Well known for its effects on arousal, attention, and wakefulness, caffeine has been a widely consumed CNS stimulant for centuries. More recently, the drug has been found to enhance laboratory tests of human athletic performance (5,20,21), spurring considerable interest in the use of caffeine as an ergogenic aid. Evidence that caffeine increases spontaneous (line-crossing and rearing movements in caged animals) and voluntary (treadmill running) locomotor activity through its actions as a CNS adenosine receptor antagonist has been obtained using an animal model (6). In humans, caffeine-induced increases in maximal voluntary activation and torque have been observed that cannot be attributed to enhanced skeletal muscle contractile properties or peripheral transmission (25,36). These observations suggest that the central modulation of motor unit activity may be altered by caffeine. The purpose of this review is to summarize the mechanisms by which caffeine may modulate the voluntary activation of human muscle and to describe recent studies that demonstrate the effects of caffeine on the human CNS.
A typical oral dose of pure caffeine in a human experiment is 6 mg·kg−1 body weight, or approximately 490 mg for a 180-lb person. While this is approximately the quantity of caffeine that would be found in four to five cups of drip coffee, the effects of caffeine are partially negated when administered in the form of coffee (20). This dose of pure caffeine would result in a plasma caffeine concentration of approximately 40 μmol·L−1 (8 μg·mL−1) within approximately 1 h (21). The drug enters the brain via diffusion as well as saturable, carrier-mediated transport resulting in a brain-to-plasma ratio of 80% in an animal model (31). Cerebrospinal fluid-to-plasma caffeine ratios range from 0.98 to 0.52 in human newborns (49) and adults (45), respectively.
Three mechanisms of caffeine's actions have been observed in vitro: 1) intracellular calcium mobilization via direct interaction with calcium channels in the sarcoplasmic reticulum, 2) phosphodiesterase inhibition, and 3) adenosine receptor antagonism. The first two of these three mechanisms require millimolar concentrations of caffeine, a range that would be toxic in vivo, suggesting that neither phosphodiesterase inhibition nor calcium mobilization plays a large role in caffeine's effects in human studies. Only studies employing low-frequency electrical stimulation suggest that caffeine has a direct effect on human muscle (30,47). Adenosine receptor antagonism, on the other hand, occurs at plasma caffeine concentrations corresponding to those expected following moderate oral doses of the drug. Consequently, the widespread effects of caffeine on human tissues are most likely due to antagonism of adenosine receptors (for review, see ref. 14).
CAFFEINE AND MUSCLE: PERIPHERAL MODULATION
The ability of caffeine to cause muscle contraction in the absence of membrane depolarization was first demonstrated in 1958 (3). This was later attributed to the release of calcium from the sarcoplasmic reticulum (52) via interaction with the ryanodine receptor (39). In vitro observations of increased tetanic force and a decreased rate of relaxation (2) are consistent with the effects of caffeine on calcium. However, these studies all use millimolar concentrations of caffeine and may not reflect caffeine's effects on contractile force in vivo. This possibility was examined in situ by James et al. (24), who compared the effects of a 70-μmol·L−1 caffeine concentration (corresponding to the plasma concentrations observed in human studies) and a 10-mmol·L−1 caffeine concentration (corresponding to the caffeine concentrations used in vitro). In their study, 10 mmol·L−1of caffeine increased force production per cross-sectional area when administered after a fatigue protocol. The micromolar caffeine concentration had no effect compared to the vehicle-only group (Fig. 1). This would suggest that the micromolar concentrations of caffeine elicited in human studies would have no direct effect on skeletal muscle. Most human studies support this hypothesis and report no effect of caffeine on twitch amplitude (25,26,36,47), twitch half relaxation time (25,26,36), or maximal instantaneous rate of twitch relaxation (25,26,36) in either unfatigued or fatigued human muscle. However, there does appear to be an interaction between caffeine and low-frequency fatigue in humans (30,47). For example, Tarnopolsky and Cupido (47) applied 2 min of either low (20 Hz) or high (40 Hz) peroneal nerve stimulation to fatigue the ankle dorsiflexors approximately 1.5 h after caffeine or placebo administration. Caffeine partially offset the decline in tetanic force in the low-frequency condition but had no effect on the high-frequency tetanic force, maximal voluntary contraction, or the twitch or mass action potential (M wave). Because low-frequency fatigue has been attributed to a reduction in calcium release by the ryanodine receptor, the selective effect of caffeine on this type of failure suggests that caffeine does have a direct action on the skeletal muscle in vivo following electrical stimulation.
