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The Role of Endogenous Opioids in Moderate Exercise Training-Induced Enhancement of the Secondary Antibody Response in Mice

ZF Kapasi, PT, PhD, is Assistant Professor, Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University School of Medicine, 1441 Clifton Rd NE, Atlanta, GA 30322 (USA) (zkapasi{at}emory.edu).
PA Catlin, PT, EdD, is Professor and Director, Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University School of Medicine
J Beck, PT, is Physical Therapist, Chippenham Medical Center, Richmond, Va
T Roehling, PT, is Contract Physical Therapist/Wound Care Consultant, Tempe, Ariz
K Smith, PT, is Staff Physical Therapist, Roosevelt Warm Springs Rehabilitation Institute, Warm Springs, Ga
Mr Beck, Ms Roehling, and Ms Smith were graduate students, Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University School of Medicine, during this study, which was undertaken in partial fulfillment of the requirements for their Master of Physical Therapy degree

Address all correspondence to Dr Kapasi

Submitted October 12, 2000; Accepted April 8, 2001

	Abstract

 
Background and Purpose. Moderate exercise training (60%–80% of maximal oxygen uptake) enhances the secondary antibody response. The mechanism underlying this enhancement, however, has not been determined. In moderate doses, endogenous opioids such as enkephalins enhance antibody response. Furthermore, serum concentrations of endogenous opioids increase in response to exercise, and training programs augment this effect. Therefore, the enhancement of the secondary antibody response induced by moderate exercise may be brought about, in part, by endogenous opioids. The purpose of this study was to examine the effects of naltrexone (an opioid antagonist) on the enhancement of secondary antibody response induced by moderate exercise in young mice. Subjects and Methods. C57BL/6 mice immunized to human serum albumin (HSA) were randomly assigned to 1 of 3 groups: naltrexone, placebo, or control (received no intervention). Then, the mice in each group were randomly assigned to either an exercise group (treadmill running at 15 m/min, 0° slope, 5 days per week for 8 weeks) or a non-exercise group. At the end of 8 weeks, booster immunization was given, and the mice in the exercise group continued to exercise. Ten days later, when high levels of antibodies are produced in secondary antibody response, anti-HSA antibodies in serum were measured by enzyme-linked immunosorbent assay (ELISA). Results. With naltrexone implantation, mice that exercised showed a depression of secondary antibody response as compared with mice that exercised and either received a placebo or did not receive any intervention. Discussion and Conclusion. Endogenous opioids may play a role in the enhancement of the secondary antibody response observed after moderate exercise.

Key Words: Moderate exercise • Opioids • Secondary antibody response

	Introduction

Top Abstract Introduction Method Results Discussion Conclusions References

 
Physical exercise is believed to influence immune function through the release of neuroendocrine mediators.¹ However, the mechanisms underlying this effect are not known. Antibody response to an antigen is a hallmark of the humoral immune response.² Primary antibody response occurs after an initial exposure to an antigen. Subsequent exposure to the same antigen leads to a stronger and secondary antibody response that results in long-lasting immunity. In young mice^3,4 and rats,⁵ secondary antibody response to an antigen is enhanced by exercise training.

In moderate doses, endogenous opioids such as enkephalins enhance antibody response.^6,7 Young rats treated with 0.2 mg/kg body weight of met-enkephalin or leu-enkephalin had greater increases in serum anti-sheep red blood cell antibody than control animals.⁷ Furthermore, serum concentrations of endogenous opioids increase in response to exercise,^8,9 and training programs augment this effect.⁸ Because endogenous opioids enhance antibody response, exercise-induced enhancement of antibody responses in young animals may be brought about, in part, by release of endogenous opioids during exercise.

