Department of Surgery, Kurume University, School of Medicine, Kurume 830, Japan
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ABSTRACT |
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Fentanyl citrate analgesia attenuates the excess
nitrogen excretion in the urine and glucose production induced by
trauma. On the other hand, intracerebroventricular injection of
morphine stimulates excretion of stress hormones, such as
catecholamines and corticosterone. Furthermore, morphine levels in the
brain are increased during fasting and sepsis. The aims of this study were to determine whether intracerebroventricular injection of tumor
necrosis factor- (TNF-
) elevates morphine levels in the rat brain
and whether prophylactic administration of fentanyl blocks metabolic
responses induced by intracerebroventricular injection of TNF-
because of a reduction of morphine levels in the brain. Morphine levels
in the brain were increased from 648 to 1,134 fmol/g at 30 min after
intracerebroventricular injection of TNF-
(P < 0.05 vs. control). This
increase was associated with an increase in stress hormones
(corticosterone: 416.1 ± 69.1 ng/ml,
P < 0.05 vs. control; epinephrine:
3,778.3 ± 681.3 pg/ml, P < 0.01 vs. control) and an enhancement of proteolysis (254.2 ± 45.7 µmol
Leu · kg
1 · h
1,
P < 0.01 vs. control) and glucose
production (7.5 ± 0.7 mg · kg
1 · min
1,
P < 0.05 vs. control). Fentanyl
reduced morphine levels in the brain to 624 fmol/g (not significant vs.
control), resulting in a reduction of stress hormone levels in the
plasma and blunted metabolic responses. In conclusion, prophylactic
administration of fentanyl prevented an increase in morphine levels in
the brain induced by intracerebroventricular injection of TNF-
,
leading to a reduction in stress hormone levels and subsequent
metabolic responses.
protein turnover; glucose turnover; cytokine
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INTRODUCTION |
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CHANGES IN THE HORMONAL MILIEU after a surgical insult cause a loss of protein (9) and an enhancement of glucose production (5). An important factor in the activation of the hypothalamic-pituitary-adrenal axis is pain at the wound site (19). Indeed, morphine analgesia can block releases of adrenocorticotropic and growth hormones in humans at the hypothalamic level (12), and epidural analgesia improved nitrogen balance after abdominal surgery (38).
Fentanyl is a phenylpiperidine derivative, a synthetic narcotic. Fentanyl-oxygen analgesia produces greater cardiovascular stability and no venovasodilation compared with morphine (34). We have previously reported that systemic fentanyl anesthesia reduced postoperative interleukin (IL)-6 levels and cortisol excretion, resulting in greater nitrogen balance than conventional anesthesia alone (43). Furthermore, Anand et al. (2) reported that high doses of sufentanil analgesia during surgery reduced the hyperactivity of the hypothalamic functions, leading to a decrease in surgical complications and morbidity rate in neonates undergoing cardiac surgery. In addition to decreasing the protein loss and improving clinical outcome, we showed that fentanyl analgesia reduced glucose production and was associated with a lower level of stress hormones after trauma than pentobarbital anesthesia in rats (40).
In contrast to analgesia with morphine and fentanyl during surgery, Molina et al. (23) demonstrated that 1 µg/h of morphine injection into the cerebroventricular space of unstressed rats led to the excretion of stress hormones and an increase in glucose production compared with rats receiving an intracerebroventricular injection of saline. In addition to these observations, they found that fasting and sepsis increased morphine levels in the brain (24, 26).
Cytokines such as tumor necrosis factor (TNF), IL-1, and IL-6 have been shown to initiate cachexia found in sepsis, surgical trauma, and the presence of tumor (13, 17, 35). The central neuroendocrine response initiated by cytokines is partially involved in protein-losing processes, because intracerebroventricular injection of either TNF or IL-1 induces excretion of stress hormones, such as cortisol, catecholamine, and glucagon in a similar manner to morphine, resulting in a loss of body weight and an associated increase in glucose production (4, 30).
The aims of this study were to determine whether morphine in the brain
was involved in the metabolic changes induced by
intracerebroventricular injection of TNF- and whether prophylactic
fentanyl citrate administration prevented an increase in morphine
levels in the brain, resulting in prevention of a loss of protein and a
subsequent increase in glucose production induced by
intracerebroventricular administration of TNF-
.