CAFFEINE AND CENTRAL MODULATION
Adenosine is an endogenous neuromodulator that exerts a tonic inhibitory influence in the CNS. It decreases excitatory neurotransmitter release (15) and the firing rates of central neurons (35). Because caffeine is very similar in structure to the purine base of the adenosine molecule, it functions as an adenosine receptor antagonist and reverses many of the inhibitory effects of adenosine at concentrations in the micromolar range. In the CNS, caffeine increases neurotransmitter release and firing rates via A1 receptor antagonism and increases dopaminergic transmission via postsynaptic mechanisms modulated by the A2a receptors (12; for review, see (14)). The role of adenosine receptors in the modulation of spontaneous motor activity as well as endurance has been demonstrated in rats by Davis et al. (6) by observing line crossing, rearing, and treadmill running time to exhaustion following intracerebroventricular and intraperitoneal injections of N-ethylcarbamidoadenosine (NECA, an A1 and A2a receptor agonist), caffeine, and caffeine + NECA. Compared to the vehicle only, intracerebroventricular caffeine injection increased spontaneous motor activity and running time, whereas NECA diminished these motor activities. Intraperitoneal injections of the drugs had no effect. While the effects of adenosine and caffeine on the CNS are certainly more complex than described in this brief review, data such as those presented by Davis et al. (6) provide a rationale for studying the effects of caffeine on the central modulation of human motor unit activity.
Two studies were conducted in our laboratory that directed our interest to the effects of caffeine on the human CNS (25,36). Both of these investigations, carried out using the quadriceps femoris muscle group, revealed that a 6-mg·kg−1 dose of caffeine increased the duration of an isometric knee extension protocol, maximal voluntary torque, and maximal voluntary activation assessed using the twitch interpolation technique. Because supramaximal electrical nerve stimulation revealed no effect of caffeine on the M wave or contractile properties either before or after the fatigue protocol in these studies, the effects on volitional muscle activation could not be attributed to peripheral changes. This led us to use transcranial magnetic stimulation to investigate caffeine's effects on central excitability in a third experiment. Transcranial magnetic stimulation (TMS) activates corticospinal motor neurons presynaptically (7). The amplitude of the resultant motor evoked potential (MEP) recorded from the muscle provides an estimate of central excitability. Using this technique, we have found that caffeine augments the increase in MEP amplitude that typically occurs at the beginning of a fatigue protocol, but before failure known as postactivation potentiation (Fig. 2) (26). These three studies (25,26,36) suggest that caffeine increases muscle activation via a central mechanism, but they do not provide sufficient insight into the mechanisms responsible for these effects. Voluntary muscle activation may be modulated by alterations in voluntary or involuntary supraspinal input, the membrane properties of spinal motor neurons, as well as afferent feedback to the spine or cortex. Accordingly, caffeine may exert an effect through any or all of these mechanisms.
CAFFEINE AND AFFERENT FEEDBACK: PAIN AND FORCE SENSATION
The effects of adenosine on nociception are complex and occur at multiple sites in the peripheral nervous system and CNS. It is pronociceptive via its actions on A2 receptors in sensory nerve terminals and antinociceptive via its actions on A1 receptors in the spinal cord (40). Nonetheless, caffeine is known for its analgesic properties and is used in a variety of pain medications.
A number of recent studies have demonstrated the effects of caffeine on pain as well as force sensation during muscular effort (Fig. 3). Motl et al. (32) assessed the effects of a 10-mg·kg−1 dose of caffeine on muscle contraction pain. In their repeated-measures, double-blind experiment, subjects ranked pain using a 10-point numeric and verbal anchor scale every 5 min during a 30-min bout of cycling at 60% V̇O2max. By the end of the exercise bout, pain was ranked significantly lower in the caffeine trial compared to that of the placebo trial (Fig. 3A). In another study (33), an ischemic model was used to evoke muscle pain by occluding blood flow to the forearm during a 1-min set of wrist curls. A visual analog scale was used to assess pain at 15-s intervals. Compared to the placebo trial, a 200-mg dose of caffeine decreased pain at 15 and 30 s but not at the end of the protocol (Fig. 3B).
One of the difficulties in assessing and comparing pain is that both pain and the scales used to quantify it are inherently subjective. To address this limitation, Plaskett and Cafarelli (36) used constant sensation contractions to provide a more objective quantification of force sensation during sustained, submaximal, isometric knee extension. Subjects were asked to reach a target force of 50% of their maximal voluntary torque. Once the target was met, visual feedback was removed and the subject was asked to maintain the same sensation of force for 100 s. With this technique, subjects must decrease torque as the contraction progresses and discomfort increases in order to maintain the sensation of a constant torque. This provides an objective, continuous, and reproducible estimate of force sensation that can be fit to a double-exponential equation. Plaskett and Cafarelli (36) report a reduction in force sensation in the first 10–20 s of the contraction following caffeine administration (Fig. 3C). A distinction should be made between pain and force sensation although the two may coexist, and force sensation may increase to the point at which it is painful. Nonetheless, the constant sensation paradigm does provide some insight into the afferent processes that may limit voluntary activation.
