistent with that of the glycogen synthase gene (Gys) recently suggested as a candidate locus by analyses of type 2 diabetes patients. Fractional glycogen synthase activity in isolated muscle was significantly lower in normal B/6J diabetic-prone mice compared with normal diabetic-resistant A/J mice, a finding similar to that reported in relatives of human patients with type 2 diabetes. These data, taken together, raise the possibility that defects in the Gys gene may in part be responsible for the propensity to develop type 2 diabetes.

Animals↗
PubMed1994

Glycemic response to stress is altered in euglycemic Pima Indians.

The aim of this work was to study the effects of a computer-driven mental arithmetic task on blood glucose in a group of four male and four female euglycemic Caucasians and a group of seven male and six female euglycemic Pima Indians. Approximately 60% of euglycemic Pima Indian Native Americans eventually develop type 2 diabetes, while only 5% of Caucasians develop the disease. All subjects had normal glucose tolerance. Subjects were given a standard breakfast; 2 h later, they were given a computerized mental arithmetic stress test for 10 min. Before, during and after the test, several variables were analyzed, including serum concentrations of glucose, insulin, glucagon and plasma cortisol and catecholamines. Heart rate, systolic and diastolic blood pressure and all the stress hormones increased during stress and decreased during recovery in all subjects. Blood glucose consistently declined one hour after the meal in all subjects. However, while it continued to decline following stress in seven out of eight Caucasian subjects, it consistently increased during and following stress in 10 out of 13 Pima Indians. Fasting serum glucose in Pima Indians and Caucasians was respectively 5.07 + 0.08 mM and 5.04 + 0.09 mM. Two-hour post-prandial values were 5.63 + 0.22 mM and 5.48 + 0.19 mM respectively, whereas post-stress values were 6.15 + 0.19 mM for Pima Indians and 5.22 + 0.20 mM for Caucasians. Both serum glucose means following stress (t = 3.1, P < 0.005) and the direction of change in serum glucose in response to mental arithmetic (chi 2 = 8.2, P < 0.01) clearly differentiated Pimas from Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

GBR12909 stimulates hypothalamo-pituitary-adrenal activity by inhibition of uptake at hypothalamic dopamine neurons.

We have previously demonstrated that the inhibition of neurotransmitter uptake at dopamine (DA) terminals stimulates the hypothalamo-pituitary-adrenal axis. In the present study we investigated the role of central DA neuronal systems in the regulation of this axis. Administration of the DA uptake inhibitor GBR12909 (3-30 micrograms) into the third ventricle dose-dependently elevated serum adrenocorticotropin hormone (ACTH) levels in rats. GBR12909 (10 micrograms) elevated serum ACTH levels following administration into the paraventricular nucleus of the hypothalamus but not into the lateral ventricle. The administration of 6-OHDA into the third ventricle significantly decreased DA content in the hypothalamus and striatum and significantly attenuated the ACTH response to GBR12909 (10 micrograms, third ventricle or 10 mg/kg, i.p.). Conversely, 6-OHDA lesions of the medial forebrain bundle, which depleted 99% of DA in the caudate but did not decrease DA content in the hypothalamus, and did not attenuate the ACTH response to i.p. GBR12909. Measurement of GBR12909-induced inhibition of [3H]DA uptake into synaptosomal preparations indicates the presence of GBR12909-sensitive DA transporters in the region of the hypothalamus surrounding the third ventricle. The present findings suggest that an endogenous DA neuronal system terminating in the hypothalamus mediates the effects of stimulants on hypothalamo-pituitary-adrenal function and might play a role in the ongoing regulation of hypothalamo-pituitary-adrenal activity.

Adrenocorticotropic Hormone↗
PubMed1993

Maternal separation in neonatal rats elicits activation of the hypothalamic-pituitary-adrenocortical axis: a putative role for corticotropin-releasing factor.

Stress elicits activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Hypothalamic neurohormones, including corticotropin-releasing factor (CRF), control and promote ACTH secretion and subsequent glucocorticoid synthesis and release. The neonatal rat has been shown to be relatively hyporesponsive to certain stressors, generating a blunted or unmeasurable hormonal response. In this study, the endocrine response of 10- and 18-day-old Sprague-Dawley rat pups to maternal separation, a naturalistic stressor, was examined. Ten-day pups subjected to maternal separation exhibited a significant reduction in median eminence CRF concentration at 24 h, with no change in pituitary CRF receptor number; in 18-day pups there was no significant change in median eminence CRF concentration by 24 h, but there was a decrease in CRF receptor binding. In adult rats subjected to stressors, an acute decrease in CRF concentration in the median eminence occurs, followed by CRF receptor downregulation with sustained stress. The results observed in the 18-day pups vs. the 10-day pups likely reflects a maturation of the HPA axis response to "stressors."

