Competition vs. Exercise-Induced Analgesia 1 Running head: COMPETITION VS. EXERCISE-INDUCED ANALGESIA Competition vs. Exercise-Induced Analgesia in Male and Female Athletes and Non- Athletes

Pain sensitivity in 52 college male and female athletes and non-athletes was assessed at baseline and then after exercise and competition while workload was held constant. Subjects pedaled on a stationary bike for 20 minutes at 60% maximum capacity in both exercise and competition conditions. Non-exercising, repeated-pain testing controls were tested at the same time intervals. Pain sensitivity was measured by heat pain threshold, thermal scaling and the cold pressor test. Subjects showed a significant decrease in pain sensitivity between baseline and exercise conditions (on thermal scaling) and again between exercise and competition conditions (on thermal scaling and heat pain threshold). Repeated pain testing in non-exercising subjects revealed a significant increase in heat pain threshold of athletes between their first and third testing sessions as well as significantly greater pain ratings of female non-athletes than female athletes on the cold pressor. Possible conclusions are that exercise and competition produce likestrength analgesia regardless of sex and athletic status, and that athletes show a lessened response to pain over time. Competition vs. Exercise-Induced Analgesia 3 Pain has been the focus of investigation for as long as humans have been examining ways to control it. From carefully calculated torture of highly sensitive body parts to careful application of a precisely appropriate anesthetic, the study of pain is one that persists due to its “natural” importance. Central to perceptual experience as the salient warning of noxious stimuli, pain is a strong motivator of behavior and hence an important subject for psychological research. To approach pain as a topic for study, the adaptive function of pain must be considered. The presence of pain-sensing circuitry in the human nervous system serves most obviously to alert the sensing being of danger so that the danger may be recognized as such and avoided. Thus an organism who can feel pain is afforded protection by this ability. However, pain can also be debilitating and construed as disadvantageous in certain situations such as when a wounded animal needs to fight or escape but might be hampered from doing so by intense pain. This construal of pain as potentially “disadvantageous” might seem to conflict with the idea of pain as “protection”, yet evidence shows that the body’s perceptual system may account for this variance of the adaptive function of pain by inhibiting pain in response to certain forms of stress. The phenomenon of analgesia, a body state in which pain threshold is heightened, supports this view. Certain forms of stress trigger adaptive, physiological mechanisms within an organism’s brain which in turn, through descending (from brain down) nerve pathways, causes an analgesic state known as “stress-induced analgesia.” The environmental stressors that trigger stress-induced analgesia within an organism are varied. However, the type of stressor researchers generally think of when considering stress induced analgesia is aptly defined as “an event, internal or external to an animal, that poses a real Competition vs. Exercise-Induced Analgesia 4 or perceived threat to the maintenance of the animal’s homeostasis” (Yamada & Nabeshima, 1994). Endocrine responses to these types of stressors, such as the release of adrenocrticotropic hormone into the bloodstream, occur reliably enough so that researchers are capable of unifying diverse forms of environmental stimuli into a single type under the common label “stressors.” Forced cold water swim, electric shock and food deprivation are examples of stressors which have been used in a laboratory to induce analgesia (Amit & Galina, 1986). Of interest to the current study, however is the finding that exercise and competition have been identified as stressors capable of inducing analgesia in humans. Having emerged only recently as a scientifically documented phenomenon, endogenous analgesia highlights the adaptive capability of the body to modulate pain perception. However, the early models generated by researchers to explain how the nervous system perceived pain did not account for such adaptive modulation of pain and instead concentrated on how a painful stimulus was directly encoded by the peripheral nervous system and communicated to the brain. Researchers at the time argued over whether or not there were specific receptors for pain. The specificity theory of pain, proposed by Von Frey in 1894, hypothesized that there were indeed specific sensory receptors for painful stimuli just as there were specific receptors for other sensations (like warmth or pressure). Yet almost contemporaneously, an alternative theory called the pattern theory of pain proposed by Goldschneider asserted that there were no specific receptors for pain, but rather specific patterns of nerve fiber discharges that were responsible for the discrimination between different sensations (Gatchel, 1999). However, much evidence then amassed which suggested that Competition vs. Exercise-Induced Analgesia 5 the central nervous system exerted a top-down control over pain perception and so both theories became inadequate. Neither theory could account for the finding that the brain could perceive the same painful stimulus differentially or that psychological factors (such as anxiety) could affect pain perception. An empirical demonstration of analgesia by Beecher (1956), however, presented evidence