Sometimes, you need to be smart just for the sake of being smart. With that in mind, I present to you the first paper I wrote as a graduate student. While it undoubtedly made me a more informed researcher and student, it’s still one week of my life that I’ll never, ever get back. Enjoy.

Introduction

The adrenal medulla is well known as a powerful modulator of the physiological response to both exercise and rest via the “Fight-Flight” response. However, in light of opioid peptide research over the past few decades, it is now quite clear that the adrenal medulla plays a more prominent role than was originally perceived. Now, the study of adrenal medullary secretory activity, which was once limited to the catecholamines epinephrine, norepinephrine, and dopamine, also encompasses the lesser understood proenkephalin family of opioid peptides. With that in mind, it is important to consider adrenal medullary response to exercise stress and subsequent recovery in a broader sense.

The Catecholamines and Adrenomedullary Activity

Before considering the widespread impacts of the catecholamines in relation to exercise, it is important to note the relative contributions of each. Norepinephrine secretion from the adrenal medulla is certainly a contributing factor to the overall sympathoadrenal-medullary response to exercise, as the plasma concentration of the hormone (which also acts as a neurotransmitter) can increase twenty-fold with high-intensity exercise (1). However, sympathetic nerve endings also directly secrete norepinephrine to target tissues; during exercise, roughly 50% of total norepinephrine secretion occurs in the active muscles (2).

Dopamine is the first catecholamine formed after the conversion of tyrosine to dihydroxyphenylalanine (dopa), the common chemical precursor for the three catecholamines. Norepinephrine and epinephrine are formed thereafter from this same pathway (3-5). Dopamine is present in the adrenal medulla and cortex, kidneys, peripheral nerves, carotid body, and sympathetic ganglia (6). In fact, it is the most abundant catecholamine in human plasma (5). However, only 2% exists in the free form; the remainder consists of biologically inactive metabolites (5,6). And, though the plasma free form dopamine concentration rivals that of epinephrine (and 20% of norepinephrine), it is not capable of the magnitude of physiological effects seen with epinephrine and norepinephrine (6). As such, although dopamine certainly plays a role in the adrenomedullary cascade of events in response to exercise, it is a less utilized measure of adrenomedullary activity during exercise and in recovery.

Although dopamine is the most abundant catecholamine in the blood, epinephrine constitutes the vast majority of adrenal-medullary catecholamine release. Shah et al. proposed that those tissues outside of the CNS that produce catecholamines be labeled the “sympathochromaffin system,” and be divided into two components: the sympathetic nervous system (neurotransmitter norepinephrine from postganglionic neurons) and the chromaffin cells (which secrete epinephrine, norepinephrine, and/or dopamine) (7). In short, plasma norepinephrine concentrations best quantifies sympathetic neuronal activity, whereas plasma epinephrine concentration is the optimal index of adrenomedullary secretions of catecholamines (7). With all these factors in mind, one can surmise that changes in plasma free epinephrine concentrations serve as the measure of choice in the discussion of the adrenomedullary catecholamine response to exercise and subsequent recovery.

Catecholamine Response to Exercise

Various intensities, durations, and modes of exercise serve as powerful stimuli to the adrenal medulla to initiate the Fight-Flight response. Numerous studies have found that epinephrine and norepinephrine secretions increase as exercise intensity increases. For instance, Kraemer et al. found that plasma epinephrine (Figure 1) and norepinephrine steadily increased during graded exercise on a bicycle ergometer from 54% to 83% and 100% of maximum oxygen consumption (VO2 max) in both trained and untrained subjects (8). Others have verified this relationship between plasma catecholamines and intensity during graded exercise sessions regardless of training status (9-12).

Designation of a specific exercise intensity at which the adrenomedullary activity becomes significant is yet to occur, as catecholamines are always at work in the body. Unloaded cycling at approximately 10% VO2 max did not increase plasma catecholamines above resting values in young men (13). Likewise, as demonstrated in Figure 1, graded exercise on a bicycle ergometer did not increase plasma epinephrine above baseline at 54% VO2 max (8). However, Greiwe et al. demonstrated that norepinephrine and epinephrine (Figure 2) both increased with each 5% increment from 60% to 85% VO2 max before and after ten weeks of endurance training (14).

Figure 1: Plasma epinephrine (Epi) concentrations at rest and after 15 min of exercise at the same relative exercise intensity before and after 10 wk of endurance exercise training.

Greiwe et al. J Appl Physiol 1999.

