p-Endorphin Response to Exercise - Springer Link

Sports Moo. 1997 Jul; 24 (1): 8-16 0112-1642/97/0XI7 {XX)8/S04.50/0

LEADING ARTICLE

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p-Endorphin Response to Exercise An Update Allan H. Goldfarb and Athanasios Z. Jamurtas Exercise and Sport Science Department, University of North Carolina - Greensboro, Greensboro, North Carolina, USA

Summary p-Endorphin, a 31-amino-acid peptide, is primarily synthesised in the anterior pituitary gland and cleaved from pro-opiomelanocortin, its larger precursor molecule. p-Endorphin can be released into the circulation from the pituitary gland or can project into areas of the brain through nerve fibres. Exercise of sufficient intensity and duration has been demonstrated to increase circulating p-endorphin levels. Previous reviews have presented the background of opioids and exercise and discussed the changes in p-endorphin levels in response to aerobic and anaerobic exercise. The present review is to update the response of p-endorphin to exercise. This review suggests that exercise-induced p-endorphin alterations are related to type of exercise and special populations tested, and may differ in individuals with health problems. Additionally, some of the possible mechanisms which may induce p-endorphin changes in the circulation include analgesia, lactate or base excess, and metabolic factors. Based on the type of exercise, different mechanisms may be involved in the regulation of p-endorphin release during exercise.

p-Endorphin levels have been measured in the circulation and in several other tissues in response to exercise. It has been reported by a number of investigators[l-5] that the intensity of exercise is important in significantly altering circulating pendorphin levels. These studies suggested that a critical intensity of exercise [>60% maximum oxygen uptake (Y0 2max )] was needed to increase circulating p-endorphin levels. Subsequent studies have confirmed that the intensity needs to be at a critical level, but may fluctuate from this minimum based on the individuaJ.l5-9]

1. Types of Exercise 1.1 Resistance Exercise There has been little information available on the effects of resistance-type exercise on circulating p-endorphin levels llO ] and recent reports have not always indicated similar findings.III-15] Pierce et aI.l14] reported that there were no significant changes in circulating p-endorphin levels in 6 trained male athletes following 3 sets of 8 repetitions at 80% of I repetition maximum (RM). In contrast, this group later reported that p-endorphin

~-Endorphin

Response to Exercise

levels decreased following a similar resistance exercise protocol in 10 male and 10 female college students. 113 ] They attributed this decline to either an enhanced clearance or psychological factors. It is not clear why there was a difference in the results, but this may be related to the fact that the participants in the initial study were trained. Kraemer et aLII I] also reported that 8 males who were well trained only demonstrated increases in circulating p-endorphin following high total work and only I minute into recovery. They suggested that the duration of the work to rest interval and the total force performed influenced the p-endorphin response. This same group previously reported that p-endorphin levels were significantly increased in 28 elite male weight-lifters following a moderateto-high intensity resistance workload,f12] Resistance exercise in 5 recreational weight-lifting females was reported to increase p-endorphin levels from 5 to 15-20 pmollL, an approximately 3.7-fold increase.l 15 ] These females lifted at 85% of 1 RM for 10 to 12 repetitions for 3 sets, performing 8 different lifts. p-Endorphin returned to baseline by 30 minutes into recovery. It appears that there is no definitive response of l3-endorphin to resistance exercise. The results examining resistance exercise and l3-endorphin response are equivocal, partly due to the selection of participants and partly due to the intensity of exercise utilised. Finally, the time at which the measurement was taken following the exercise has varied, which may have influenced the results. Future studies are needed to clarify pendorphin response to resistance exercise. 1.2 Aerobic Exercise

Aerobic exercise of sufficient intensity and duration has previously demonstrated increases in circulating p-endorphin.l I-4 ,16] The more recent reports seem to support these papers. In one study, 16 males were examined cycling at 85 and 100% of their individual anaerobic threshold (lAT), to exhaustion for the 100% IAT and for the same length of time at 85% lAT. 16] p-Endorphin measured in 8 of the participants increased only in the 100% IAT sample from 13.42 to 42.09 pmollL. © Adis International Umited. All rights reserved.