To test this hypothesis, naltrexone or placebo pellets were implanted in mice that exercised and mice that did not exercise. Naltrexone binds to opioid receptors and is an opioid antagonist.¹⁰ Naltrexone binds to mu, kappa, delta, and epsilon opioid receptors in vitro with high affinity.¹¹ Chronic, in-vivo exposure to naltrexone (two 30-mg naltrexone pellets) causes a time-dependent increase in the binding of naltrexone to all receptor sites.¹¹ Although selective antagonists for the different receptor sites are available, naltrexone pellets provide the most convenient way of ensuring sustained blockage of the receptor sites over the duration of an experiment. Thus, depression of the secondary antibody response in mice that exercised regularly and received naltrexone versus mice that exercised and either received a placebo or did not receive a pellet would support our hypothesis that endogenous opioids play a role in enhancing the secondary antibody response after moderate exercise.

	Method

Top Abstract Introduction Method Results Discussion Conclusions References

 
Design

A randomized, multiple-observation, multiple-comparison group design was used. Mice were randomly assigned to 1 of 3 groups: a group receiving naltrexone pellets by surgical implantation (naltrexone group), a group receiving placebo pellets by surgical implantation (placebo group), and a group that received neither naltrexone nor the placebo implantation (control group). Mice in each group then were randomly assigned to receive either moderate-intensity exercise training or no exercise. Antibody response was measured 21 days after the initial human serum albumin (HSA) injection (primary antibody response-1), after 8 weeks of moderate exercise training and immediately prior to the booster HSA injection (primary antibody response-2), and 10 days after the booster injection of HSA (secondary antibody response) (Tab. 1).

Instrumentation

Moderate-intensity exercise training consisted of the mice running on a Vitamaster Rhythm Walker Plus treadmill. This treadmill was modified for this experiment by the University Medical Engineering Department. The treadmill was a manual human treadmill that was motorized to drive the treadmill belt and to control the speed accuracy. The treadmill speed was calibrated (±0.05 m/min) before the study commenced and after 3 weeks and 6 weeks of exercise using an electronic calibrator, which was placed on the treadmill, that measured the speed in meters per minute. The treadmill consisted of 6 lanes that were separated by aluminum partitions. The treadmill belt formed the floor of the lanes and the roof of the lanes consisted of hinged plexiglass.

Anti-HSA antibody levels were measured by assaying the serum using an enzyme-linked immunosorbent assay (ELISA) microplate reader.^,12 The antibody level measurements included all immunoglobulins in the blood against HSA. The ELISA microplate reader was calibrated by the manufacturer. For the ELISA, HSA in carbonate buffer (0.05 M Na₂CO₃ and NaHCO₃; pH=9.6) at a concentration of 50 µg/mL was adsorbed to the surface of polystyrene, 96-well, flat-bottom plates (50 µL/well) by incubation overnight at 4°C. The plates were emptied and washed 3 times with distilled water. One hundred microliters of 1% bovine serum albumin (BSA) were added to the wells. After incubation for 30 minutes at room temperature, the plates were emptied. The antibody standard was a pooled sample of mouse anti-HSA antiserum containing 1 mg/mL of anti-HSA as determined by quantitative precipitation. Fifty microliters of an antibody standard and of each serum sample was diluted 6 times from 1:250 to 1:32,000 in 1% BSA solution in phosphate-buffered saline (PBS) in triplicate wells for each dilution.

The solutions were incubated for 1 hour at room temperature and then washed 3 times in distilled water as described. Fifty microliters of 1:5,000 1% BSA/PBS diluted alkaline phosphatase-conjugated rabbit F(ab')₂ anti-mouse IgG (H+L) antibody was added to each well and incubated for 1 hour at ambient temperature. The plates were washed 3 times with distilled water and 100 µL of substrate solution (1 mg p-nitrophenyl phosphate [p-NPP]/mL of substrate buffer; 48 mL diethanolamine [(C₄H₁₁)NO₂]; 24.5 mg magnesium chloride hexahydrate [MgCl₂·6H₂O]; 400 mL glass-distilled water; pH=9.8) was added to each well, resulting in a yellow-colored reaction.

