Anesth Analg 2006;103:156-161
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000221186.64599.78
CRITICAL CARE AND TRAUMA
Morphine Sulfate Attenuates Hemorrhagic Shock- Induced Hyperpermeability
Craig Charleston, MD*,
Rudolph Puana, MD*,
Russell K. McAllister, MD*,
Felicia A. Hunter*, and
Ed W. Childs, MD
From the Departments of *Anesthesiology and Surgery, Scott and White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A&M University System Health Science Center College of Medicine, Temple, Texas.
Address correspondence and reprint requests to Ed W. Childs, MD, Scott and White Clinic and Memorial Hospital, Department of Surgery, 2401 South 31st St., Temple, Texas 76508. Address e-mail to echilds{at}swmail.sw.org.
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Abstract
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Morphine sulfate is often administered for patients requiring surgical intervention for the control of hemorrhage. Recent data implicate morphine as an immune modulator that affects white blood cells and increases infection rates. In addition, morphine releases histamine, an inflammatory mediator that increases microvascular permeability. Both of these actions of morphine could aggravate the inflammatory progress after hemorrhagic shock. In this study, we evaluated the role of morphine sulfate on microvascular permeability and its effects on leukocyte adherence after hemorrhagic shock. After a control period, blood was withdrawn to reduce the mean arterial blood pressure to 40 mm Hg for 1 h in urethane-anesthetized Sprague-Dawley rats. Mesenteric postcapillary venules in a transilluminated segment of small intestine were examined to quantify changes in permeability and leukocyte adherence. The rats received an IV injection of fluorescein isothiocyanate-bovine albumin during the control period. The fluorescent light intensity emitted from the fluorescein isothiocyanate-bovine albumin was recorded with digital microscopy within the lumen of the microvasculature and compared with the intensity of light in the extraluminal space over time. These images were downloaded to a computerized image analysis program that quantitates changes in light intensity. This change in light intensity represents albumin extravasation. In addition, bright-field images were recorded on compact disk for playback to determine leukocyte adherence. Leukocytes stationary for more than 30 s or longer in a 100-micron segment of venule was considered adherent. Our results demonstrated a marked increase in fluorescein isothiocyanate-bovine albumin leakage into the extravascular space after hemorrhagic shock. Hemorrhagic shock was also associated with an increase in leukocytes adhering to the postcapillary venular endothelium. Morphine sulfate 10 µg/kg given before the shock period, attenuated both the hyperpermeability (P < 0.05) and the increase in leukocyte adherence (P < 0.05) after hemorrhagic shock. These results suggest that instead of aggravating the inflammatory response after hemorrhagic shock, morphine may provide protection to the microvasculature.
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Introduction
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Hemorrhagic shock induces an acute inflammatory response characterized by increases in vascular permeability and leukocyte adherence (1,2). The interaction of leukocytes with the microvascular endothelial cells is a key component of this inflammatory response. This cytokine-mediated process increases P-selectin and intracellular adhesion molecule-1, causing rolling and adhesion of the leukocyte within the lumen of venules. These leukocytes eventually immigrate into the extravascular space and incite an inflammatory cascade (3,4).
The administration of morphine mediates a histamine release (5–7). The role of histamine as a mediator of this inflammatory process has been extensively studied (8–11). Histamine alone or in synergy with other mediators contributes to the core features of inflammation, namely, blood vessel dilation, increased temperature, pain and an increase in microvascular permeability (8,11). This histamine response on the microvasculature also plays a role in leukocyte-endothelial cell interaction (10,11).
In addition to morphine's known effect on histamine release (5–7), data suggest that it may also play a role in altering the immune response (12,13). The µ receptor is the major target for morphine immunosuppression. Agonists specific for the µ, 
, and 
opioid receptors have been shown to suppress antibody responses in vivo. Wang et al. (14,15) and Eisenstein and Hilburger (16) showed suppression of antibody production by morphine administration and the abolishment of spleen atrophy, apoptosis, inhibition of leukocyte proliferation and cytokine production by splenocytes in chronically stressed mice. Chronic administration of opioids increases infection and decreases the ability of the host recipient to mount a response to infection and wound healing (14,17–22).
The purpose of this study was twofold: (a) to study the microvascular permeability properties of morphine after hemorrhagic shock and (b) to examine morphine's effect on leukocyte dynamics in postcapillary venules (15).
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METHODS
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The surgical procedures and experimental protocols were conducted at Scott and White Hospital and Texas A&M University Health Science Systems after approval by the Animal Care and Use Committee. The facility is approved by the American Association for Accreditation of Laboratory Animal Care in accordance with National Institutes of Health guidelines.