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Cycling at 85% V0 2max was reported to elevate p-endorphin levels from approximately 10 pmollL at rest to 30 pmollL at the end of the exercise.117 ] Running on a treadmill at 60 and 90% V0 2max , 27 active women demonstrated significant increases in p-endorphin only at the higher workload. IIS ] Eight women trained in aerobic dance demonstrated an increase in p-endorphin levels from 8.62 to 11.96 pg/ml following a 45-minute aerobic dance routine.l 19] Blood samples were taken from 16 trained marathon runners via an indwelling catheter prior to the marathon, after 60 and 120 minutes, at the finish and during recovery. 17] 13Endorphin levels increased at 60 minutes and continued to increase at 120 minutes and at the end of the run. p-Endorphin levels increased 6.9-fold to approximately 40 pmollL by the end of the marathon. This supports the work of Goldfarb et aLl2] which suggests that duration of exercise increases circulating p-endorphin levels. The responses to exercise still seem to vary dependent on the intensity of exercise utilised, the individuals involved and the type of assay utilised to assess the changes. 1.3 Incremental Exercise

Graded exercise has typically demonstrated increases in circulating p-endorphin following exercise above a certain critical intensity.lI,20] Heitkamp et aLl7] examined the response of pendorphin to a graded treadmill test which lasted approximately 30 minutes. The level of l3-endorphin increased from a resting value of 10 to 30 pmollL at the end of the exercise. This concurs with previous reports. II ,20j Graded or incremental exercise of an aerobic nature appears to increase circulating p-endorphin. It is unclear what produces this response or what factors during the exercise may stimulate p-endorphin release (section 3).

2. Special Populations 2.1 Trained Individuals

Training has been shown to have conflicting responses to p-endorphin in the circulation, both at Sports Med. 1997 Jul: 24 (1)

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restI21-23] and in response to exercisep,IO,24-26] The level of ~-endorphin at rest has been reported to be both lower[22,23,27] and unchanged[3,19,21] in response to aerobic training. Training has also been reported to have increased,[24,25,28] made no difference to[3,12,21 ,25] or decreased[IO,26] ~-endorphin levels following exercise, but some of these studies did not compare response with that of a control group. The discrepancy in the literature is in part related to the type of training, the methods used to measure ~-endorphin and the mode of exercise utilised. Most of the studies have examined trained individuals and compared them with untrained,[3,5,24,25,28] but few studies have trained the participants,f2I-23,27] The training intensity and the selection of participants varied greatly in these studies. Methods utilised to measure ~-endorphin have varied with several studies having both ~­ endorphin and ~-lipotrophin immunoreactive activity. Finally, the determination of an alteration in ~-endorphin response could be related to a different relative intensity of exercise. ~-Endorphin response either at rest or during exercise was reported to be simi lar in trained indi viduals if relati ve exercise intensity was utilised.[3] Recently, Lobstein et aJ.f27] examined the effects of an 8-month training programme in 10 middleaged males compared with 6 males who were not trained. They reported that resting levels of ~­ endorphin decreased from 48.5 ± 3.3 to 3l.7 ± 4.4 ng/L in the trained group, with no change in the untrained males. The only other report that trained participants was an animal study.[29] Rats were trained twice a day for 5 days per week on a motor-driven treadmill, for 10, 21 or 56 days, in either normobaric or hypobaric conditions. The ~-endorphin levels at rest were not significantly altered in any of the conditions. A study examining already trained individuals and comparing them with untrained individuals has also been reported. 18 ] This paper reported on 12 endurance-trained males compared to 11 untrained males. Mild exercise of 49 ± 4% V0 2max for 2 hours did not demonstrate any changes in ~-endorphin, although it was indicated that the © Adis International Limited. All rights reserved.

Goldfarb & Jamurtas

metabolites of ~-endorphin increased. No changes in ~-endorphin were observed in the trained individuals. Exercise at 66 ± 6 and 57 ± 7% V0 2max was reported to increase plasma ~-endorphin in the untrained and trained individuals respectively. The authors indicated that the ~-endorphin levels did not differ significantly between the endurancetrained and untrained participants either prior to or during exercise. However, these authors indicated that levels of y- and a-endorphin and the ratios to ~-endorphin were significantly higher in the untrained individuals. This may indicate that endurance training alters the metabolism of ~-endorphin. Few studies have examined ~-endorphin levels in resistance-trained individuals.[l2,15] It is unclear if resistance training influences the ~-endorphin response. These studies exercised participants in relationship to their maximum lifting capacity. Future research should determine if resistance training has an effect on the ~-endorphin response by controlling intensity of exercise and total work. More research is needed to clarify the role of training on exercise-induced ~-endorphin response. 2.2 Individuals with Health Problems