The sensations of force and pain are modulated at several locations in the CNS and peripheral nervous system, making the interpretation of the above experiments somewhat speculative. Peripherally, the discomfort accompanying prolonged muscular effort may be modulated by the concentration of metabolites within skeletal muscle as well as the sensitivity of nociceptive afferent terminals. However, caffeine's antinociceptive effects are not likely due to enhanced removal of metabolites for the following reasons: 1) exercise hyperemia is strongly correlated with increased adenosine concentration (23); 2) exercise-induced skeletal muscle blood flow is attenuated when adenosine receptors are blocked with theophylline (a methylxanthine very similar in structure to caffeine) (38) such that caffeine would prevent rather than promote the removal of metabolites; and 3) caffeine diminishes force sensation and pain at the onset of fatigue protocols when metabolite accumulation would be lowest (33,36). Finally, caffeine has no effect on contractile properties over the course of voluntary isometric fatigue protocols (25,26,36), which would suggest that the drug does not diminish force and pain sensation by slowing the production of metabolites via an improved efficiency of the contractile apparatus. On the other hand, adenosine increases the release of histamine and serotonin from mast cells, resulting in pain and edema via A3 receptor activation (42). Adenosine's pronociceptive actions have also been attributed to increased cAMP in sensory nerve terminals (46). Thus, as an adenosine receptor antagonist, caffeine may decrease nociceptor activation and peripheral pain transmission.
Pain sensation may be modulated centrally by inhibition or facilitation of nociceptive transmission at a spinal or supraspinal level or by cortical modulation of pain perception. Spinal adenosinergic transmission is antinociceptive and, accordingly, the effect of adenosine receptor antagonism at a spinal level is increased pain transmission (37), and it may therefore be assumed that caffeine would enhance spinal pain transmission. There is some evidence to suggest, however, that caffeine may diminish pain at a supraspinal level via increased cholinergic (19), noradrenergic, and serotonergic transmission (41). Finally, it could be hypothesized that caffeine improves the efficiency of motor unit activation by opposing the decline in motor unit firing rates that occur subsequent to muscle pain elicited with hypertonic saline or capsaicin injection (11,44). While caffeine does not increase motor unit firing rates during short-duration, nonfatiguing, submaximal contractions (25), its effects on pain-induced reductions in motor unit firing rates have not yet been explored.
SPINAL EFFECTS OF CAFFEINE
The terms “spinal excitability” and “motorneuronal excitability” have been used to describe the output (e.g., force, EMG) of a motor neuron pool to an input stimulus (e.g., tendon tap, vibration, nerve stimulation) of a given intensity in humans. The effects of caffeine on spinal excitability have been examined in a number of studies using the Hoffman reflex (H reflex). This technique uses a low-intensity, long-duration percutaneous electrical stimulus to preferentially activate large diameter afferents that project to the motor neuron pool. This afferent input depolarizes a portion of the pool dependent on pre- and postsynaptic input as well as motor neuron membrane properties. Initial attempts used the maximal H reflex (Hmax), a single point on the H reflex recruitment curve, as an estimate of the excitability of the motor neuron pool and revealed no effect of caffeine (9,25). However, it has been suggested that the slope of the H reflex recruitment curve (Hslp) is a more sensitive measure than Hmax (16). Walton et al. (50) found an increase in soleus Hslp following a 6-mg·kg−1 dose of caffeine when compared to a placebo trial (Fig. 4), but no effect on Hmax. This was the first study to report an effect of caffeine on the excitability of a human motor neuron pool; however, the H reflex technique does not reflect the mechanism by which motor neuronal excitability is altered.
The excitability of a motor neuron, or the likelihood that an EPSP of a given intensity will result in an action potential, is dependent on the sum of all synaptic input to the motor neuron as well as the membrane properties. While shifts in the resting membrane potential cannot be assessed directly in humans, there are a few techniques that can be used to estimate the intrinsic excitability of the motor neuron. One approach is to use paired motor unit recordings to record the incidence of self-sustained firing (28). Very briefly, the firing rate of a single motor unit is used as an estimate of synaptic input in a muscle that is known to be rate coded. The subject, provided with visual and auditory feedback, is asked to maintain a constant firing rate before and after tendon vibration. If the firing rate of the control unit remains constant, or drops, it is assumed that synaptic input common to the motor unit pool has not increased. In some instances, despite a constant pre- to postvibration synaptic input, a second unit (test unit) is recruited and continues to fire even after the stimulus has been removed. This is interpreted as a shift in the membrane potential toward threshold due to the activation of voltage-sensitive, noninactivating L-type Ca2+ channels and the resultant persistent inward current (28). Using this paired motor unit technique, Walton et al. (51) demonstrated an increase in the incidence of self-sustained firing following caffeine administration when compared to a placebo trial. Thus, caffeine may increase the excitability of alpha motor neurons by facilitating plateau potentials. This may occur via a caffeine-induced increase in tonic descending input to the motor neuron known to facilitate the production of plateau potentials (e.g., serotonergic or noradrenergic input) or perhaps through a more direct effect on motor neuronal calcium conductance. These explanations, however, are entirely speculative.