The test solute for the permeability measurements was fluorescein isothiocyanate-bovine albumin (FITC-albumin; Sigma, St. Louis, MO). The test solution was prepared by dissolving 50 mg/kg of FITC in saline. Morphine sulfate 2 mg solution was dissolved in 200 mL of 0.9% NaCl solution (Baxter HealthCare Corporation, Deerfield, IL).
Male Sprague-Dawley rats weighing 275–325 g were selected for study. The rats were fasted for 18 h and given water ad libitum before each experiment. The rats were anesthetized by an IM injection of 50% urethane (1.5 g/kg). Polyethylene cannulas (PE-50, 0.58-mm ID) were placed in the right internal jugular vein to give fluids IV and in the right carotid artery for withdrawal of blood. Mean arterial blood pressure (MAP) was measured continuously using a PE-50 cannula in the left femoral artery connected to a blood pressure analyzer (Dig-Med, BPA 400A; Micromed, Louisville, KY). The rats were placed in the lateral decubitus position on a temperature-controlled Plexiglas plate mounted to an intravital upright microscope (Nikon E 600, Tokyo, Japan). The rat's temperature was maintained at 37°C. A midline laparotomy incision was performed to expose a section of small bowel mesentery. The externalized segment of mesentery from the small intestine was draped over a temperature-controlled Plexiglas stage and used for microscopic examination. The mesentery was superfused with normal saline at 2 mL/h and covered with plastic wrap to reduce evaporation. Venules with diameters of 20–35 µm were selected for study with a Nikon 20x flat-field objective, 0.45–2.16-mm working distance (Nikon Instruments, Inc., Natick, MA). Images were obtained with a Cascade CCD florescent camera (Photometrics, Tucson, AZ). A video time and date generator (WJ-8 10; Panasonic, Secaucus, NJ) provided onscreen time, date, and stopwatch functions. The image was projected onto a video monitor (Trinitron 20-in. monitor, Sony, New York, NY), captured digitally on computer, and stored on compact disk. Data were analyzed using MetaMorph 5.7 (Universal Imaging Corp., Downingtown, PA).
The extravasation of FITC-albumin was measured by determining the changes in integrated optical intensity by image analysis. Areas in the small bowel mesentery, postcapillary venules and the adjacent extravascular space were selected for study. 
I = Ii – Io/Ii, where is the change in light intensity Ii is the light intensity inside the vessel, and Io is the light intensity outside the vessel. Each experimental frame was digitized into 512 x 512 pixels. Each pixel is associated with a 16-bit gray scale value (a number between 0 and 65,535). Gray scale values were measured in the postcapillary venules and in the extravascular space adjacent to the predetermined venule (per unit area) throughout the experiment at selected times using the MetaMorph image analysis systems. The images were standardized to those taken at the beginning of each experiment within the same animal and at set timed intervals among different animals. This method of standardization was selected to minimize the bias incurring with changes in room lighting and hematocrit concentration within each animal. This method of measuring vascular permeability using image analysis has been validated by Bekker et al. (23) and Wood et al. (24).
Leukocyte measurements were recorded on compact disk and analyzed by video playback. Leukocytes were considered adherent if they remained stationary for at least 30 s. A 100-micron segment of vessel was studied, and leukocyte-endothelial interaction was recorded at baseline and 10, 30, and 60 min after hemorrhagic shock. Leukocyte adherence was not recorded during the hemorrhagic shock period because of stagnant blood cell flow. The video playback data analysis was performed by a research technician and verified independently by the lead author. This method of measuring leukocytes adherence has been used by Granger and Kubes (25) and others (26,27).
Eight experimental groups, consisting of sham-control (n = 5), hemorrhagic shock (for 60 min) (n = 5), morphine alone at 5 µg/kg (n = 5), 10 µg/kg (n = 5), and 15 µg/kg (n = 5), and hemorrhagic shock plus morphine at 5 µg/kg (n = 5), 10 µg/kg (n = 5), and 15 µg/kg (n = 5) were studied to determine changing microvascular permeability and leukocyte dynamics. In a pilot study, an effective dose of morphine sulfate was determined to be 10 µg/kg. The 5-µg/kg dose of morphine showed minimal changes in vascular permeability after shock, and the 15-µg/kg dose of morphine resulted in the animals dying during the shock process. The animals were allowed to recover from surgical manipulation for 30 min before the start of all experiments, and baseline variables were recorded. Morphine was then injected followed by a 10-min recording of the following variables: MAP, red cell centerline velocity, vessel diameter, and number of adherent leukocytes per 100 µm of postcapillary venule. During this period, animals were dosed with FITC-albumin at 50 mg/kg for permeability determination, and baseline integrated optical intensities were obtained intra- and extravascularly with predetermined areas. The animals then underwent 60 min of hemorrhagic shock. To produce hemorrhagic shock, the MAP was decreased to 40 mm Hg by withdrawing 40% of their blood volume from the right carotid artery into a syringe containing 100 U of heparin. By continually measuring the MAP, pressures were kept at 40 mm Hg throughout the procedure by reinfusing or withdrawing more blood volume. After 60 min of shock, the shed blood was reinfused to resuscitate the animal, along with lactated Ringer's solution (10–15 mL) to maintain a MAP of 90 mm Hg. To determine permeability, images were taken at 10, 30, and 60 min during resuscitation. Exposure time of <15 s was performed to prevent quenching of the fluorescent indicators. In the leukocyte dynamic group, the images were recorded before shock and at 10, 30, and 60 min into resuscitation for 5 min each.