Designation of a specific exercise intensity at which the adrenomedullary activity becomes significant is yet to occur, as catecholamines are always at work in the body. Unloaded cycling at approximately 10% VO2 max did not increase plasma catecholamines above resting values in young men (13). Likewise, as demonstrated in Figure 1, graded exercise on a bicycle ergometer did not increase plasma epinephrine above baseline at 54% VO2 max (8). However, Greiwe et al. demonstrated that norepinephrine and epinephrine (Figure 2) both increased with each 5% increment from 60% to 85% VO2 max before and after ten weeks of endurance training (14).

Figure 1: Plasma epinephrine (Epi) concentrations at rest and after 15 min of exercise at the same relative exercise intensity before and after 10 wk of endurance exercise training.

Greiwe et al. J Appl Physiol 1999. (PICTURE)

As such, it appears that the cutoff point for significant adrenomedullary stimulation during endurance exercise is in the 55-60% VO2 max range.

Exercise duration is also of appreciable significance in determining the adrenomedullary response to exercise. Galbo et al. found that although plasma epinephrine increased steadily with prolonged treadmill exercise to exhaustion at 76% VO2 max, graded exercise in the same subjects at 44, 77, and 100% of VO2 max yielded greater increases (9). Others have verified the trend of increasing plasma epinephrine with longer duration exercise (15,16).

Clearly, there is an appreciable lag time between the onset of exercise and increases in plasma catecholamine concentrations. In bicycle ergometer exercise to exhaustion at 36, 55, 73, and 100% of maximal leg power (the equivalent of 115, 175, 230, and 318% VO2 max, respectively), significant immediate post-exercise increases in plasma epinephrine were only observed at 36 and 55% of maximal leg power. The mean duration of exercise at these two intensities were 3.31 and 0.781 minutes, respectively. At maximal leg power, mean duration was approximately six seconds, and the significant increase in epinephrine was not seen until 15 minutes post-exercise (17). Jezova et al. examined the differential responses of two bicycle ergometer tests of the same total work output but different duration and intensities. The researchers concluded that the overall catecholamine response is more dependent on exercise intensity than duration or total work output (18).

Resistance training also has a profound impact on adrenomedullary activity. Bush et al noted significant increases in plasma epinephrine following two different resistance exercise protocols –one high force and the other high power – of the same total work. There was not, however, a significant difference in adrenomedullary activity between the two (19). In another study comparing body builders with powerlifters, Kraemer et al. found that a ten station resistance training session (comprising 30 total sets at 10 repetition maximum for various exercises) with short rest periods increased plasma epinephrine, norepinephrine, and dopamine significantly over pre-exercise values. No difference was noted between body builders and powerlifters on these measures (20). Pullinen et al. noted that although plasma epinephrine increased significantly with knee extensions to exhaustion at 20, 40, 60, and 80% of 1 repetition maximum (RM), the strongest stimulus to epinephrine, 20%, did not yield a significantly greater plasma epinephrine increase than the other three intensities (21). In contrast, Guezennec et al. observed that six sets of eight bench presses at 70% of 1RM yielded less of a plasma epinephrine and norepinephrine response than six sets of maximal repetitions at the same load (22). Therefore, intensity again appears to be paramount in determining the adrenomedullary response to exercise.

Catecholamine Response to Recovery

Several studies have noted abrupt drops in epinephrine values in the 5-15 minutes after the cessation of endurance, graded exercise, and resistance training sessions (8,17,19,23). In light of the aforementioned lag between the onset of exercise and increases in plasma catecholamine concentrations, one should note that epinephrine levels continue to increase for 15 minutes or more after very short duration, high-intensity exercise (e.g. sprints) (17,24). Additionally, 15 minutes following a 1000km ultra-marathon, free epinephrine concentrations remained well above pre-exercise values; clearly, the extensive nature of this duration appeared to be sufficient to elicit prolonged adrenomedullary activity (25).

Chronic catecholamine adaptations to training have also been noted. Kjaer and Glabo found that endurance trained athletes demonstrated a greater ability than untrained subjects to secrete epinephrine in response to infusion of glucagon and acute hypercapnia and hypobaric hypoxia (26). This finding is significant, as Kjaer et al. had found previously (via epinephrine infusions in resting and cycling subjects) that plasma epinephrine concentration changes during exercise signify enhanced secretion rather than reduced clearance (27). In other words, endurance training appears to increase secretory capacity of the adrenal medulla. Lehmann et al. verified this phenomenon in finding that trained cyclists demonstrated lower plasma epinephrine concentrations than untrained subjects at the same relative oxygen uptake (28).

