James W. Grau is a professor of behavioral neuroscience in the Department of Psychology and a member of the Faculty of Neuroscience at Texas A&M University. He has been a visiting professor at the University of North Carolina at Chapel Hill and the University of Texas at Austin. In addition to investigating pain modulation, he is examining the nature of plasticity within the spinal cord. He is currently a consulting editor for Behavioral Neuroscience and a member of the executive committee of Division 6. He obtained his PhD in 1985 from the University of Pennsylvania.
Mary W. Meagher is an assistant professor with joint appointments in clinical psychology and behavioral neuroscience in the Department of Psychology, a member of the Faculty of Neuroscience, and the coordinator of the clinical health psychology training program at Texas A&M University. Her research has focused on psychological and neural bases of pain modulation using both animal and human laboratory models. Meagher received her doctorate in psychology from the University of North Carolina at Chapel Hill in 1989 and subsequently completed a clinical internship at the Audie L. Murphy San Antonio VA Hospital in 1994.
The National Institute of Mental Health funds the joint research described in this article.
Pain is a state that can force itself upon us, capturing our full attention, motivating our behavior, and at the extreme, overwhelming us. In the natural environment, much of what an organism does is motivated by pain. In fact, survival is a challenge in the absence of pain and people who lack this perceptual-emotional state often die prematurely from the cumulative impact of inadvertent injuries.
The reigning force in other modalities is constancy. We naturally see objects in a consistent manner irrespective of their distance or level of illumination. In contrast, one of the most striking features of pain is its variability. The same stimulus can at one time elicit severe pain and at another time be ignored. Our research attempts to explain this variability by identifying the systems that modulate pain, their periods of engagement, their functional consequences, and their underlying neurobiological mechanisms.
Historically, researchers have focused on just one source of pain variability, the processes that inhibit pain. This bias stems from theoretical and empirical developments in the 1970s. For example, Solomon and Corbit (1974) argued that an aversive stimulus engages a compensatory opponent process that reduces its affective impact. In a similar vein, Maier, Seligman, and Overmier suggested that exposure to an uncontrollable aversive event can lower an organism's motivation to respond (learned helplessness). Shortly thereafter, neuroscientists discovered that our bodies manufacture opioid peptides (endorphins) that can attenuate pain. Psychologists soon realized that exposure to an aversive event, or the expectation of such an event, could undermine learning and behavior by inducing the release of an endorphin. Working with Steve Maier, Grau found that the inescapable shock schedule used to induce learned helplessness in rats produces a powerful opioid analgesia and sensitizes this system. This sensitization reflects a general increase in opiate reactivity that extends to exogenous opiates, a modification that could predispose the organism to opiate abuse.
Other studies during the 1980s explored the role of opioids in classical conditioning. Michael Fanselow linked opioid analgesia to conditioned fear, whereas Grau suggested that the memory of an aversive event elicits analgesia. Though they differ in detail, both accounts propose that a conditioned stimulus which has been paired with an aversive unconditioned stimulus (US) elicits an opioid analgesia, which decreases the effectiveness of the US. This opioid analgesia depends on both the amygdala and a region of the brainstem, the ventral periaqueductal gray (vPAG).
Meagher and Grau began their collaborative research in 1985. It had become evident that earlier theories of pain modulation were too simplistic, that pain can be modulated at multiple levels of the nervous system, and that nonopioid systems are also involved. To study how pain mechanisms are organized, they first sought to identify when each system is engaged. Meagher proposed that lower level systems within the spinal cord are only enlisted under the most extreme circumstances. Brainstem systems might take over under less severe conditions, and forebrain systems are assumed to regulate pain in response to moderately severe stimuli, those that the organism is most likely to encounter on a regular basis. Subsequent research has supported this view and led to the development of a simple mathematical relation, derived from Steven's power law, that can be used to characterize the severity of aversive stimuli and predict when these pain inhibitory systems are engaged.
Research from the 1980s might lead one to conclude erroneously that pain modulation is unidirectional -- that the body always responds to pain, or the expectation of pain, by engaging systems that attenuate it. But this raises a fundamental paradox: why would organisms evolve a system to generate pain only to curtail it? Obviously, pain serves an adaptive function and under many circumstances, pain is not diminished. Indeed, it is often enhanced, a phenomenon known as hyperalgesia.