Few recent studies have examined the exerciseinduced ~-endorphin response in individuals with diabetes.[30,31] Eight individuals with insulindependent diabetes under normoglycaemic and hyperglycaemic conditions were compared with 8 healthy individuals.f 31 ] Those with diabetes were infused with insulin and/or glucose to maintain glucose at either normal or hyperglycaemic levels for a minimum of 60 minutes. The participants cycled at 60 rpm at an initial power output of 25W for 2-minute intervals until exhaustion. The ~­ endorphin level at rest was lower in the individuals with diabetes when compared with the control group, independent of the glucose level. With increased percentage of maximal power output, there was an increase in ~-endorphin in the control group only at the end of the exercise (81.1 ± 8.1 ng/L). In contrast, the individuals with diabetes did not demonstrate significant alterations in ~-endorphin (38.8 ± 3.8 and 29.5 ± 2.2 ng/Lin normoglycaemic Sports Med. 1997 Jul; 24 (1)

~-Endorphin

Response to Exercise

and hyperglycaemic participants respectively). ~-Endorphin levels following exercise were lower in individuals with diabetes and silent myocardial ischaemia (SMI) as compared with those with SMI who were not diabetic.[30] It appears that the ~-endorphin response to exercise may be diminished with diabetes. This is supported by previous animal research which has indicated that ~-endorphin levels are diminished in diabetic animals under stress.[32-34] Additionally, it was reported that ~-endorphin levels in response to pain were reduced in individuals with diabetes.[35,36] It is unclear what factors in diabetes may contribute to this alteration in ~-endorphin response. Individuals with cardiac or circulatory abnormalities may have an alteration in the ~-endorphin response to exercise.[37-40] Middle-aged males suspected of coronary artery disease (n = 18) were compared with individuals with confirmed coronary artery disease (CAD) [n = 35].[37] A cycle ergometer test, increasing the load 25W every 2 minutes until maximal effort, increased ~­ endorphin at peak exercise and during recovery in the participants who were suspected of having CAD. The individuals with CAD and negative stress tests (n = 9) demonstrated an increase in ~-endorphin whereas those with a positive test did not. No difference in workload was noted between individuals with CAD having positive or negative stress tests. Perna et al.[39] examined the ~-endorphin response at rest and following exercise in individuals with left ventricular dysfunction (n = 28). They were compared with agematched healthy individuals (n =9). They noted that those with left ventricular dysfunction had elevated ~-endorphin levels at rest (3.52 ± 2.31 pmol/L) when compared with healthy individuals (1.77 ± 0.84 pmollL). Similar values in ~-endorphin were reported following the exercise. Females with confirmed coronary heart disease (CHD) demonstrated low exercise tolerance with low ~­ endorphin levels.[41] It is not clear if the ~-endorphin response was low due to the CHD or to the low exercise intensity. It appears that symptom-limited © Adis International Limited, All rights reserved,

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exercise tests probably result in lower intensities of exercise in individuals with CHD and CAD. Individuals with SMI have been examined in a number of studies to determine if ~-endorphin is implicated in the response to exercise,l3°,42-48] ~­ Endorphin levels at rest in individuals with SMI as compared with healthy individuals or those with angina has been reported to be elevated[47,48] or unchanged.[43,44] The ~-endorphin response to exercise has been reported to be higher[30,45,47,481 or no different[42-44,46] compared with that of a control group or those with angina. Naloxone was infused to block opioid receptors in individuals with SMI, but there was no difference in pain or ischaemia despite ~-endorphin levels being higher.[44,46] Depression has been suggested as a possible contributing factor to the higher ~-endorphin levels.l 491 It is possible that individuals with SMI have greater amounts of ~-endorphin, which could prevent the pain despite the myocardial ischaemia. Since these studies generally included few participants, and not all studies compared ~-endorphin response with that of healthy individuals,[42,43] more research is needed in this area.

3. Proposed Mechanisms There have been several mechanisms proposed for the increase in ~-endorphin in the circulation as a result of exercise.l9,16,51-52] 3.1 Analgesia

One proposed mechanism for ~-endorphin is related to analgesia.[52] The studies examining opioid receptors and pharmacological interventions in the modulation of pain in animals suggest that ~­ endorphin is involved in the analgesic response.[52] Data from the studies with SMI and diabetes in humans also indicate that ~-endorphin contributes to the modulation of pain perception during exercise.l47 ,48] 3.2 Lactate, pH, Base Excess

Acid-base balance (pH or lactic acid levels) has been postulated as a mechanism for the increase in Sports Med, 1997 Jul;