that discounted both theories. Beecher systematically noted the differences in perceived pain between wounded WWII soldiers and wounded civilians through their subjective reports and pain killer requests for similar procedures (Gatchel, 1999). His striking results that soldiers recently returned from battle felt significantly less pain contributed to the factors which made a revision of pain theory necessary. Thus a new theory replaced the old with the advent of the gate control theory (1965). Proposed by Melzack and Wall, the gate control theory proposed that the perception of pain was modulated by the central nervous system and hence accounted for the impact of psychological factors on pain perception. It accounted for the finding that the firing of nonnociceptive afferents (peripheral nerves which communicate to the central nervous system information other than the pain message) inhibits the firing of nociceptive afferents (peripheral nerves which do communicate a pain message to the central nervous system) in the spinal cord. The discovery of this “gate” for the pain message which could be “opened” by nociceptive stimulation and “closed” by nonnociceptive stimulation popularized a pain reduction therapy tactic in which nonnociceptive afferents in the spinal cord were stimulated by electrodes on the skin (Basbaum & Jessel, 2000). The theory also viewed pain perception as a complex system which operated not only with different brain structures (all of which could influence the Competition vs. Exercise-Induced Analgesia 6 pain message passed to the brain from the peripheral nervous system), but with different types of sensory pain receptors for different types of pain. However, the gate control theory is no longer a complete explanation of pain perception since it does not account for new chemical understandings of the pain message. The evidence amassed in the last fifty years has extensively expanded our knowledge of pain. Nervous system anatomy has become much more classifiable as techniques have improved and allowed researchers to probe even microscopic levels of activity. Due to such advancement, it has been possible to identify specific sensory receptors for pain. Von Frey’s 1894 specificity theory of pain was therefore confirmed half a century after it had been so hotly debated. These specific pain receptors are called “nociceptors” and must be present in a tissue for the encoding of the pain message. Sensitive to mechanical, thermal and chemical noxious stimuli, nociceptors encode the pain message and transmit it to the central nervous system. It is in the central nervous system, in the brain more specifically, where the subjective perceptual event of pain occurs. Examination of the nerves which start the pain message and perform this transduction process has revealed three basic types of nociceptors: Aδ mechanoreceptors, Aδ mechanothermal receptors and C-polymodal receptors. Type C polymodal nociceptors are the slowest conducting of the three types since speed of transmission is positively correlated with wide axonal diameter and the presence of a myelin sheath and C nociceptors are small and unmyelinated. Conversely, type Aδ nociceptors are faster conducting by merit of their possessing a larger diameter as well as a myelin sheath. Type C fiber afferents are the most common element in the peripheral Competition vs. Exercise-Induced Analgesia 7 nerve (3/4 of all primary afferents in primates) and are overwhelmingly (completely in humans) nociceptive (Fields, 1987). The C fiber nerves in humans are all “polymodal” in that they all respond to stimulus from several modalities; they are responsive to noxious thermal, mechanical and chemical stimuli applied to the skin. Type Aδ nociceptors (mechanothermal receptors and mechanoreceptors) respond differentially to noxious stimuli. The type Aδ nociceptors responsive to noxious mechanical as well as noxious thermal stimuli are Aδ mechanothermal receptors. This type of nociceptor constitutes about 20-50% of Aδ nociceptors. The remainder of Aδ nociceptors are referred to as high-threshold mechanoreceptors. Aδ nociceptors are referred to as high-threshold mechanoreceptors because although they do respond to noxious mechanical stimuli just as mechanothermal Aδ do, they do not discharge in response to noxious thermal stimuli unless it is of high intensity—for these neurons do not respond to the first application of noxious thermal stimulus by definition. Instead Aδ mechanoreceptors respond and give progressively larger responses to repeated noxious thermal stimuli and their discharge does increase as the stimulus intensity increases into the range that produces tissue damage. Therefore when a Aδ mechanoreceptor is sensitized to thermal stimulus, it behaves much like a Aδ mechanothermal receptor. Sensitization, or hyperalgesia, occurs as a result of repeated stimulus and as a neuronal reaction to substances in the extracellular space (such as what’s been released from damaged cells). The unique contributions of these different types of nociceptors to the perceptual experience of pain is most clearly evidenced by an experimental manipulation which selectively blocks either Aδ or C nociceptors. Brief intense stimuli delivered to the distal Competition vs. Exercise-Induced Analgesia 8 limb has been observed to give rise to two distinct sensations: an initial sharp and brief, pricking sensation (first pain) and then a prolonged, dull sensation (second pain). However, when researchers selectively block Aδ nociceptors, the first pain sensation vanishes. Conversely, when C nociceptors are selectively blocked, second