Animals↗
PubMed1993

Hypertension in CB57BL/6J mouse model of non-insulin-dependent diabetes mellitus.

The C57BL/6J (BL/6) mouse develops non-insulin-dependent diabetes mellitus (NIDDM) when fed a high fat-high simple carbohydrate (HFHSC) diet, whereas A/J mice do not. The purpose of the study was to determine whether hypertension occurred with NIDDM and whether it was sustained by sympathetic nervous system (SNS) hyperactivity. After 3 mo on an HFHSC diet with a low Na content (0.06%), awake, tail-cuff systolic blood pressure (BP) increased 20% above the control diet in BL/6 (138 +/- 3 vs. 115 +/- 4) but not in A/J (115 +/- 6 vs. 113 +/- 2 mmHg) mice. On a normal Na (0.4%)-HFHSC diet, BL/6 mice had a higher BP than on 0.06% Na (149 +/- 3 at 3 mo, 162 +/- 6 at 4.5 mo). After 1 mo on the 0.06% Na-HFHSC diet, direct BP of anesthetized BL/6 mice was 18% higher than control. The hypotensive response to interruption of SNS activity by ganglionic blockade (chlorisondamine) increased in the BL/6 mice (50%), whereas the heart rate response increased in both strains (20-30%). Analysis of variance (ANOVA) on glucose detected significant effects of strain and diet and a strain x diet interaction (P = 0.0007). At 1 or 3 mo, HFHSC-fed BL/6 mice were hyperglycemic (> 11 mM) compared with diet or strain controls. The ANOVA on insulin detected strain and diet effects but not a strain x diet interaction (P = 0.3). HFHSC increased insulin above the control of 140-160 pM in A/J and BL/6 strain (20-70% at 1 mo, 400% at 3 mo).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1992

Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam.

Populations of dopamine (DA) neurons in the rat brain are selectively activated by stress, and the response is attenuated by the administration of anxiolytics. Given the role of the component nuclei of the amygdaloid complex in conditioned associations, stress responses and the anxiolytic effects of benzodiazepines, we hypothesized that particular mesoamygdaloid DA projections might be especially sensitive to the effects of conditioned stress and to diazepam (DZ). We mapped the effect of a conditioned stressor on the concentration of the DA metabolite homovanillic acid (HVA) in distinct amygdaloid nuclei and other brain nuclei and areas and the effect of DZ (1 or 3 mg/kg) on the conditioned response in drug-experienced subjects. The conditioned stress paradigm resulted in significant elevations in classical indices of stress, including serum corticosterone and plasma epinephrine. Conditioned stress-induced increases in the estimated activity of DA neurons were specific for DA neurons projecting to the central, basolateral and lateral amygdaloid nuclei, and for DA projections to the dorsal septal nucleus. Conditioned stress-induced increases in the HVA concentration of responsive amygdaloid nuclei were antagonized by low, anxiolytic doses of DZ. These results indicate a role for a subset of mesoamygdaloid DA projections in transducing the impact of perceived stressors on the output of the amygdaloid complex. A role for particular amygdaloid DA projections in the formation of conditioned fear or anticipatory anxiety and its modulation by anxiolytics is also suggested.

Amygdala↗
PubMed1992

Menstrual cycle effects on caffeine elimination in the human female.

Increases in the levels of sex steroids due to pregnancy or oral contraceptive steroid use are known to decrease significantly the rate at which caffeine is eliminated from the body. An investigation has now been made into whether the changes in sex steroid levels that occur during normal menstrual cycling also affect the rate of caffeine elimination, especially whether hormonal shifts in the luteal phase are associated with slower elimination of caffeine. Repeated 24-hour caffeine elimination studies were conducted during the follicular and luteal phases of the menstrual cycle in 10 healthy women. Comparisons of the follicular and luteal phases revealed that systemic clearance of caffeine was slower in the luteal phase, although the t1/2 did not differ. The slowing effect was related to the proximity to onset of menstruation and to levels of progesterone. The evidence suggests that caffeine elimination may be slowed in the late luteal phase, prior to the onset of menstruation. Such a reduction would lead to increased accumulation of caffeine with repeated self-administration during the day, but the effect may be too small to be of clinical significance in the majority of women.

Administration, Oral↗
PubMed1992

Chronic administration of U50,488H fails to produce hypothalamo-pituitary-adrenal axis tolerance in neonatal rats.

