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C H McIntosh

Publications and source records attributed to C H McIntosh.

At least 37 records · Page 2Linked to original sources
PubMed1998

Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.

Animals↗
PubMed1997

GIP(6-30amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro.

GIP (Glucose-dependent Insulinotropic Polypeptide) is an important regulator of insulin secretion. The effects of truncated forms of the peptide, GIP(10-30), GIP(6-30amide) and GIP(7-30), on binding of 125I-GIP(1-42) to GIP receptors in transfected CHO-KI cells, and on cyclic AMP responses to GIP(1-42), have been studied with a view to defining further the receptor binding region of GIP, and to establish whether such truncated peptides exhibit agonist or antagonist activity. All three peptides were found to be receptor antagonists, however GIP(6-30amide) exhibited receptor binding affinity equivalent to that of GIP(1-42) in competitive binding studies (IC50 = 3.08+/-0.57 nM). GIP(6-30amide) inhibited GIP(1-42)-induced cAMP production by 58% at a concentration of 100 nM, whereas GIP(10-30) and GIP(7-30), inhibited only in the microM range. GIP(6-30amide) therefore contains the high affinity binding region of GIP and is a potent inhibitor of GIP(1-42) action in vitro.

Animals↗
PubMed1997

Localization of the domains involved in ligand binding and activation of the glucose-dependent insulinotropic polypeptide receptor.

The receptors for the two structurally related insulinotropic hormones Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) share approximately 40% sequence identity and demonstrate complete specificity for their endogenous ligands, while utilizing similar second messenger pathways. In the current study chimeric GIP-GLP-1 receptors were prepared, and the effect of domain-exchange on ligand binding and adenylyl cyclase activation examined. A chimera (CH-2) consisting of the first 132 amino acids of the external N-terminal (NT) domain bound 125I-GIP with high affinity (27.77 +/- 11.85 nM). However, for receptor coupling to cAMP production it was necessary to extend the NT into the first transmembrane (TM-1) region (CH-3: IC50 = 9.04 +/- 1.07 nM; EC50 = 17.1 +/- 3.5 nM). A chimera which included part of TM-3 (CH-4) demonstrated binding and signalling (IC50 = 8.33 +/- 0.14 nM; EC50 = 467.5 +/- 173.6 pM) similar to the wild type receptor (IC50 = 1.33 +/- 0.19 nM; EC50 = 497.9 +/- 211.7 pM). Surprisingly constructs CH-2 and CH-3, while devoid of detectable 125I-GLP-1 binding, were capable of eliciting GLP-1-specific cAMP production (EC50s CH-2 = 81.4 +/- 19.6 nM; CH-3 = 5.99 +/- 0.68 nM) suggesting that receptor activation is not completely dependent on high affinity receptor binding. These data clearly demonstrate that the NT domain of the GIP receptor acts as the ligand-specific binding domain and that the first transmembrane domain is important for receptor activation.

Adenylyl Cyclases↗
PubMed1996

Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach.

The incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and glucagon-like peptide-1-(7-36)-amide (GLP-17-36), hormones that potentiate glucose-induced insulin secretion from the endocrine pancreas, are substrates of the circulating exopeptidase dipeptidyl peptidase IV and are rendered biologically inactive upon cleavage of their N-terminal dipeptides. This study was designed to determine if matrix-assisted laser desorption/ionization-time of flight mass spectrometry is a useful analytical tool to study the hydrolysis of these hormones by dipeptidyl peptidase IV, including kinetic analysis. Spectra indicated that serum-incubated peptides were cleaved by this enzyme with only minor secondary degradation due to other serum protease activity. Quantification of the mass spectrometric signals allowed kinetic constants for both porcine kidney- and human serum dipeptidyl peptidase IV-catalyzed incretin hydrolysis to be calculated. The binding constants (Km) of these incretins to purified porcine kidney-derived enzyme were 1.8 +/- 0.3 and 3.8 +/- 0.3 microM, whereas the binding constants observed in human serum were 39 +/- 29 and 13 +/- 9 microM for glucose-dependent-insulinotropic polypeptide and glucagon-like peptide-1-(7-36)-amide respectively. The large range of Km values found in human serum suggests a heterogeneous pool of enzyme. The close correlation between the reported kinetic constants and those previously described validates this novel approach to kinetic analysis.

Animals↗
PubMed1996

Isolation of a murine glucose-dependent insulinotropic polypeptide (GIP) cDNA from a tumor cell line (STC6-14) and quantification of glucose-induced increases in GIP mRNA.