Thirty minutes after the reaction began, the optical density of each well was read at 405 nm, using a calibrated Vmax kinetic microplate reader with Softmax software. The number of anti-HSA antibodies (Ig) was determined by comparing the optical density of the subject's anti-HSA antibodies with the optical density of the known, anti-HSA antibody standard and expressed in milligrams per milliliter. The values from each set of triplicate wells from a given serum sample were averaged to give the value of anti-HSA antibodies for that particular mouse.

Interrater reliability for exercise duration (about 30 minutes of exercise time) and for antibody levels from the ELISA microplate reader was maintained as exact agreement of values obtained by concurrent, independent measurement by 2 investigators (ie, the same value read by 2 investigators from the printout). Two raters monitored the time of exercise duration for the mice on a single stopwatch at each exercise session. Similarly, 2 raters recorded ELISA readings from the computer printout. The variation in anti-HSA values by ELISA from repeated tests on the same serum sample is within 10% and is typical of ELISA.¹³

A 30-mg naltrexone (N-cyclopropylmethyl-14-hydroxydihydromorphinone) or placebo pellet was implanted subcutaneously in the dorsum of the trunk of mice using a sterile technique.¹¹ Mice receiving naltrexone were anesthetized. A 2-cm² area on the caudal dorsum of the trunk was shaved to expose the implantation site. Isopropyl alcohol was applied with sterile gauze to sterilize the incision site. A 1-cm incision was made with iris scissors through the skin to the fascia. A 30-mg naltrexone pellet was surgically implanted subcutaneously. Two surgical staples were applied for primary intention. Mice recovered in a clean holding cage for 15 minutes and were then returned to their housing cages. Mice receiving the placebo intervention underwent the same procedure to control for effects of surgical stress. Surgeries were repeated 3, 6, and 9 weeks following initial naltrexone or placebo implantation because a 30-mg dose of naltrexone is effective for 24 days. Mice rested 36 hours following each surgery.

Procedure

Because transportation is a stressor of animals, a period of adaptation is needed to restore homeostasis.¹⁴ Mice, therefore, were acclimatized for at least 5 days in our vivarium after arrival. Mice were randomly assigned to groups, tagged, and caged according to group assignment. All mice of a given group were housed in 3 separate cages, with no more than 5 mice per cage.

Primary immunization was given subcutaneously in the nape of the neck with a 0.1-mL injection of antigen solution (HSA, 200 µg/mL in the adjuvant 9% potassium aluminum sulfate). Human serum albumin is a potent protein antigen known to initiate antibody responses in young mice.¹⁵ After a 3-week waiting period for the development of primary antibody response, a blood sample was drawn from the tail vein to test for anti-HSA antibody level (primary antibody response-1). A second blood sample also was drawn from the tail vein after 8 weeks of exercise or after a period without exercise.

The secondary antibody response was initiated by a booster injection given as 4 injections of 0.05 mL of antigen solution subcutaneously in the dorsum of each foot (total=0.2 mL) after 8 weeks of moderate-intensity exercise or sedentary activity. The secondary antibody response was measured 10 days after the booster immunization from a blood sample drawn intracardially immediately after sacrifice. All blood samples were taken 36 to 48 hours after exercise to ensure that the changes detected in the antibody response reflected exercise training effects and not acute changes in response to the last exercise session.¹⁶ After collection, the blood was centrifuged and the serum was extracted and stored at –70°C in Eppendorf tubes for later ELISA analysis.

Following the drawing of blood, mice receiving naltrexone or placebo pellets underwent surgical pellet implantation. Control mice did not receive pellet implantation but rested 36 hours following bleeding.