It was serendipity that led us to the study of hyperalgesia. For years, we had studied pain inhibition in rats using the most common test, tail-withdrawal from radiant heat (the tail-flick test). Neurobiological studies suggested that neural systems within the brainstem (e.g., vPAG) reduce pain through descending pathways that inhibit afferent pain signals (nociception) and nociceptive reflexes within the spinal cord, a kind of top-down processing. The rodent tail-flick test was thought to provide a window into this inhibitory process, yielding a form of construct validity that fueled its popularity. Using this test, we had shown that exposure to a few moderate tail-shocks has an inhibitory effect, an outcome we took as evidence for analgesia. Both theory and data suggested that such analgesia should decrease the affective impact of subsequent shocks, and thereby undermine learning. To test this hypothesis, our student Paul Illich assessed vocalization thresholds to a continuous tail-shock that was gradually increased. Much to our surprise, previously shocked rats were hyperreactive, not hyporeactive. We thought that this hyperreactivity might reflect a memorial effect (priming) or a conditioned response, but we found no evidence for either notion. Instead, the hyperalgesia turned out to be an unconditioned response that passively decays over time.
Working in our laboratory, Tamara King developed a technique that could be used to measure both a spinal reflex (tail-flick) and a brain-mediated response (vocalization) to a noxious thermal stimulus. She found that previously shocked rats vocalized to heat before the unshocked controls, even though shock inhibited the tail-flick response. Apparently, the process that inhibits tail-withdrawal does not necessarily inhibit the afferent pain signal relayed to the brain, an observation that raises serious concerns regarding the widespread reliance on the tail-flick test. More generally, to infer the impact of an experimental manipulation on pain, we must rely on multiple measures (converging operations).
If prior shock exposure enhances the affective impact of aversive stimuli, it should also increase their capacity to reinforce learning. Supporting this, we showed that pretreatment with shock can facilitate the acquisition of both an avoidance response motivated by thermal pain and conditioned fear to a context paired with a weak gridshock. Interestingly, Maier and Shors have shown that a more extended exposure to shock can facilitate Pavlovian conditioning for up to 48 hrs. As Rosen and Schulkin (1998) suggest, this sensitization effect could contribute to the development of pathological anxiety, and we propose that it may underlie some forms of pathological pain.
More recently, we have begun to examine the neural systems that mediate hyperalgesia. We reasoned that hyperalgesia could be linked to the induction of active defensive behaviors organized by the dorsolateral periaqueductal gray (dlPAG). Supporting this, we showed that neurochemical lesions of the dlPAG eliminate hyperalgesia. Recent studies in our laboratory by Eric Crown suggest that the dlPAG enhances learning and affect by sensitizing systems within the central nucleus of the amygdala.
Other studies have tried to clarify the conditions under which pain facilitory versus inhibitory processes are engaged. We found that mild to moderately-intense shocks enhance pain whereas more severe shocks (that activate a brainstem-mediated nonopioid system) induce a true analgesia. Interestingly, Michael Davis has observed a similar trend in the acoustic startle paradigm, suggesting that these modulatory effects extend to noncutaneous stimuli.
Currently, we are attempting to characterize the psychological state associated with the induction of hyperalgesia. One hypothesis is that it is linked to a form of anxiety, or anxious apprehension. Psychologically, this state could augment surprise and taint stimuli with negative affect. Physiologically, arousal is enhanced, and our student Amy Sieve has shown that there is an increase in active defense (aggression). Further, Rhudy and Meagher (in press) have shown that anticipatory anxiety induces hyperalgesia in humans.
Other recent studies, by Coderre, Maier, Watkins, Willis, and Woolf, have shown that a variety of noxious stimuli can sensitize pain, including illness and tissue damage. Again, multiple neural systems appear capable of facilitating pain, and here, too, stimulus severity seems to determine, in part, which pro-nociceptive system is engaged. Whereas the pain facilitory effects we observe after moderate stimuli depend on neural systems within the brain, severe noxious stimuli sensitize nociceptive neurons within the spinal cord, a form of long-term potentiation that depends on the NMDA receptor.