A 537 base pair cDNA clone for murine GIP has been isolated. The elucidated sequence encodes an open reading frame of 432 base pairs which codes for a 144 amino acid precursor. Murine GIP is predicted to differ from the human hormone by three amino acid substitutions: arginine for histidine at position 18, arginine for lysine at position 30 and serine for lysine at position 34. GIP mRNA levels in STC6-14 cells incubated in the presence of varying glucose concentrations was investigated using a competitive-PCR method. In the presence of a 5-mM glucose stimulus, 1 x 10(5) GIP cells were found to contain 3.9 +/- 0.59 amol of GIP mRNA while the same number of cells contained 11.6 +/- 1.4 amol when subjected to a high (25 mM) glucose stimulus.

Amino Acid Sequence↗
PubMed1996

The enteroinsular axis in dipeptidyl peptidase IV-negative rats.

Evidence has accumulated that the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1(7-36) amide) are degraded and rendered biologically inactive in plasma by the enzyme dipeptidyl peptidase IV (DPIV). A strain of Fischer rats lacking the DPIV enzyme were used in the current investigation as a model for examining the enteroinsular axis under conditions in which normal inactivation of GIP and GLP-1(7-36) does not occur. This was assessed by comparing GIP and GLP-1(7-36) responses following oral glucose in normal versus DPIV-deficient Fischer rats, and by comparing the insulinotropic potency of both peptides in the perfused pancreas of both groups. The insulin response to an oral glucose challenge was decreased slightly in DPIV-negative rats compared with control animals. Of the two incretins, the GIP response to oral glucose was reduced by 50% compared with controls, whereas GLP-1(7-36) release in response to glucose was unchanged. A decrease of 30% in the sensitivity of the perfused pancreas of DPIV-negative rats to GIP was observed, whereas the insulin response to GLP(7-36) was identical in both groups. Incubation of both peptides in plasma from DPIV-positive and -negative rats was performed to determine the effect of the presence or absence of DPIV on the insulinotropic activity of GLP-1(7-36) and GIP in the isolated perfused rat pancreas. Incubation in plasma from DPIV-positive rats resulted in a 65% decrease in insulinotropic activity of both incretins compared with incubation in plasma from DPIV-deficient rats. It was hypothesized that the reduced GIP response and decreased sensitivity of the pancreas to GIP are compensatory mechanisms that maintain insulin and glucose levels within a normal range despite abnormal degradation of GIP. An explanation of the lack of effect of the absence of DPIV on the GLP-1(7-36) response to oral glucose and insulinotropic action of this peptide must await further study.

Animals↗
PubMed1996

The insulinotropic region of gastric inhibitory polypeptide; fragment analysis suggests the bioactive site lies between residues 19 and 30.

Glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide (GIP) is a 42 amino acid intestinal hormone, which exhibits several direct and indirect effects on fat and glucose metabolism. To determine the bioactive region(s) of the molecule, synthetic and proteolytic fragments of the hormone were generated and tested for their ability to induce a biological response in the isolated, perfused rat pancreas and stomach. A synthetic fragment corresponding to porcine GIP residues 1-30 retained strong insulinotropic activity in the isolated, perfused rat pancreas but greatly reduced somatostatinotropic activity in the isolated perfused rat stomach. A synthetic fragment corresponding to porcine GIP residues 15 to 30 was biologically inactive. However, enterokinase treatment of the synthetic 15-30 fragment restored partial insulinotropic activity in the isolated, perfused rat pancreas. The hypothesis that the restoration of biological activity was due to the enzymatic removal of the amino-terminal dipeptide (Asp-Lys) of GIP15-30 was supported by the observation that a synthetic fragment lacking these two residues was also insulinotropic. Further fractionation of the molecule generated a biologically active 19-30 fragment, suggesting that the residues necessary for the insulin response are contained within this region.

Animals↗
PubMed1995

Effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-I-(7-36) on insulin secretion.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-I-(7-36) are probably the most important "incretins," but there is controversy as to their relative insulinotropic activities. The effects of natural (np) and synthetic porcine (sp) GIP, synthetic human (sh) GIP, and GLP-I-(7-36) on insulin secretion from the perfused rat pancreas were compared using gradient perfusion. Insulin secretion was increased by both spGIP and GLP-I-(7-36) at concentrations of approximately 16 pM. Maximal responses to GLP-I-(7-36) in the presence of 16.7 mM glucose were slightly greater than with npGIP or spGIP, but with 10 mM glucose spGIP and GLP-I-(7-36) exerted equivalent effects. Responses to shGIP were greatly reduced compared with spGIP. In the presence of 50 pM spGIP or GLP-I-(7-36) the glucose threshold was 4.5 +/- 0.11 mM. The data indicate that GLP-I-(7-36) and porcine GIP are equally insulinotropic and share the same glucose threshold for activity, whereas shGIP is less active. At the concentrations found postprandially, however, GIP is likely to be the more important incretin.