pain vanishes (Fields, 1987). Thus it appears that Aδ nociceptors are the peripheral nerve responsible for fast communication of the first, pricking pain and that C nociceptors are the peripheral nerve responsible for the communication of the second, duller pain. The faster conduction velocity of Aδ nociceptors relative to C nociceptors (from their greater diameter and myelin sheath) logically compliments this observation since the Aδ nociceptor pain is perceived first. Also, it stands to reason that the first pain communicated by the Aδ nociceptors, if it is thermal stimulus, is communicated by the Aδ mechanothermal receptors rather than the high-threshold Aδ mechanoreceptors since the latter does not respond to thermal stimulus unless sensitized. Despite the attraction to assign these distinct qualities of the pain experience to the activity of the distinct types of nociceptors, doing so would be an oversimplification of the process of transduction of painful stimuli since any naturally occuring stimulus will simultaneously activate a broad range of receptors and nociceptors. The communication of the pain message within the central nervous system begins with the ascension of the message up the spinal cord and then from the spinal cord to the brain along five ascending pathways. The five pathways which carry the pain message from the spinal cord to the brain terminate in either the thalamus or the cortex. These pathways include the spinothalamic tract (the most prominent of the ascending nociceptive pathways of the spinal cord which transmits the information from the spinal Competition vs. Exercise-Induced Analgesia 9 cord to the thalamus), the spinoreticular tract (which communicates the message to both the thalamus and the reticular formation of the cortex), the cervicothalamic tract (which terminates in the thalamus and the midbrain), the spinohypothalamic tract (brings the message to brain’s autonomic control centers such as the hypothalamus), and the spinomesenphalic tract (which carries the message to the mesencephalic reticular formation and the periaqueductal gray matter of the cortex and, through a link with the parabrachial nucliei, sends the pain information on to the amygdala, a sub-cortical structure of the neural system involved in emotion (limbic system). The spinomesenchephalic tract is thought to contribute the affective component of pain due to it’s connection to this emotional system (Basbaum & Jessel, 2000). The dissection of the pain experience as having an affective-motivational component (“unpleasantness”) and a sensory-discriminative component (“intensity”) is a commonly accepted division due to evidence which includes the identification of distinct brain regions related to the distinct affective and sensory experiences of pain. Tolle, Kaufmann & Siessmeier et al. (1999), utilizing the brain imaging technique of positron emission topography, found that the degree of activation of certain brain regions significantly corresponded to independent subjective ratings of unpleasantness and intensity. The coding of pain intensity appeared to be related to activity in the periventicular gray matter as well as to the posterior cingulate cortex, whereas the encoding of pain unpleasantness appeared to be related to the activity in the posterior sector of the anterior cingulate cortex. The results of this data therefore support the notion that spatially distinct regions within the brain specifically process the sensory and affective components of pain. Competition vs. Exercise-Induced Analgesia 10 The specific anatomy of the nervous system which corresponds to the activation of analgesic mechanisms (the previously discussed modulatory circuitry) has also begun to be identified. The periaqueductual gray region of the cortex is one brain structure which, upon stimulation, produces analgesia (Basbaum & Jessel, 2000). Rats with stimulating electrodes implanted in this region underwent abdominal surgery and did not have aversive reactions to any of the surgical procedures (Reynolds, 1969). The analgesia produced, however, is not a heightening of general sensory thresholds since only pain perception, and not other sensory perception, is affected. For example, the rats who were operated upon, although showing no aversive response to the surgical procedure, did show startle and struggle when there were quick movements in their visual field (Reynolds, 1969). Research has shown that the animal experiencing analgesia from stimulation in this region maintains responsiveness to other sensory stimuli such as touch, pressure and temperature; it just feels less pain (Basbaum & Jessel, 2000). Therefore the periaqueductal gray matter is a brain region specific to the modulation of nociceptive information in particular through a descending (from brain to periphery) pathway. The heightening of the pain threshold achieved by analgesia by descending inhibition occurs at the level of the spinal cord. The firing of peripheral nociceptive neurons is not affected by descending pathways. However, the greater electrical charge (greater ion influx) required to cause a firing of a spinal cord nociceptive neuron as a result of brain stimulation is evidence of the brain’s ability to use a descending pathway to raise the pain threshold (Basbaum & Jessel, 2000). Inhibitory connections from the periaqueductal gray region of the cortex to the nociceptive neurons in the dorsal horn of the spinal cord (accomplished mostly via excitatory connections with the serotenergic Competition vs. Exercise-Induced Analgesia 11 neurons of the nucleus raphe magnus of the medulla) enable that brain