Following initial pellet implantation, mice either began exercise or underwent a non-exercise protocol. Mice doing exercise were placed in treadmill lanes. Based on previous studies,^17,18 moderate-intensity exercise training (60%–80% of maximal oxygen uptake; 15 m/min represents an exercise intensity of mid to high 70% of maximal oxygen uptake) consisted of mice running on a motorized Vitamaster Rhythm Walker Plus treadmill at 15 m/min for 30 minutes with a 0-degree slope, 5 days per week for 8 weeks. The speed of the treadmill started at 3 m/min and was increased 3 m/min for each minute up to 15 m/min. Fifteen meters per minute was sustained for 30 minutes, during which the mice exercised without rest. The non-exercise protocol consisted of placing mice in a plexiglass cage and placing the cage on the lid over the treadmill lanes with the treadmill on to expose them to the noise and vibratory effects of the treadmill to control for any effects that noise or vibration might have on immune response. The non-exercising mice were placed in this position for 30 minutes, 5 days per week for 8 weeks. After the booster injection, the exercise or non-exercise protocol was received for 10 additional days. Because mice are nocturnal animals, the exercise/non-exercise sessions were always conducted in the dark cycle of a 12-hour, light/dark cycle. For a given animal, an exercise session occurred only once in a 22-hour period.

Data Analysis

Antibody levels were determined for each group at each of the 3 measurement times (Tab. 2). Prior to statistical analysis, normality of distribution and homogeneity of variance of antibody levels were ensured using the Shapiro-Wilk test and Bartlett's test, respectively. Antibody levels were compared among exercise conditions (exercise or non-exercise), groups (naltrexone, placebo, or control), and the time the sample was taken for measurement (primary antibody response-1, primary antibody response-2, and secondary antibody response) using a 3-way analysis of variance (ANOVA) with one repeated factor (measurement time). Tukey's Honestly Significant Difference test was performed, as indicated, for significant ANOVA findings. All statistical analyses were 2-tailed, and a criterion significance level () of P.05 was used. Power for effect due to exercise and opioid was 0.88 and 0.80, respectively.

	Results

Top Abstract Introduction Method Results Discussion Conclusions References

View larger version (21K): [in this window] [in a new window] Figure. Mean (±SD) anti-HSA antibody levels at primary antibody response 1 and 2 and secondary antibody response in non-exercising and exercising mice in control, placebo, and naltrexone groups. Mice in the naltrexone group that exercised showed a significant suppression (*) of anti-HSA antibody levels during secondary antibody response when compared with mice in the placebo group that exercised or mice in the control group that exercised.

Secondary Antibody Response

Within control, placebo, and naltrexone groups among different exercise conditions.
Within the control group, anti-HSA antibody levels during secondary antibody response were not different between the non-exercise and exercise conditions. Within the placebo group, anti-HSA levels were greater in the exercise condition than in the non-exercise condition; however, within the naltrexone group, anti-HSA levels were greater in the non-exercise condition than in the exercise condition (Tabs. 2 and 3, Figure).

Among control, placebo, and naltrexone groups among different exercise conditions.
For the exercise condition, anti-HSA levels were not different between the control and placebo groups; however, the anti-HSA levels were greater in both the control and placebo groups than in the naltrexone group. For the non-exercise condition, anti-HSA levels were greater in the naltrexone group than in the control or placebo group. In addition, anti-HSA levels were greater in the control group when compared with the placebo group (Tabs. 2 and 3, Figure).

Comparison of Secondary Antibody Response With Primary Antibody Response Within the Control, Placebo, and Naltrexone Groups

Anti-HSA levels during secondary antibody response were greater than during primary antibody responses 1 and 2 within the non-exercising naltrexone and control groups and the exercising placebo group. However, the anti-HSA levels during the secondary antibody response were not different than either the primary response within the exercising naltrexone and control groups or the non-exercising placebo group (Tabs. 2 and 3, Figure).