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~-endorphin during exercise.l 16 ,I,5l) Since exercise intensity greater than 60% V'02max has been generally reported to increase ~-endorphin, several studies have related this increase to anaerobic threshold or lactic acid production. II ,5,53) Recently, Taylor et aJ.l51) examined the effect of acidosis on ~-endorphin release during exercise. Seven male participants were exercised at 85% V'02max for 20 minutes, with either a placebo drink or a 0.3 g • kg- I sodium bicarbonate drink (500ml) ingested 1 hour prior to exercise. Buffer or saline was also infused during the exercise. The buffer significantly increased blood pH at rest and during the entire exercise test compared with placebo. Lactate levels were significantly higher in the buffer trial as compared with the placebo trial. ~-Endorphin increased over time with exercise in both groups, but there was a tendency (p =0.08) for lower ~­ endorphin levels in the buffer group. Base excess was maintained at a higher level in the buffer group. These authors (51 ) concluded that the stimulation of ~-endorphin during exercise was related to metabolic acidosis, and that base excess was the best indicator of ~-endorphin release. In contrast, endurance exercise of longer duration than 30 minutes and of sufficient intensity has been reported to produce increases in ~-endorphin but not necessarily high lactate levels.l7,54] Individuals who ran a marathon demonstrated that ~-endorphin levels increased each hour despite a constant lactate level of 3.3 to 3.5 mmollL,17] In addition, it has been reported that lactate levels were not related to ~-endorphin levels during steady-state cycling. 13 ] ~-Endorphin levels increased with time during the steady-state cycling but lactate levels remained the same or tended to decrease. Further research is needed to clarify the role of base excess, pH and lactic acid on ~-endorphin release during exercise.

3.3 Metabolic Regulation

Another factor which may stimulate ~-en­ dorphin release during exercise is metabolic or glucoregulation.l9,50,55,56] ~-Endorphin and opioidlike material have been isolated from sites involved in glucose homeostasis such as the adrenal glands, © Adis International Umited. All rights reserved.

the gut and the hypothalamic-pituitary axis.l 5o ,57,58] Several studies have attempted to elucidate the role of ~-endorphin in glucose homeostasis during exercise using either opioid antagonism or direct infusion of ~-endorphin. Table I summarises the studies which investigated the effects of ~­ endorphin on metabolic regulation during exercise. Some of the studies have examined energy substrates or determined the level of hormones involved with substrate mobilisation. It appears that ~-endorphin may be related to hormonal regulation, since opioid antagonism through the use of naloxone or naltrexone can alter hormonal responses to exercise.155 ,59-63) Angelopoulos et aJ.l55) reported that catechol amines were significantly higher during exercise at 80% V'02max with naloxone treatment as compared with a control group. Farrell et aJ.l60) reported an increase in sympathetic activity with naloxone when participants performed an isometric handgrip. This group previously reported that naltrexone treatment increased adrenoline (epinephrine) response to 70% V'02max exercise. 161 ] Naloxone infusion in 8 male participants exercising at either 70 or 90% V'02max resulted in enhanced adrenoline during exercise.162 ] Ten males exercising at 66% V'02max with naloxone treatment showed elevated catecholamine response.l 64 ] Naloxone infusion in dogs has also been reported to elevate adrenoline to a greater extent during exercise compared with saline infusion.163 ] In contrast, naloxone treatment during exercise has not always demonstrated increases in catecholamines during exercise.165-67] The lack of a response in the later studies may be related to the intensity of the exercise or the type of exercise. It is probable that ~­ endorphin has an effect on the sympatho-adrenal axis, since opioid receptors have been identified in this area. 158 ,68) The pancreatic hormones insulin and glucagon appear to be affected by either naloxone treatment or ~-endorphin infusion at restI69.71] and during exercise,155,59,62,72] although these findings are not always obtained l62 ,66] and appear to be dependent on the dose of ~-endorphin infusion or naloxone. 150,69] Sports Med. 1997 Jul; 24 (1)

~-Endorphin

Response to Exercise

Table I. Studies of the role of Study

~-endorphin

13

in metabolism during exercise Sample

Treatment

Results

Angelopoulos et al. [55J 80% \102max

Exercise

9M, humans

Naloxone

i GLU, i A, iNA, i LA

Angelopoulos et al. [59J 80% \102max

9M, humans

Naloxone

i GLCN

Bramnert et al.l65[

80%MWC

9M, humans

Naloxone

-7

A,

Corio et alJ73J

Incremental to exhaustion

7M, humans

Naloxone

-7

GLU,

-7

GH,

Farrell et al.[61J

70% \102max

8M, humans

Naltrexone

-7

GLU,

-7

FFA,

Farrell et al.(66)