region to inhibit the communication of the pain message within the spinal cord (Basbaum & Jessel, 2000). The pain message in the spinal cord is also inhibited by virtue of other descending pathways, such as those that originate in the brain regions of the medulla and pons. These pathways inhibit spinal cord neurons by both direct and indirect inhibitory actions. The chemical identity of the inhibitory messages has also been analyzed. So far, the chemicals associated with communication of the analgesic message have been identified as opioid. Opiates are a type of chemical most certainly known to cause analgesia since experimental evidence implicating opiates as the identity of the neurotransmitters involved in communication of the analgesic message is extensive. Morphine and codiene, for example, are opiates which have long been used by doctors to lessen the pain of their patients because the human body responds to opiate administration by decreasing pain sensitivity. The notion that our bodies have endogenous opioids, and therefore possess a “natural narcotic”, was confirmed further by the discovery of opioid receptors in the nervous system (Basbaum & Jessel, 2000). This discovery revealed specifically that the body is prepared to receive opiates as neurotransmitters and recognizes opiates as a valid form of inter-neuronal communication. High concentrations of opioid receptors in central nervous system structures specifically identified as important to the modulation of pain (ie: periaqueductal gray matter, ventral medulla, dorsal horn of the spinal cord) further implicate opiates as carriers of the analgesic message. Opiate-induced analgesia has also been shown to utilize the same pathways as the stimulation-produced analgesia (such as that produced by stimulation of periaqueductal gray matter (Reynolds, 1969)) Competition vs. Exercise-Induced Analgesia 12 because microinjections of the opiate morphine into those specific, pain-mediating brain regions produces a powerful analgesia by inhibition of the nociceptive neurons in the dorsal horn of the spinal cord (Basbaum & Jessel, 2000). However, when neurotransmitters are discussed in terms of their role in communication of the analgesic message, they are referred to as “opioid” or “nonopioid” although those terms specifically mean “μ-opioid” and “non-μ opioid” respectively. Because a high correlation exists between the strength of an analgesic and its affinity for binding to the opioid receptor type μ, affinity for receptor μ serves as a fundamental distinction between types of analgesics (Basbaum & Jessel, 2000). Although other classes of endogenous opiates (such as opiates κ and δ) exist, experimental manipulation which blocks μ opiate receptors through the administration of the drug naloxone has demonstrated the strength of μ opiates as communicators as the analgesic message. Naloxone acts as an opiate antagonist by specifically binding to opioid receptors (with the highest affinity for type μ) without itself activating the receptor. Therefore after administration of naloxone, the μ opioid receptor is blocked and any analgesia caused by μ opioid receptor communication vanishes. The analgesic effect of the opiate morphine, for example, vanishes when an injection of naloxone is made into pain modulating regions such as the periaqueductal gray region or the serotenergic nucleus of the medulla (Basbaum & Jessel, 2000). Also, the pain relief afforded to human patients with intractable pain problems through electrical stimulation of the periaqueductal and periventricular gray matter was reversed with administration of naloxone (Hosobuchi, Adams & Linchitz, 1976). Hence, analgesic effects were eradicated when μ opiate receptor communication in the nervous system was disabled. Competition vs. Exercise-Induced Analgesia 13 However, research has demonstrated that analgesia does not always completely vanish with the administration of naloxone and the disablement of μ opiate receptors. Thus a non-μ opioid, or “naloxone-insenstive”, category of analgesics is revealed. Although this category is one which could contain opioids which are just not type μ, it is nonetheless commonly referred to in the literature as “nonopioid”. Conversely, the μ opioid category is simply referred to as “opioid” despite the fact that it only really encompasses one type (μ) of several endogenous opioids (such as κ and δ). A model which attempts to explain the existence of both opioid and nonopioid systems is the collateral inhibition model. The collateral inhibition model proposes that one analgesic system, which is initially activated by the specific intensity and temporal pattern of the stressor, inhibits the other system. Some researchers have reasoned that this would be adaptive for an organism since one pain-inhibition system would always remain functional (Kirchgessner, Nodnar, & Pasternak, 1982 as cited by Amit & Galina, 1986). Evidence for the existence of collateral inhibitory mechanisms between opioid and nonopioid mediated analgesia has been provided by Steinman, Farris, Mann, Olney, Komisaruk, Willis and Bodnar (1990). They showed that the analgesia produced by the opiate morphine is significantly reduced when rats are exposed to a nonopioid, analgesiainducing stressor (like continuous cold water swim) prior to morphine administration (Yamada & Nabeshima, 1995). This result indicates that the ability of opiates to produce analgesia is somehow inhibited if the nonopioid form of analgesia is also induced. Therefore, just as the collateral inhibition model would have stipulated, the activation of one of the analgesic mechanisms inhibited