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METHODS |
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Animal preparation and experimental protocol. Male Sprague-Dawley rats (n = 163, body weight: 225-250 g) were purchased from the Kuroda Animal Facility Center (Kumamoto, Japan) and housed in the animal facility of Kurume University under the condition of a 12:12-h light-dark cycle. The animals were fed standard rat chow (Clea, Tokyo, Japan) and water ad libitum for 7 days before the insertion of catheters into the lateral ventricular space and jugular vein. The experimental protocol was approved by the Kurume University Ethical Committee.
On day 0, the rats were anesthetized with an intramuscular injection of pentobarbital sodium (50 mg/kg, Dainippon Pharmaceutical, Tokyo, Japan) and positioned in a stereotaxic apparatus (Neuro Science, Tokyo, Japan). The skin and connective tissues were removed from the skull, a hole was drilled, and a 24-gauge cannula (Terumo, Tokyo, Japan) was placed into the unilateral ventricle by use of stereotaxic coordination: 0.3 mm posterior to bregma, 1.3 mm lateral from the midline, and 4.25 mm below the surface of the skull. The cannula was secured with dental cement (Hy-bond Glasionomer CX, Shofu, Kyoto, Japan) and anchored to the skull with two stainless steel screws. After the cannulation into the lateral ventricular space, the catheter was inserted into the jugular vein for administration of fentanyl citrate and total parenteral nutrition (TPN) solutions as described previously (41, 44). The rats were placed in the individual metabolic cages and maintained on standard rat chow and water ad libitum for 5 days. On day 4, food was removed from the metabolic cages to eliminate gut absorption of glucose and amino acids as sources of glucose and leucine appearance from the gut. TPN was begun with a half-strength solution for the next 12 h to allow the animals to adapt to TPN, and a full-strength diet (10.4 kcal · kgAnalytic procedures and measurements. The specific activity of plasma glucose was measured as described previously (40). The specific activity of [1-14C]leucine in supernatant and protein of muscle and plasma was measured as described previously (42, 44). Briefly, sulfosalicylic acid (4%, 3 ml, Wako Pure Chemical, Osaka, Japan) was added to plasma and skeletal muscle, sonicated on ice, and centrifuged. The supernatant was lyophilized overnight and reconstituted. Because the aliquot consisted of doubly labeled (3H, 14C) quenched samples, four standard quench correction curves were used for counting 14C in the aliquot (1 ml) by a scintillation counter (Aloka) (39). The other aliquot was analyzed for leucine concentration by HPLC (Hitachi, Tokyo, Japan). The precipitated protein was dissolved in 8 ml of 1 N NaOH. The amount of protein in the aliquot was measured by a modified Lowry method (Sigma Chemical, St. Louis, MO), and 14C was counted in a liquid scintillation counter (Aloka).
Corticosterone, glucagon, and insulin levels in the plasma were analyzed by RIA as described previously (40). Epinephrine and norepinephrine levels in the plasma were measured by HPLC with fluorescence detection (Special Reference Laboratory, Tokyo, Japan). Seromucoid fraction was obtained by sequential precipitation of serum in 0.6 M perchlorate and 2% phosphotungstic acid, as described by Hellerstein et al. (16), and the concentration of this fraction was measured colorimetrically using the Bradford reagent (Sigma Chemical). Morphine levels in the brain were measured according to the modification of the two previously published methods (21, 28) by use of a coulometric analytic system equipped with an L-7100 pump (Hitachi), an MCM column (ODS 5 µm, 4.6 × 150 mm, MC Medical, Tokyo, Japan), a recorder (Chromelon Chromatography Data Systems, Gynkotek HPLC, Munich, Germany), and an electrochemical detector (Coulochem II 5200 A, ESA, Bedford, MA) with a 5022 guard cell and a 5011 analytic cell (ESA).Calculations.