Animals↗
PubMed1995

Gastric inhibitory polypeptide release from a tumor-derived cell line.

A cell line derived from intestinal tumors of transgenic mice (STC-1) was subcloned to produce a stable line with approximately 30% immunoreactive gastric inhibitory polypeptide (irGIP)-containing cells (STC 6-14). High-performance liquid chromatography (HPLC) of STC 6-14 extracts indicated that the tumor cell-derived irGIP had the same retention time as synthetic porcine GIP-(1-42) (pGIP). Approximately 30% of the cells also contained immunoreactive somatostatin (irSS), which eluted as a single peak on HPLC, corresponding with SS-(1-14). On average, each well of extracted cells (5.0 x 10(5) cultured 4 days) contained 33.3 +/- 1.4 ng irGIP and 18.4 +/- 1.5 ng irSS. Basal release of irGIP in the presence of 5 mM glucose was 733 +/- 58 pg.ml cells-1.2h-1 (2.20 +/- 0.17% of total cell content; TCC) and doubled at 20 mM glucose (4.20 +/- 0.42% TCC). The response to glucose was augmented by addition of a SS neutralizing antibody (SOMA-10) and suppressed by 10 nM SS. Basal release of irSS in 5 mM glucose was 377 +/- 35 pg.ml cells-1.2h-1 (2.05 +/- 0.19% TCC) and was increased by glucose (> or = 15 mM) and the addition of pGIP (> or = 1 nM). The STC 6-14 cell line represents a model to study the synthesis, storage, and release of GIP and SS in a controlled environment.

Animals↗
PubMed1995

Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties.

Incretins are endogenous peptides released from the gastrointestinal tract into the circulation during a meal that potentiate glucose-stimulated insulin secretion. At present, there are two established incretins: glucose-dependent insulinotropic polypeptide (GIP) and the truncated glucagon-like peptides (tGLPs), which are now being investigated for use in the treatment of diabetes mellitus. In the present study we cloned a rat islet GIP receptor complementary DNA (GIP-R1) to answer several important questions regarding the ligand-binding and intracellular signaling properties of the GP receptor. GIP-R1, when expressed transiently in monkey kidney (COS-7) or stably in Chinese hamster ovary (CHO-K1) cells, demonstrated comparable high affinity binding for either synthetic porcine (sp) GIP or synthetic human (sh) GIP. The IC50 values for displacement of [125I]spGIP in CHO-K1 cells were 2.6 +/- 0.8 and 3.1 +/- 0.9 nM for two different preparations of shGIP, and 3.7 +/- 1.5 and 3.6 +/- 0.4 nM for two preparations of spGIP. Saturation isotherms obtained with both intact cells and membranes gave monophasic binding curves with apparent Kd values of 204 +/- 17 and 334 +/- 94 pM, respectively. Cells expressed 12-15 x 10(3) receptors/cell. In COS-7 cells, spGIP and shGIP also exhibited similar IC50 values (7.6 +/- 1.2 and 8.9 +/- 1.8 nM, respectively). The receptor in CHO-K1 cells bound GIP-(1-30) with lower affinity (IC50 = 39 +/- 17 nM), whereas the fragments GIP-(19-30), GIP-(18-28), and GIP-(21-26) showed no apparent binding. The specificity of the receptor was further examined using several structurally related peptides. Surprisingly, exendin-(9-39) [Ex-(9-39)], a GLP-1 receptor antagonist, and Ex-4-(1-39), a GLP-1 receptor agonist, demonstrated some affinity for the GIP receptor, with 39% and 21% displacement of [125I]spGIP, respectively, at 1 microM. Other members of the secretin/vasoactive intestinal peptide family of peptides tested showed no interaction. GIP-R1 receptor binding correlated with activation of the adenylyl cyclase system, whereby spGIP and shGIP evoked concentration-dependent increases in cAMP accumulation with EC50 values of 8.7 +/- 1.5 x 10(-10)M and 8.1 +/- 1.6 x 10(-10)M for spGIP and shGIP, respectively. Increases in cAMP in the presence of 10 nM spGIP were not dependent on the ambient glucose concentration, with 22- and 18-fold increases in cAMP accumulation at 0.1 and 5.5 mM glucose, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.