SUPRASPINAL EFFECTS OF CAFFEINE
The effects of caffeine on supraspinal processes such as vigilance, attention, wakefulness, and arousal have been of great research interest (for reviews, see (13,43)). Well known to consumers, at least anecdotally, these effects likely contribute to the high caffeine consumption in countries worldwide. For the purposes of this review, the effects of adenosine and caffeine on the central modulation of locomotor activity are of particular interest. Intracerebroventricular injection of adenosine analogs results in decreased spontaneous motor activity (4,6) and run time to fatigue (6). The effects of caffeine on rodent locomotor activity are biphasic, with a threshold effect at approximately 3 mg·kg−1, the greatest increase in locomotor activity at approximately 25 mg·kg−1, and locomotor depression at 100 mg·kg−1 (10,18). It has been proposed that increased motor activity at low doses of caffeine are due to A2a receptor blockade, while the motor depressant effects are due to A1 receptor antagonism (10). Furthermore, the effects of caffeine on motor activity are modulated, at least in part, by dopaminergic transmission (18) likely via adenosine-dopamine interactions in the basal ganglia (for review, see ref. 13). While the preceding data suggest that caffeine modulates motor unit activation supraspinally, there is no direct evidence of supraspinal modulation in human studies currently available in the literature. This lack of empirical evidence may be attributed to the difficulty of localizing central effects to supraspinal mechanisms using conventional techniques employed in human neurophysiological research.
There are alternative experimental approaches that could be used to reveal the supraspinal effects of caffeine on motor unit activation in future studies. For example, paired-pulse TMS has been used to assess intracranial inhibition and facilitation of the corticospinal motor neuron in a large number of pharmacological and pathophysiological studies (53). This technique may therefore lend itself to the study of caffeine's effects on cortical excitability and motor unit activation. Alternatively, cortically evoked twitch interpolation and the cortical silent period, which have been used effectively to investigate central failure (17,48) may provide some insight into the cortical effects of caffeine on voluntary activation.
The known effects of caffeine on the human neuromuscular system include a decrease in low-frequency fatigue (30,47), increased voluntary activation and maximal voluntary force production (25,36), increased postactivation potentiation of the motor evoked potential (26), decreased force sensation (36), and muscle pain (32,33), increased spinal excitability (50), and an increased incidence of self-sustained firing (51). Once caffeine's supraspinal effects are better characterized, it may be possible to use it as a perturbation at various sites to study the human neuromuscular system from the muscle to the motor cortex.
Despite the ease with which caffeine may be used in neuromuscular studies, several limitations should be taken into consideration. First and foremost, the fact that caffeine appears to affect motor unit activation at several sites along the motor pathway requires a judicious interpretation of experimental results. For example, if caffeine is used to study central fatigue, it is necessary to assess peripheral transmission and contractile properties before attributing any caffeine-induced changes in muscle activation to central mechanisms. It may also be necessary to restrict the selection of subjects to obtain a population homogeneous with respect to the variables that effect caffeine metabolism. This is particularly important if plasma caffeine concentrations are not assessed. Factors that alter the rate of caffeine metabolism and clearance include menstrual cycle (29), oral contraceptive drugs (1), obesity (27), and smoking (34). Habituation to the drug should also be taken into consideration. While some studies have reported that habitual caffeine consumption diminishes the effects of an acute dose of caffeine on endurance performance (5), habituation does not appear to diminish the ergogenic effects of caffeine in other studies (8). However, a person who is habituated may suffer withdrawal symptoms such as headache and fatigue (22) during the washout period that is required before each experiment. Furthermore, these withdrawal symptoms may alter performance on the days that the habituated subject receives a placebo. Finally, as with most drugs, there is a variable response to caffeine in any sample of subjects. The distribution of caffeine's effect on isometric knee extension time to exhaustion is illustrated in Figure 5 as an example. Therefore, while the magnitude of caffeine's effect on neuromuscular endurance is quite reproducible, a large sample size may be required for adequate statistical power.
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