Because the substrate specific activity reached a plateau at 120 min in
TNF-treated rats receiving
[6-3H]glucose (775 ± 220 dpm/µmol), we used the steady-state method for calculation
of glucose production. In agreement with our prior report (44) and data
of others (18), free leucine specific activity reached a plateau at 180 min both in plasma (39,666 ± 1,250 dpm/µmol) and in
supernatant (10,476 ± 4,200 dpm/µmol) of skeletal muscle after
intracerebroventricular injection of TNF-, as well as in control
rats receiving saline via intracerebroventricular catheter (data not
shown); thus a steady-state method was used in calculation of the
substrate flux and protein synthesis rate in the skeletal muscle and
plasma protein. The fluxes of glucose and leucine were calculated by
dividing the tracer infusion rate by the substrate specific activity in
the plasma obtained at the end of a 4-h isotope infusion, by use of the
Steele equation. Endogenous glucose and leucine production rates were
calculated by a subtraction of the exogenous glucose and leucine
infusion rates from the total glucose and leucine production rates,
respectively (glucose infusion rate: 34.1 ± 0.6 mg · kg
1 · min
1;leucine
infusion rate: 289.1 ± 7.2 µmol
leucine · kg
1 · h
1).
In estimation of leucine flux, the use of the plasma leucine specific
activity results in a small underestimation compared with the value
found when
-ketoisocaproate (KIC) specific activity is used for the
calculation. Because Castellino et al. (7) reported that differences in
the response of leucine flux to insulin infusion are not large,
irrespective of whether leucine or KIC specific activity is used, we
(42, 44) and other authors (18) have used the plasma leucine specific
activity for the calculation of leucine flux instead of KIC. Because it
is unclear whether plasma leucine or KIC specific activity more closely
reflects the actual precursor pool for the fractional synthesis rate,
leucine specific activity was also used to calculate fractional
synthesis rate of muscle and mixed plasma protein by use of Garlick's
1973 formula (11)
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Statistical analysis. All data are expressed as means ± SE. Statistical analysis was done by analysis of variance, and Fisher's least significant test was employed to differentiate significant differences among the means, with use of Macintosh Performa 588 (Apple Computers, Cupertino, CA; Statview 412 supplied by Abacus Concepts, Berkeley, CA). Mean differences were considered statistically significant at P < 0.05.
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RESULTS |
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Intracerebroventricular injection of TNF- caused a 100% increase in
glucose production compared with the control rats [control: 3.6 ± 0.9 mg · kg
1 · min
1
vs. TNF (icv): 7.5 ± 0.7, P < 0.05, Table 1], whereas systemic injection of TNF-
did not alter glucose production rate.
TNF-
-induced increase in glucose production was prevented by
prophylactic administration of fentanyl (fentanyl+TNF: 4.8 ± 0.7 mg · kg
1 · h
1,
not significant vs. control). Like glucose production, plasma glucose
levels were increased with intracerebroventricular injection of TNF-
compared with the control [control: 95 ± 6 g/dl vs.
TNF(icv): 182 ± 27, P < 0.01], and prophylactic administration of fentanyl reduced
glucose levels from 182 to 108 g/dl.
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The fractional synthesis rate (FSR) of muscle in the
intracerebroventricular injection of TNF--treated animals was
depressed by 50% compared with control rats [control: 14.1 ± 1.6 %/day vs. TNF (icv): 7.7 ± 0.7, P < 0.01]. Fentanyl prevented
this reduction of the muscle FSR (Table 1). In contrast to the decrease
in the muscle FSR, the plasma mixed protein FSR was increased with
intracerebroventricular injection of TNF-
compared with that of
control rats [control: 37.6 ± 4.9 %/day vs. TNF (icv): 57.4 ± 7.1, P < 0.01]. Giving the same dose of TNF-
via the intravenous catheter did not alter the
plasma mixed protein FSR. Fentanyl prevented the increase in mixed
plasma protein FSR caused by intracerebroventricular injection of
TNF-
, and no differences were found between fentanyl plus TNF-
and control groups. In association with an increase in FSR of plasma
mixed protein with intracerebroventricular injection of TNF-
, the
seromucoid protein fraction levels in the serum were elevated with
intracerebroventricular injection of TNF-
compared with control
[control: 445.2 ± 22.3 µg/ml vs. TNF (icv): 675.1 ± 28.5, P < 0.01]. As with the
plasma mixed protein FSR, fentanyl blocked this increase in the serum
seromucoid protein fraction levels. The whole body protein breakdown
rate, as evaluated from the endogenous leucine production rate, was
also greater with intracerebroventricular injection of TNF-
than
with the control treatment [control: 90.9 ± 18.3 µmol
Leu · kg
1 · h
1
vs. TNF (icv): 254.2 ± 45.7, P < 0.01], and fentanyl blunted this increase in whole body protein
breakdown rate induced by intracerebroventricular injection of TNF-
.