The combined actions of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) may fully account for the incretin effect. These hormones are released from the small intestine in response to oral glucose and stimulate insulin release. Recently, evidence has been provided demonstrating the degradation of GIP-(1-42) and GLP-1-(7-36)NH2 by the serum enzyme dipeptidyl peptidase IV (DPP IV) into the biologically inactive products GIP-(3-42) and GLP-1-(9-36)NH2. The objective of the current investigation was to develop a method to monitor the degradation of these hormones in vivo. Synthetic peptides were radiolabeled and purified by HPLC. Subsequent degradation of the peptides under various conditions was then monitored by further HPLC analysis. Incubation of [125I]GIP-(1-42) or [125I]GLP-1-(7-36)NH2 with Wistar rat serum or purified DPP IV resulted in the major N-terminal-truncated products [125I]GIP-(3-42) and [125I]GLP-1-(9-36)NH2. These products were significantly reduced when the specific DPP IV inhibitor diprotin A was included in the incubation mixture and were absent when serum from DPP IV-deficient rats was used. When the labeled peptides were infused into rats at hormone levels within the physiological range, over 50% was metabolized to the truncated forms within 2 min. These products were absent when the tracers were infused into DPP IV-deficient animals. It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo. As the N-terminal-truncated products of the DPP IV cleavage may not be distinguished from the biologically active hormone by currently employed assays, reports of circulating hormone levels should be reconsidered. The method described in this manuscript may be useful for investigating the durations of action of GIP and tGLP-1 in normal and pathophysiological conditions.

Animals↗
PubMed1995

Altered glucose dependence of glucagon-like peptide I(7-36)-induced insulin secretion from the Zucker (fa/fa) rat pancreas.

In previous studies on the enteroinsular axis in Zucker rats, it was found that glucose-dependent insulinotropic polypeptide (GIP) levels were normal in obese animals, but the glucose threshold for the insulinotropic action of GIP in the perfused rat pancreas was reduced. Glucagon-like peptide I (GLP-I)(7-36) is also an important incretin, and in the current study, glucose, insulin, and immunoreactive (IR)-COOH-terminal GLP-I responses to oral glucose were compared in lean (Fa/?) and obese (fa/fa) rats. In addition, the concentration thresholds for stimulation and glucose dependence of perfused pancreases to GLP-I(7-36) were examined. Glucose responses to oral glucose were similar in fa/fa and Fa/? rats. Obese animals were hyperinsulinemic when fasting and after oral glucose. Significant increases in IR-GLP-I levels in response to glucose were only observed in fa/fa rats. Perfused pancreases from fa/fa rats hypersecreted insulin at all glucose concentrations. In the presence of 4.4 mmol/l glucose, GLP-I(7-36) increased insulin secretion in fa/fa pancreases approximately 25-fold, whereas there was only a 5-fold increase in Fa/? pancreases. Pancreases from fa/fa rats, perfused with a glucose gradient (2.8-11 mmol/l) in the presence of GLP-I(7-36), responded with an immediate increase in insulin secretion, i.e., at a glucose concentration of 2.8 mmol/l, whereas Fa/? pancreases required a minimum of 4.22 mmol/l glucose for stimulation. With high glucose (16.7 mmol/l), both fa/fa and Fa/? rat pancreases exhibited similar responsiveness to GLP-I(7-36), having thresholds of < 50 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Gastric inhibitory polypeptide and glucagon-like peptide-1(7-36) amide exert similar effects on somatostatin secretion but opposite effects on gastrin secretion from the rat stomach.

Previous studies on the isolated perfused stomach have shown that gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(7-36) amide (GLP-1(7-36) amide) stimulate release of somatostatin (somatostatin-like immunoreactivity, SLI). GIP produced a paradoxical increase in gastrin secretion, whereas GLP-1(7-36) was inhibitory. In the current study, the actions of synthetic (sp) and native (np) porcine and synthetic human (sh) GIP, GLP-1(7-36), and GLP-1(7-37) on SLI and gastrin secretion were compared using a gradient perfusion of peptide. All peptides increased SLI secretion at a threshold concentration of approximately 50 pmol/L (p < 0.05). The initial rate of increase in response to spGIP (119 +/- 39 pg/min) was greater than with other forms of GIP or GLP-1. Maximal increases obtained with the two porcine peptides did not differ. Gastrin secretion was increased by concentrations of spGIP and npGIP similar to those increasing SLI secretion, but the maximal response to shGIP was lower. In contrast to GIP-induced increases, both GLP-1(7-36) and GLP-1(7-37) suppressed gastrin secretion. It is concluded that human and porcine GIP, GLP-1(7-36), and GLP-1(7-37) all stimulate SLI secretion but with different maximal effects, and GIP stimulates gastrin secretion whereas both forms of GLP-1 inhibit gastrin secretion.