Data were initially analyzed to determine significance among groups by the repeated-measured analysis of variance. The procedure was followed by the Bonferroni test for multiple comparisons. Comparisons were made regarding permeability and leukocyte adherence in the hemorrhagic shock versus sham-operated and the hemorrhagic shock and morphine groups. The difference was considered significant when P < 0.05.
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RESULTS
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Figure 1 is a composite image (20x) of a rat's mesenteric postcapillary venule demonstrating vascular permeability. Images labeled sham and preshock demonstrates an intense fluorescent signal inside the vessels injected with FITC-albumin. Images labeled shock illustrates an increase in vascular leak 60 min after the shock, indicated by the magnitude of FITC-albumin in the perivascular space. Figure 2 shows the effective relationship comparatively between preshock, shock, and shock plus morphine on vascular permeability. As illustrated by the images, morphine 10 µg/kg pretreatment 10 min before the shock period resulted in a significant decrease (P < 0.05) in the amount of perivascular FITC-albumin, representing a decrease in vascular leak. Figure 3 is a graphic and table display of the cumulative data demonstrating attenuation of hemorrhagic shock-induced permeability with pretreatment with morphine sulfate at 10 µg/kg (P < 0.05). The attenuation was significant, occurring immediately after the shock period and was maintained throughout the resuscitation phase of the experiment. Morphine alone (data not shown) was similar to control-sham animals.
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Figure 1. Composite image (20x) of a rat's mesenteric postcapillary venule demonstrating vascular permeability. The first image is before the shock period, labeled preshock, demonstrating an intense fluorescent signal inside the vessel. The second image is of a rat at 60 min, sham-operated (nonshock induced). The third image is of a rat after hemorrhagic shock taken at 60 min during resuscitation. Note the marked increase in fluorescein isothiocyanate-bovine (FITC) albumin in the extravascular space.
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Figure 2. Composite image of a rat's mesenteric postcapillary venule, preshock, shock, and morphine + shock. Morphine is given 10 min before the shock period. Morphine pretreatment attenuated fluorescein isothiocyanate-bovine (FITC) albumin leak.
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The effect of hemorrhagic shock on leukocyte adherence to the venule wall is illustrated in Figure 4. In this image of a sham-operated rat mesenteric venule (20x), equivalent to 60 min postshock in the experimental groups, there were minimal leukocytes observed adhering to the endothelium labeled sham. The image labeled shock shows a postcapillary venule after shock with increased leukocyte adherence. This adherence increases almost 10-fold compared with sham-operated rats. Figure 5 is a composite image of a rat's mesenteric postcapillary venule in 3 periods, under 3 conditions: preshock, shock + morphine (10 µg/kg) given 10 min before the shock period, and shock.
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Figure 4. Composite image of a rat's mesenteric postcapillary venule demonstrating leukocyte adhesion. The first image is before the shock period, labeled preshock, demonstrating a minimal number of leukocytes present inside the vessel. The second image is of a rat at 60 min, sham-operated (nonshock induced). The third image is of a rat after hemorrhagic shock taken at 60 min during resuscitation. Note the marked increase in the number of adherent leukocytes after hemorrhagic shock.
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Figure 5. Composite image of a rat's mesenteric postcapillary venule labeled preshock, morphine + shock, and shock. Morphine was given 10 min before the shock period in the morphine + shock group.
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Pretreatment with morphine before shock revealed a marked decrease in leukocyte adherence compared with shock alone (P < 0.05). Cumulative data are shown by graph and table format in Figure 6, and demonstrate a significant decrease in leukocyte adherence to the microvasculature compared with the corresponding shock state without morphine 10-µg/kg pretreatment (P < 0.05). Morphine significantly attenuated leukocyte adherence after the shock period at 10, 30, and 60 min.