Cortisol, epinephrine, norepinephrine, and glucagon levels in the
plasma were all increased with intracerebroventricular injection of
TNF- at 30 min after the injection but returned to control levels at
240 min (Table 2). Fentanyl inhibited this
elevation at 30 min induced by TNF-
. Neither fentanyl alone nor
intravenous injection of TNF-
caused an increase in stress hormone
levels at 30 min after the injection. In agreement with the stress
hormone levels in the plasma, a significant increase in the brain
morphine levels with intracerebroventricular injection of TNF-
compared with the control rats was found at both 30 and 240 min after
the intracerebroventricular injection of TNF-
[at 30 min,
control: 648 ± 102 fmol/g vs. TNF (icv): 1,134 ± 80 fmol/g,
P < 0.05; at 240 min, control: 806 ± 142 fmol/g vs. TNF (icv): 1,162 ± 92 fmol/g, P < 0.05; Table 2], and
fentanyl inhibited this increase. Morphine levels in the brain were not
elevated either by fentanyl alone or by intravenous injection of
TNF-
. The anabolic hormone insulin was not altered with
intracerebroventricular injection of TNF-
, and there were no
significant differences among the five groups (Table 2).
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DISCUSSION |
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Molina et al. (25) demonstrated that 80 µg of intracerebroventricular
injection of morphine enhanced proteolysis, probably due to an increase
in epinephrine and corticosterone, but they were unable to eliminate
the effects of hypoxia and acidosis induced by this dose of morphine on
protein metabolism. In a preliminary study, we found that 1 µg of
morphine bolus injection via intracerebroventricular catheter caused
neither acidosis nor hypoxia but did cause an increase in whole body
protein breakdown rate (32), which was associated with an elevation of
glucose production due to an increase in catecholamine and
corticosterone levels compared with the control rats. As with morphine,
100 µg of fentanyl by intravenous injection depressed breathing and
caused acidosis in rats (41). Fifty micrograms of intravenous fentanyl
did not reduce the blood pH of rats compared with those receiving
saline [pH, saline: 7.453 ± 0.003 vs. fentanyl (iv): 7.458 ± 0.009]. Although high doses of TNF- (700 µg/kg) cause
metabolic acidosis in rats (37), acidosis did not occur with an
0.6-µg injection of TNF-
into the brain (pH: 7.478 ± 0.017) in
this study. The effect of acidosis on protein turnover and glucose
production was, therefore, not a factor in the present study.
Bernardini et al. (4) reported that 0.2 µg of TNF- injection via
intravenous catheter did not cause any elevation of adrenocorticotropic hormone (ACTH) and corticosterone levels (130 ng/ml) in the plasma. Similarly, in the present study, 0.6 µg of TNF-
injection via intravenous catheter did not cause any increase in corticosterone levels in the plasma. Furthermore, the dose of TNF-
that causes an
elevation of corticosterone levels to 350 ng/ml was 10 µg of TNF-
injection via intravenous catheter, and an increase in corticosterone levels was necessary to cause protein catabolism by TNF-
injection (22). Therefore, probably more than 10 µg of TNF-
injection via
intravenous catheter are required for alteration of metabolic response
in rats.
The central administration of TNF- caused an elevation of stress
hormone levels, resulting in a decrease in the muscle protein synthesis
rate, an increase in whole body protein breakdown, and an enhancement
of glucose production. In agreement with the present study,
Plata-Salaman et al. (29) demonstrated that intracerebroventricular injection of 0.5 µg of TNF-
caused anorexia and a loss of body weight. The present study suggested that metabolic change with intracerebroventricular injection of TNF-
was independent of an
impairment of food intake resulting from anorexia, because the rats
received TPN solution during the measurement of protein turnover and
glucose production.
The present study showed that acute-phase protein synthesis was
increased with intracerebroventricular injection of TNF-, similar to
that observed in trauma and sepsis. De Simoni et al. (10) reported that
0.4 µg of TNF-
via intracerebroventricular injection did not
enhance IL-6 levels in the plasma, and in this study the systemic
administration of TNF-
altered neither seromucoid levels in the
plasma nor mixed plasma protein synthesis rate compared with control
rats. Because corticosterone enhanced seromucoid protein synthesis (3),
an increase in acute-phase protein synthesis induced by
intracerebroventricular injection of TNF was probably due to an
increase in corticosterone excretion (Table 1).