The present study investigated the effect of chronic administration of a kappa opioid receptor agonist on the function of kappa and mu opioid, serotonergic and cholinergic regulation of secretion from the hypothalamo-pituitary-adrenal axis in neonatal rats. After chronic treatment with saline or U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide methane sulfonate), a kappa opioid receptor agonist and subsequent pharmacological challenge, corticosterone (CS) in serum was determined. Kappa tolerance did not develop in pups treated on postnatal days 5-9 with increasing doses of U50,488H (0.5-2.5 mg/kg). When the rats were treated with the same chronic regimen of U50,488H at different stages of development from birth through weaning, only weanling rats became tolerant to U50,488H. In the absence of measurable kappa tolerance, the responses of corticosterone in serum to morphine, quipazine, a serotonin receptor agonist and physostigmine, an inhibitor of acetylcholinesterase, were attenuated in neonatal rats, treated with U50,488H. These studies suggest that kappa tolerance is more difficult to induce in developing rats than in adults and that regulation of the function of the hypothalamo-pituitary-adrenal axis by other neurotransmitter systems is altered by treatment with kappa opioid receptor agonists, even in the apparent absence of tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

D1 and D2 dopamine receptors stimulate hypothalamo-pituitary-adrenal activity in rats.

A stimulatory role for endogenous dopamine (DA) in the regulation of hypothalamo-pituitary-adrenal activity has previously been demonstrated. In the present study, the roles of D1 and D2 subtypes of DA receptors in the regulation of activity of the hypothalamo-pituitary-adrenal axis were investigated. The intraperitoneal administration of either the D1 agonist, SKF 383393 (1-phenyl-2,3,4,5 tetrahydro-(iH)-benzazepine-7,8diol HCl, 5-20 mg/kg) or the D2 agonist quinpirole (0.05-1 mg/kg) dose-dependently elevated both adrenocorticotropic hormone (ACTH) and corticosterone (CS) in serum. Similarly, administration of either SKF 38393 or quinpirole (1-100 micrograms) into the third ventricle dose-dependently elevated ACTH in serum. The response of ACTH to intraperitoneal SKF 38393 was blocked by pretreatment with the D1 antagonist SCH 23390 (1-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5 tetrahydro-1H-3-benzazepine, 0.25 mg/kg, i.p.) but not by the D2 antagonist sulpiride (50 mg/kg, i.p.). The response of ACTH to intraperitoneal injection of quinpirole was blocked by pretreatment with sulpiride and attenuated slightly by pretreatment with SCH 23390. Further, the co-administration of sub-maximum doses of SKF 38393 and quinpirole caused additive increases in ACTH in serum. These results suggest that both D1 and D2 subtypes of DA receptors contribute to the dopaminergic regulation of function of the hypothalamo-pituitary-adrenal axis and support a role for DA neurons in the hypothalamus in this response. Further, these findings suggest that the D1 and D2 receptors, mediating the response of the hypothalamopituitary-adrenal axis are not tightly coupled.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

The effects of liver denervation on the regulation of hepatic biliary secretion.

Effects of liver denervation on bile formation were studied in eight dogs prepared with chronic biliary fistulas. The animals were studied in the basal state, after feeding, and during infusion of glucagon 50 ng/kg/min, secretin 2 U/kg/hr, or somatostatin 200 ng/kg/min. After this first set of experiments the animals underwent a total hepatic denervation that consisted of section of the hepatic ligaments and a careful dissection of the portal vein, hepatic artery, and common duct with stripping of all the surrounding connective tissue and topical application of phenol. The above experiments were then repeated. Denervation did not modify bile flow, or bile salts, cholesterol, or phospholipid concentration or output. Biliary response to glucagon and secretin was similar before and after denervation. Somatostatin had an anticholerectic effect in both intact and denervated animals, but significantly reduced bile salt output only in the intact dogs. Feeding had a choleretic effect pre- and postdenervation, and the infusion of somatostatin following feeding decreased bile flow to the same degree before and after denervation. In the intact animals the output of all three biliary lipids was reduced by somatostatin after feeding but they were unaffected by somatostatin after denervation. Moreover, cholesterol and phospholipid outputs were stable after feeding in intact animals, but significantly decreased after denervation. 14C-erythritol clearance studies indicated no change in the canalicular component of bile flow with denervation, except again during somatostatin suppression of feeding. These data indicate that basal bile flow is normal after denervation but that innervation may play an important role in the modulation of responses to somatostatin and more complex stimuli such as feeding.

Animals↗