Animals↗
PubMed1994

Characterization of acetylcholine-induced increases in cytosolic free calcium concentration in individual rat pancreatic beta-cells.

The intracellular free Ca2+ ion concentration ([Ca2+]i) was measured using fura-2 microspectrofluorimetry in individual rat pancreatic beta-cells prepared by enzymatic digestion and fluorescence-activated cell sorting. The mean basal concentration of [Ca2+]i in beta-cells in the presence of 4.4 mM glucose and 1.8 mM Ca2+ was 112 +/- 1.6 nM (n = 207). The action of acetylcholine (ACh) was concentration-dependent, and raising the concentration resulted in [Ca2+]i spikes of increasing amplitude and duration in some, but not all of the beta-cells. In addition, the beta-cells demonstrated variable sensitivity to ACh. The increases in [Ca2+]i were rapid, transient and were blocked by atropine at 10(-6) M. A brief exposure to 50 mM K+ resulted in a transient increase in [Ca2+]i similar to that induced by ACh, but resistant to atropine. A high concentration of ACh (100 microL 10(-4) M or 10(-3) M) induced [Ca2+]i oscillations in 11 out of 57 beta-cells in the presence of 4.4 mM glucose. Using calcium channel blockers and Ca2+ free medium, the source of the increase in [Ca2+]i was deduced to be from extra-cellular spaces. Changing the temperature from 22 to 37 degrees C did not affect the action of ACh on [Ca2+]i. These data strongly suggest that ACh exerted a direct action on [Ca2+]i in normal rat pancreatic beta-cells and support a role for Ca2+ as a second messenger in the action of ACh.

Acetylcholine↗
PubMed1993

The release of somatostatin-14 from human submucosal ganglia in tissue culture.

A dispersed culture of cells from the submucous plexus of the human small intestine has been developed to examine the localization, release, and molecular characteristics of somatostatin immunoreactivity. Forty percent of the submucosal neurones per ganglion in tissue sections and 35% of cells per group of cells in culture contained somatostatin immunoreactivity. Acetic acid extracts of culture contained 1990 +/- 809 pg somatostatin immunoreactivity/10(6) cells. Incubation of cultures with phorbol 12-myristate 13-acetate (beta PMA), an activator of protein kinase C, at concentrations up to 10(-6) M for 120 min increased the release of somatostatin immunoreactivity by up to 23 times the basal level, and up to 27 times the basal level when extracellular K+ was increased from 5 to 10 mM. Of the total somatostatin immunoreactivity released in response to beta PMA (10(-6) M, 10 mM K+), 59% was present in the medium after 30 min and 80% after 60 min. Basal release of somatostatin immunoreactivity could be reliably measured only after 120 min. The release of somatostatin immunoreactivity by beta PMA was not due to nonspecific membrane effects, since the inactive 4 alpha-phorbol at the same concentrations did not alter basal release. Greater than 90% of somatostatin immunoreactivity present in acid extracts of cultures and released by beta PMA eluted with the same retention time as synthetic somatostatin-14 on reverse-phase high-performance liquid chromatography.

Adult↗
PubMed1992

Chronic naltrexone treatment of rats: effects on gastrointestinal opioid peptide content.

The gastrointestinal tract contains immunoreactive enkephalins and beta-endorphin. The objective of the current study was to determine whether chronic treatment of rats with naltrexone altered the gastrointestinal tissue content of these opioid peptides. Opioid activity measured by radioreceptor assay was detectable throughout the gastrointestinal tract. There were regional differences in the [Met5]enkephalin: [Leu5]enkephalin-immunoreactivity (IR) ratios, possibly due to cell specific differential processing of precursor molecules or degradation of the peptides. Chronic naltrexone treatment increased opioid activity in the duodenum and jejunum, decreased [Met5]enkephalin-IR in the duodenum and [Leu5]enkephalin-IR in the gastric corpus, and increased beta-endorphin-IR in the duodenum. However, the changes were small, and it is unlikely that any functional changes resulting from naltrexone treatment can be reliably ascribed to such changes in tissue content.

Animals↗