The Opioid Peptides and Adrenomedullary Activity

Since its discovery in the 1970s, the proenkephalin family of opioid peptides has become a recognized secretory product of the adrenomedullary chromaffin cells. Nonetheless, research regarding the opioid peptide response to exercise is limited (8,17,19). Perhaps the most studied member of the opioid peptide family is proenkephalin peptide F, which has responded to similar stimuli as epinephrine in previous studies (8,17,29).

Kraemer et al. noted differential peptide F responses during graded bicycle ergometer exercise in trained and untrained subjects. As Figure 2 demonstrates, in untrained subjects, peptide F increased similarly to epinephrine, whereas it peaked at 54% VO2 max and began to decline in trained subjects as exercise intensity increases to 83 and 100% VO2 max (8).

Figure 2: Plasma Epinephrine and Peptide F as a function of exercise intensity

Kraemer et al. Proc Natl Acad Sci U S A. 1985

Note: squares indicate Trained group; triangles indicate untrained group. (PICTURE 2)

In a separate study, the differential responses between trained and untrained subjects were once again readily apparent when fit women had significantly higher plasma peptide F concentrations than their unfit counterparts at 80% VO2 max cycling (30).

Interpreting the peptide F response to varying exercise intensities proves to be challenging. Peptide F increased significantly during high intensity cycle exercise at 36% maximal leg power (roughly 115% VO2 max), but not at three greater intensities with shorter durations (17). Another study found that plasma peptide F increased significantly with graded exercise at 75 and 100% VO2 max (31). Conversely, recall that the aforementioned Kraemer study noted a drop-off point in plasma peptide F at 54% VO2 max in trained subjects (8). In support of this drop-off point, exercise at 80-85% VO2 max did not yield a significant increase in plasma peptide F (32). Likewise, when strength-trained men took part in separate high force and high power resistance training protocols, plasma peptide F was significantly decreased from baseline values at the end of the exercise sessions. Meanwhile, epinephrine increased dramatically as expected. The researchers hypothesized that epinephrine increases are made possible by decreases in enkephalin-containing polypeptides in the adrenal medulla (19). This theory is supported by research by Angelopoulos et al., who asserted that the opioid peptides have an inhibitory effect on the release of catecholamines during intense exercise (33). On a related note, in a study involving purposeful resistance exercise overtraining of trained subjects, peptide F concentrations were not significantly different between the overtrained and control groups. This similarity was present in spite of the protocol’s previously demonstrated propensity to induce dramatic increases in epinephrine (29). The fact that chronic training increases adrenomedullary secretory capacity for epinephrine certainly supports this inverse relationship and helps to elucidate the question of why trained and untrained subjects have different peptide F responses during exercise.

Opioid Peptides Response to Recovery

Perhaps the most intriguing aspect of the opioid peptides as they relate to exercise is the recovery period response. Increases in plasma peptide F have been noted not only in the first 5-15 minutes of the post-exercise period (9,17,19), but also at 240 minutes after resistance training sessions, when the mean concentration was more than 80% above the mean pre-exercise value (19). Researchers hypothesize that this post-exercise proenkephalin surge is indicative of the opioid peptides’ crucial role in recovery (9,17,19,29,34). Additionally, enkephalin-containing polypeptides appear to play an essential role in the immune response through mechanisms such as neutrophil activation, natural killer cell modulation, and coagulation facilitation (29, 35). Given the negative impact of the catecholamines on overall immunity, the opioid peptides may serve as a means for the adrenal medulla to counteract immunosuppression during and after exercise (29).

Conclusions

The adrenal medulla is stimulated to secrete catecholamines by a variety of exercise intensities, durations, and modes, with a minimum intensity of 55-60% VO2 max likely being the most requisite factor. Generally speaking, as exercise intensity and duration increase, so does catecholamine secretion (most notably epinephrine) by the adrenal medulla. In untrained subjects, increases in plasma proenkephalin-containing peptides parallel increases in catecholamines. At the cessation of exercise, free catecholamine concentrations in the plasma decline sharply. Simultaneously, in trained subjects, concentrations of opioid peptides, which were relatively unaffected by exercise above 54% VO2 max, increase to values well above baseline. As the potentially immunosuppressive catecholamines (which are secreted at higher rates in trained individuals) dissipate, the enkephalin-containing peptides can begin to enhance recovery from exercise while enhancing the immune response. In spite of this theoretical paradigm, more research is clearly warranted in order to fully understand the causes of the differential opioid peptide response to exercise in trained and untrained subjects. Furthermore, the exact interaction scheme of the opioid peptides and the catecholamines remains to be definitively agreed upon.

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