	Discussion

Top Abstract Introduction Method Results Discussion Conclusions References

 
In our study, primary antibody response to HSA was initiated prior to the exercise/non-exercise intervention, and the first measurement of this antibody response (anti-HSA level) was taken at day 21 following primary immunization (primary antibody response-1). Following 8 weeks of moderate-intensity exercise training, however, the anti-HSA level (primary antibody response-2) was not different between non-exercising and exercising animals in the control, placebo, and naltrexone groups. This is consistent with previous findings that also showed no effect from moderate-intensity exercise training on primary antibody response.^4,19,20

In contrast to other researchers who showed enhancement of secondary antibody response induced by moderate exercise training,^3–5 anti-HSA antibody levels during secondary antibody response in our study were not different between exercising and non-exercising control mice. Observed differences in antibody response in our study may be related to timing of booster immunization. In other studies,^3–5 booster immunization was given earlier during training; we gave the booster immunization near the end of exercise/non-exercise protocol. Despite the use of earlier booster immunization indicated in the literature, we waited 8 weeks before giving booster immunization because we believe it takes a minimum of 8 weeks of exercise to induce a training effect in mice.^21,22 This training effect is indicated by an increase in muscle oxidative capacity as determined by an increase in muscle enzyme activity (citrate synthase and succinic dehydrogenase).^21,22 Other researchers^3–5 gave booster immunization earlier during the training period and assessed secondary antibody response before the 8-week period. Moreover, other researchers monitored the secondary antibody response for longer than 10 days as compared with our study. We did not do this because we have found that the secondary antibody response reaches a high level by day 10 and peaks by day 14. Other researchers used antigens other than HSA and therefore may have monitored longer due to differences in the kinetics of the response. Based on our data and data from other studies,^3–5 a training effect (as reflected by an increase in muscle enzyme activity) may not be necessary to induce enhancement of secondary antibody response. Recent data from our laboratory shows that a moderate exercise protocol between 2 and 8 weeks in length may be sufficient to improve secondary antibody production in mice (Kapasi et al, unpublished observations).

In the placebo group, anti-HSA antibody levels during secondary antibody response in the non-exercising mice were less in comparison with levels in non-exercising mice of the control group. This finding suggests to us that surgical stress caused suppression of secondary antibody response (Figure). However, the mice in the placebo group that exercised did not show suppression of anti-HSA antibody levels in comparison with exercising mice in the control group. This finding suggests to us that the stress of surgery may have been counteracted by endorphins released during exercise training, as evidenced by a complete suppression of anti-HSA antibody levels in naltrexone implanted exercising mice during secondary antibody response (P.01, Figure). Immunosuppression following surgery is documented in both humans and animals.^23,24

Postsurgical immunosuppression may play a role in wound infections and other infections, which are common and serious complications following surgery and are known to prolong hospitalization by 5 to 20 days and to substantially increase medical costs.^25,26

Ours is the first study that showed that a period of moderate exercise prior to surgery can prevent the decline in humoral immunity that follows a surgical procedure and that this effect is brought about by endogenous opioids. We believe that this finding, if confirmed in humans, is relevant to the physical therapist. Physical therapy goals for presurgical management of patients could include a moderate exercise program designed to minimize postsurgical immunosuppression.

The profound increase in anti-HSA antibody levels during secondary antibody response in naltrexone-implanted mice that did not exercise in comparison with the levels in all other groups of mice is consistent with previous studies, which showed that naloxone (a short-acting analogue of naltrexone) enhanced several indicators of immune response. This could occur through modulation of opioid receptors at the second messenger level.²⁷

Although our data demonstrate a role of endogenous opioids in exercise-induced mediation of secondary antibody response, we cannot rule out the role of other neuroendocrine hormones. Antibody production requires the coordination of B cells, T-helper cells, and follicular dendritic cells.²⁸ Two-way communication is thought to occur between the neuroendocrine and immune systems, both systems being capable of synthesizing and sharing many of the same messenger molecules (eg, stress hormones, cytokines).²⁸