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DISCUSSION
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Morphine is a mediator of histamine release. Because of the potent vasoactive response of histamine on vascular permeability, morphine therapy should cause this permeability to increase. However, results of our study suggest the opposite effect on the microvasculature. This study describes two actions of morphine sulfate on the microvasculature. First, pretreatment with morphine in a hemorrhagic shock model shows attenuation of microvascular permeability. Second, morphine pretreatment attenuated leukocyte adherence in the microvasculature after hemorrhagic shock.
Histamine has a profound effect on vascular permeability (8–10) through the phosphoinositol pathway. This pathway of increasing vascular permeability is well described starting with the activation of receptor tyrosine kinase on the surface of endothelial cells. This activation triggers phospholipase C along with calcium to stimulate the production of nitric oxide (NO) through endothelial-derived NO synthetase. NO activates soluble guanylate cyclase that converts guanine triphosphate to cyclic guanine monophosphate (cGMP). cGMP through protein kinase G stimulates the mitogen activated kinase pathway via Raf-1. Raf-1 stimulates mitogen activated kinase (Mek1/2) and extracellular signal-regulated kinase (Erk1/2) to increase vascular permeability (1,4,8). This pathway is mediated via histamine along with other activators of the tyrosine kinase receptor including vascular endothelial growth factor (28,29).
Morphine's known properties including analgesia are activated via µ receptors located on the endothelial cell surface and other neuromuscular sites. The µ receptor is a seven transmembrane G-protein receptor on endothelial cells (12,30). It is our hypothesis that morphine binds to the endothelial cells via the µ receptors and sets forth a cascade of events that promotes the activity of adenylate cyclase, which increases the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate. cAMP then binds to the R-group of protein kinase A (PKA). PKA then dissociates and inhibits Raf-1 (30,31). The balance between the secondary messenger cGMP and cAMP is thought to be important in maintaining vascular permeability homeostasis. He et al. (32) has demonstrated that cAMP may be the dominant regulator of microvascular permeability.
Morphine's effect on the release of histamine (3,13,30), which activates the phosphoinositol pathway, could be the balance between cGMP and the activation of cAMP via the µ receptor. Activation of the µ receptor, causing an increase of cAMP that inhibits Raf-1 through PKA, may retard vascular permeability, as demonstrated in our hemorrhagic shock model. Our results suggest that, although morphine is a histamine-releasing drug (5), the histamine effect that increases hyperpermeability is overshadowed by the dominant µ receptor-driven pathway that inhibits Raf-1 in the mitogen-activated kinase hyperpermeability pathway.
Morphine is also a potent regulator of the immune response (24). Acute and chronic morphine administration has been shown to decrease the immune response by decreasing chemotaxis of human neutrophils and macrophage inflammatory proteins (22,29,33). Acutely, leukocyte and human monocyte chemotaxis (20,21) response has shown to be retarded after morphine administration. Chronic opioid use can have deleterious effects on the immune system suppressing natural killer cells, decreasing chemotaxis and leukocyte mobilization causing increased infections and sepsis (3,14–16). Although these studies confirm much of the speculation that opiate stimulation suppresses the immune response, there is little clinical correlation to these studies in vivo. Our findings demonstrate the ability of morphine to inhibit leukocyte adherence acutely.
Morphine is the standard of care in many disease states from chronic cancer pain (22,34) to acute myocardial infarction (33). Our study indicates that morphine can play a vital role in treatment of acute shock because of morphine's dual role of inhibition of the hyperpermeability pathway through the µ receptor pathway and attenuating leukocyte adherence. Morphine may have therapeutic benefit in the treatment of hemorrhagic shock in an acute setting in which its use decreases leukocyte adherence (12,14–16). Morphine may thus be of benefit in the management of hemorrhagic shock-induced inflammation.
In conclusion, this study demonstrates that pretreatment with morphine before inducing a shock state decreases leukocyte adhesion and vascular permeability in the microcirculation of the mesenteric venule. The results were unexpected and hypothesized to be a balance between the histamine response of increased vascular permeability and the apparently dominant effect of µ receptor to attenuate Raf-1 and decreased vascular permeability. We also demonstrated that morphine sulfate decreases leukocyte adherence acutely. Morphine sulfate administered after hemorrhagic shock may provide protection to the microvasculature. Further studies to investigate the survival benefit of morphine sulfate and the potential benefit during acute resuscitation are warranted.
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Footnotes
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Accepted for publication March 7, 2006.
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Abstract
Introduction
sham (n = 5), <shock (n = 5), and 
morphine + shock (n = 5) on the extravasation of fluorescein isothiocyanate-bovine (FITC) albumin. (B) Table format comparing change in fluorescent intensity at 10, 30, and 60 min after the shock period. Morphine was given 10 min before shock in the morphine + shock group. An increase in fluorescent intensity in the extravascular space represents an increase in FITC-albumin leak.