Both glucose levels and production rate were increased by
intracerebroventricular administration of TNF-, and fentanyl
administration blocked this response. An enhancement of glucose
metabolic alteration by intracerebroventricular injection of TNF
occurred probably because plasma glucagon levels were increased as a
result of an increase in catecholamine levels (14). Insulin levels, on
the other hand, were unaltered by intracerebroventricular injection of
TNF-
in the present study. Insulin is a major anabolic hormone, and
secretion of insulin was depressed by
-action of catecholamines on
the pancreatic
-cells after surgical stress (1). Because glucose
utilization with glucose challenge was not completely impaired in
catabolic patients (6) and high-glucose TPN solution was infused in the
present study, insulin levels were not depressed by
intracerebroventricular injection of TNF-
. Our previous study showed
that prophylactic administration of fentanyl results in lower insulin
levels 24 h after the surgery than pentobarbital anesthesia alone and
that this is associated with a depression of glucose production in rats
receiving TPN solution (40). Thus insulin was probably involved in
glucose and protein metabolism at the later period of this experimental
protocol.
The release of ACTH is mediated by prostaglandins (15), and both
TNF- and IL-1 induce prostaglandin
E2 production in the brain (4,
20). We found that fentanyl citrate blocked the catabolic response
induced by intracerebroventricular injection of TNF-
. One possible
reason for this inhibition by fentanyl citrate is that opiates inhibit
the biosynthesis of both prostaglandins and cAMP (8). If opiates do in
fact inhibit the biosynthesis of prostaglandins and cAMP, it is not
implausible that prostaglandins and morphine both mediate the catabolic
response induced by intracerebroventricular injection of TNF-
.
Fentanyl and morphine are synthetic and natural narcotics, respectively. The effects of these opiates, however, are not exactly identical, because we found no enhancement of stress hormone levels with systemic administration of fentanyl, whereas a study by Radosevich et al. (31) showed that systemic morphine administration caused an increase in glucose production in dogs. Fentanyl is ultra short acting, and the narcotic potency of fentanyl citrate is 150-fold greater than that of morphine (33). In addition to these characteristic differences between fentanyl and morphine, the important discrimination between these opiates is that morphine stimulates production of histamine from mast cells, but fentanyl does not (36). Because Molina et al. (27) showed that cymetidine, a histamine receptor blocker, inhibited the catabolic response induced by hypoglycemia in the brain, histamine synthesis induced by endogenous morphine in the brain may facilitate a catabolic response. However, it still remains unclear why, for morphine and fentanyl, which are both involved in a µ-receptor of opiate (34), there is a difference between these opiates on catabolic response in unstressed rats.
In summary, the catabolic responses initiated by an
intracerebroventricular injection of TNF- were associated with an
increase in morphine levels in the brain, resulting in an elevation of stress hormone levels and subsequent changes in protein and glucose metabolism. These catabolic responses were blocked by a prophylactic administration of fentanyl. One possible mechanism for this blocking is
that fentanyl reduced morphine levels in the brain. The prevention of
elevated morphine levels in the central nervous system by the systemic
injection of fentanyl citrate, therefore, explains how fentanyl
analgesia reduces surgical stress levels after surgery.
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ACKNOWLEDGEMENTS |
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We thank Professor T. Peter Stein (Univ. of Medicine and Dentistry of New Jersey, Stratford, NJ) for assistance in editing this manuscript.
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FOOTNOTES |
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This study was supported by Japanese Ministry of Science, Sports, and Culture Grant-in-Aid for Scientific Research (C)(2)37104.
Some of the data in this article were presented at the 83rd Clinical Congress in Surgical Forum in Chicago, in October 1997, and at the 22nd Clinical Congress of the American Society of Parenteral and Enteral Nutrition, Orlando, FL, in January 1998.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: S. Yoshida, Kurume Univ., Dept. of Surgery, Metabolic Unit, 67 Asahi-machi, Kurume-shi, Fukuoka 830, Japan.
Received 23 February 1998; accepted in final form 22 June 1998.
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