The neuroendocrine system can influence the antibody response both directly (through an influence on B cell function) and indirectly (through actions on regulatory cells such as T-helper and antigen presenting cells).²⁹ B cells express ß-adrenergic receptors, and adrenergic innervation influences antibody synthesis.³⁰ For example, norepinephrine has been shown to enhance specific antibody synthesis in response to an antigen by increasing the number of antigen-specific B cells that differentiate into antibody-secreting plasma cells.³⁰

Norepinephrine appears to mediate both suppression and stimulation of antibody synthesis, depending on the dosage and timing of administration in relation to antigen exposure.³¹ Exposure to norepinephrine early in the antibody response appears to enhance antibody synthesis, whereas later administration is associated with suppression of antibody synthesis.

There are possible explanations for the neuroendocrine control of antibody response to both acute exercise and moderate exercise training.³² Acute exercise rapidly causes leukocytosis and lymphocytosis, presumably because of cells released from the spleen, possibly through sympathetic activation of receptors on contractile elements and blood vessels of the spleen.³³ Despite the large increase in B cell numbers, however, these changes are transitory, and the time course of an increase in B cells is too short to influence serum immunoglobulin levels. When a person engages in regular exercise, repeated elevation in the number of lymphocytes (especially B cells), coupled with increases in norepinephrine, may lead to enhanced antibody synthesis over time.^3–5 Exercise training also leads to downregulation (decreased function) of lymphocyte ß-adrenergic receptors and an attenuation of the catecholamine response to exercise. This indicates that some other mechanisms, possibly endogenous opioids as shown in this study, may be involved in the chronic effects of exercise training on antibody synthesis.³² Studies using several hormone-receptor antagonists should help assess all the mechanisms involved in exercise-induced enhancement of antibody responses to booster immunizations.

	Conclusions

Top Abstract Introduction Method Results Discussion Conclusions References

 
Physical exercise is believed to influence immune function through the release of neuroendocrine mediators.¹ This is the first study that showed a role of endogenous opioids in exercise-induced modulation of the secondary antibody response. This suggests a neuroendocrine basis for modulation of immune function through exercise. Furthermore, we also show for the first time that a period of moderate exercise prior to surgery can prevent the decline in humoral immunity that follows a surgical procedure and that this effect is brought about, in part, by endogenous opioids. Surgery is a physically stressful event, and patients with poor exercise tolerance have been shown to have more postoperative complications including infections.³⁴ Current goals of preoperative physical therapist management often include improvement of exercise tolerance with the aim of returning the patient to functional independence following surgery. If a moderate exercise program is shown to prevent immunosuppression following surgery in humans, then, in our opinion, preoperative physical therapy could also aim to minimize morbidity and additional health care costs from extended hospitalization caused by infections resulting from postoperative immunosuppression.

	Footnotes

 
All authors provided research design, writing, data analysis, project management, and consultation (including review of manuscript before submission). Dr Kapasi provided concept and data collection. Dr Kapasi and Dr Catlin provided fund procurement, subjects, facilities/equipment, and institutional liaisons. Mr Beck, Ms Roehling, and Ms Smith provided data collection and clerical support.

This study was approved by the Institutional Animal Care and Use Committee of the Emory University School of Medicine.

This research was presented at the Third International Society of Exercise and Immunology (ISEI) Symposium, November 7–8, 1997, Paderborn, Germany, and at Physical Therapy '99: Annual Conference and Exposition of the American Physical Therapy Association, June 5–8, 1999, Washington, DC.

^* Charles River Laboratories, 251 Ballardvale St, Wilmington, MA 01887.

Road Master Corp, 4501 Old Troup Hwy, Tyler, TX 75707.

Rohm & Haas Co, Independence Mall W, Philadelphia, PA 19105.

Molecular Devices Corp, 1311 Orleans Ave, Sunnyvale, CA 94089-1136.

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