24 m/min, 0% gradient

8M, rats

Naloxone

-7

GLU,

-71,

Farrell et al.[60J

Isometric handgrip

19M & F, humans

Naloxone

i sympathetic activity

Fatouros et al. [72J

22 m/min, 0% gradient

6M, rats

Naloxone

-7

~-Endorphin

i GLU, ,j, I, i GLCN, i LA

Hickey et al. [62J

90% \102max

8M, humans

Naloxone

70% \102max Imai et al.[63J

5 mph (8 km/h), 6% gradient

11M, dogs

Naloxone

2.5 mph (4 km/h), 6% gradient

NA

-7

GLU,

I,

-7

-7

i A,

-7

LA

-7

I, i A,

-7

NA,

GLCN,

-7

-7

-7

NA, iDA, i GH

Cortisol

LA

i GLU,

-7

I, i GLCN, i A, iNA,

i GLU,

-7

I,

-7

GLCN, i A,

-7

-7

LA

NA

i A A,

-7

NA

McMurray et al.[67J

Stair climbing

8M, humans

Naloxone

-7

A,

-7

NA

Staessen et al.l64J

66% \102max

10M, humans

Naloxone

-7

GLU,

Vettor et al.[77]

Swim

8, rats

Naloxone

-7

GLU, ,j, FFA

-7

-7

I, i A, iNA, -7 GH, i cortisol

Abbreviations and symbols: DA =dopamine; A =adrenoline (epinephrine); F =female; FFA =free fatty acids; GH =growth hormone; GLCN =glucagon; GLU =glucose; I =insulin; LA =lactic acid; M =male; MWC =maximum work capacity; NA =noradrenoline (norepinephrine); \102m,x =maximum oxygen uptake; i =significantly higher vs placebo; -7 = not significant vs placebo; ,j, =significantly lower vs placebo.

Higher insulin and glucagon levels were reported at rest with ~-endorphin infusion[69,7 I ,72] and in individuals who exercised with naloxone treatment,l59,62] Recently, it was noted that ~-endorphin infusion increased glucagon and decreased insulin levels at 60 and 90 minutes of exercise in rats, compared with saline infusion,l72] Further studies are needed to elucidate the role of ~-endorphin on the regulation of pancreatic hormones during exercise. The glucose response to naloxone and exercise has been reported to have either no effect[6 I ,64,66,72-74] or an enhanced effect,[55,62] The discrepancy in results may be related to the type and duration of exercise. In addition, the dose of opioid antagonist is crucial since the antagonist may stimulate the opioid receptors at high doses.[75,50] Both studies that reported elevated glucose response with naloxone utilised exercise intensities of 80 and 90% 'V0 2max .[55,62] In contrast, incremental exercise[73] and exercise at 66 and 70% 'V02maX£61,64] reported naloxone to have no effect on glucose. It is possible that the intensity and duration of the exercise influences the ~-endorphin response, which © Adis International Limited. All rights reserved.

probably contributes to factors influencing glucose homeostasis. Recently, it was shown that types III and IV muscle afferent nerves, which are active during muscle contraction, influence glucose production, plasma glucose and ~-endorphin depending on the magnitude of threshold stimulation.[9] Threshold stimulation needed to activate group IV muscle afferent fibres increased ~-endorphin, corticotrophin (adenocorticotrophic hormone), plasma glucose and decreased insulin compared with a control group. It was proposed that muscle afferent fibres (III and IV) are a link to activating hormonal and metabolic factors during exercise. ~-Endorphin and the opioid system have also been shown to have effects in vitro and in vivo on lipolytic activity,l74,76,77] Limited information is available concerning ~-endorphin effect on lipolysis during exercise,l61,77] Opioid antagonism with naltrexone was reported to hllve no effect on circulating free fatty acids in 8 males exercising at 70% 'V0 2max ,l61] In contrast, naloxone was shown to decrease circulating free fatty acids in 8 rats which swam.[77] Clearly, further research is warranted to Sports Med. 1997 Jul;

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elucidate ~-endorphin role in the regulation of free fatty acids. In conclusion, ~-endorphin appears to be released during exercise of a sufficient intensity and duration. Exercise response may be affected by the training status of the individual and the population being investigated. The response of ~-endorphin in special populations should, if possible, indicate the relative exercise intensity. Finally, the implications of ~-endorphin in modulating pain and hormonal and metabolic responses during exercise need to be clarified.

Acknowledgements This manuscript was supported in part by the Department of Exercise and Sport Science, University of North Carolina - Greensboro.

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Correspondence and reprints: Dr Allan H. Goldfarb, Exercise and Sport Science Deparnnent, University of North Carolina - Greensboro, Greensboro, NC 27412, USA. E-mail: [email protected]

Sports Mad. 1997 Jut 24 (1)