the other. Competition vs. Exercise-Induced Analgesia 14 Investigation into the question of when nonopioid vs. opioid analgesic systems are activated has only definitively illustrated that the type of system activated depends on the nature of the stress. Research that sought to define the discrimination between the opioid and nonopioid pain modulation systems pointed to the trend that naloxone was less likely to eradicate analgesic effects when the stressor which induced the analgesia was one of higher intensity and longer duration. Thus a shift from the opioid system to the nonopioid system was triggered by an increase in severity of stressful stimuli, such as colder water and continuous instead of intermittent swimming in a forced swim (Mogil, Sternberg, Bailian, Liebeskind, & Sadowski, 1995). However, for exceptionally severe stress, a shift from nonopioid to opioid systems occurs. It has been suggested that for such severe stress (20-30 minutes of intermittent foot-shock or 60-80 tailshock delivered to rats), the organism has learned the stress is inescapable and this perception of “learned helplessness” results in the shift to opioid analgesia (Maier, Sherman, Lewis, Terman & Liebeskind, 1982). However, the shift from opioid to nonopioid systems that accompanies increased severity of stress may not be uniform cross species since the female Quackenbush mouse exhibits the opposite: a shift from nonopioid to opioid systems with increasing severity of the stress (Tierney, Carmody, & Jamieson, 1991 as cited by Mogil et al., 1995). This opposite finding contrasts to the trend found in rats as well as in other mice (Mogil et al., 1995). Possible reasons for this apparent divergence in findings are the researchers’ utilization of different rodent species and different stress stimuli. Consequently, the exact conditions which would reliably produce either the opioid or nonopioid analgesia cross Competition vs. Exercise-Induced Analgesia 15 species are not clear. What is clear is that increasing severity of stressful stimuli results in a shift of one neurochemical analgesic system to another. The nature of a stressor is also an important determinant of whether the stressor can or cannot induce analgesia. The stressors of exercise and competition are two stressors that can, depending on their nature (exercise parameters), induce analgesia. Research (discussed below) suggests that the analgesia produced by exercise is not uniform in that different analgesic mechanisms are triggered (opioid or non-opioid) by different exercise (aerobic vs. anaerobic, for example), only some forms of stimulus pain used to measure pain sensitivity (such as cold pressor vs. thermal pain) elicit analgesic response, and women may be more stressed by exercise than men. The stressor of competition may also not be uniformly impactful and analgesia-inducing cross sex and different individuals. Research examining the analgesia induced by exercise has yielded highly nonunified results and indicates a need to standardize experimental procedures along several parameters. One study by Olaussson, Eriksson, Ellmarker et al. (1986) demonstrated the diverse analgesic systems (opioid and nonopioid) involved in exercise-induced analgesia by pain testing subjects before and after 20 minutes of leg and arm exercises (as cited in Koltyn, 2000). Subjects experienced significantly elevated dental pain thresholds after exercise, yet naloxone only attenuated analgesia in subjects following arm exercise. Thus exercise can trigger both naloxone-sensitive (μ opioid) and naloxone-insensitive (non-μ opioid) analgesia mechanisms and the type of exercise performed (here, arm or leg) 1 The cold pressor measure of pain sensitivity is done by submerging a subject’s arm in ice water for a period of time while they continuously rate the pain they feel. The thermal pain measure of pain sensitivity can be done by applying noxious, hot stimulus to the skin and measuring at what temperature a subject feels pain (heat pain threshold) or by exposing the subject to different hot temperatures and recording their pain ratings (thermal scaling). Competition vs. Exercise-Induced Analgesia 16 contributes to the determination of which one of the systems will be activated. This finding is further complicated by the results of a study by Janal, Colt, Clark et al. (1984) which found that post-run analgesia was reversed by naloxone only in response to an ischaemic pain measure stimulus (pressure) but not for the thermal pain measure stimulus (as cited in Koltyn, 2000). Thus the detection of exercise-induced analgesia not only depends on the condition of whether naloxone has been administered to the subject, but also on the particular stimulus used in the pain measure. In sum, in order to detect whether opioid or nonopioid systems have been activated, experimenters must use an array of pain stimuli for the pain measure (in combination with opioid receptor blockers). Use of more than one painful stimulus to measure analgesia in subjects is also now validated as a standard method in analgesia research due to many study results such as the above which indicate that analgesia detected by using one pain stimulus may not be detected by using another. Because pain threshold after exercise is altered differentially for different types of painful stimuli, current research must follow this multi-stimulus pain methodology. Which stimulus allows detection of which analgesia after which exercise is still unclear. This is so because trends of which stimulus allows detection of which analgesia after which exercise are not clear (or at least in the mind of