The notion that exposure to an aversive event elicits an opioid-mediated opponent process which grows with experience and functions to reduce pain has beautiful simplicity. It is now clear, however, that this account describes just one facet of a complex system that is designed to regulate pain and motor behavior at multiple levels of the nervous system, yielding a hierarchical control system. Furthermore, experience does not necessarily engage an opponent pain-attenuating process. Instead, under a variety of circumstances, exposure to an aversive stimulus seems to sensitize pain.
The discovery of the endorphins fueled the search for procedures that could alleviate pain by triggering their release (e.g., transcutaneous electrical stimulation, acupuncture). Likewise, the discovery of neural systems that enhance pain suggests new approaches to pain treatment. By minimizing the sensitization of pain (e.g., by reducing anxiety and neural wind-up), we can lessen both acute pain and the development of pathological pain syndromes.
Reprinted from Psychological Science Agenda (1999) with permission from American Psychological Association.
We would like to thank, Ludy Benjamin, Eric Crown, Michael Domjan, Adam Ferguson, Jack Nation and Amy Sieve for their comments on an earlier draft of this paper. Correspondence concernding this article should be addressed to James W. Grau or Mary W. Meagher, Department of Psychology, Texas A&M University, College Station, Texas 77843. Electronic mail may be sent to either J-Grau@tamu.edu or M-Meagher@tamu.edu.
Grau, J. W., Salinas, J. A., Illich, P. A., & Meagher, M. W. (1990). Associative learning and memory for an antinociceptive response in the spinalized rat. Behavioral Neuroscience, 104, 489-494.
Illich, P. A., Salinas, J.A., & Grau, J. W. (1994). Latent inhibition and overshadowing of an antinociceptive response in spinalized rats. Behavioral and Neural Biology, 62, 140-150.
Joynes, R. L., & Grau, J. W. (1996). Mechanisms of Pavlovian conditioning: The role of protection from habituation in spinal conditioning. Behavioral Neuroscience, 110, 1375-1387.
Grau, J. W., Barstow, D. G. & Joynes, R. L. (1998). Instrumental learning within the spinal cord: I. Behavioral properties. Behavioral Neuroscience, 112, 1366-1386.
Solomon, R. L., & Corbit, J. D. (1974). An opponent-process theory of motivation: I. Temporal dynamics of affect. Psychological Review, 81, 119-145.
Schull, J. (1979). A conditioned opponent theory of Pavlovian conditioning and habituation. In G. Bower (Ed.), The Psychology of Learning and Motivation, Vol. 13. New York: Academic Press.
Overmier, J. B., & Seligman, M. E. P. (1967). Effects of inescapable shock upon subsequent escape and avoidance learning. Journal of Comparative and Physiological Psychology, 63, 23-33.
Seligman, M. E. P., & Maier, S. F. (1967). Failure to escape traumatic shock. Journal of Experimental Psychology, 74, 1-9.
Seligman, M. E. P., Maier, S. F., & Solomon, R. L. (1971). Unpredictable and uncontrollable aversive events. In Aversive conditioning and learning, ed. F. R. Brush. New York: Academic Press.
Peterson, C., Maier, S. F., & Seligman, M. E. P. (1993). Learned helplessness: A theory for the age of personal control. New York: Oxford University Press.
Terman, G. W., Shavit, Y., Lewis, J. W., Cannon, J. T., & Liebeskind, J. C. (1984). Intrinsic mechanisms of pain inhibition: Activation by stress. Science, 226, 1270-1277.
Watkins, L. R., & Mayer, D. J. (1982). Organization of endogenous opiate and nonopioid pain control systems. Science, 216, 1185-1192.
Basbaum, A. I., & Fields, H. L. (1984). Endogenous pain control systems: Brainstem spinal pathways and endorphin circuitry. Annual Review of Neuroscience, 7, 309-338.
Maier, S. F., Davies, S., Grau, J. W., Jackson, R. R., Morrison, D. H., Moye, T., Madden, J., and Barchas, J. D. (1980). Opiate antagonists and the long-term analgesic reaction induced by inescapable shock in rats. Journal of Comparative and Physiological Psychology, 94, 1172-1183.
Grau, J. W., Hyson, R. L., Maier, S. F., Madden, J., and Barchas, J. D. (1981). Long-term stress-induced analgesia and activation of the opiate system. Science, 213, 1409-1411.
Maier, S. F., Drugan, R. C., and Grau, J. W. (1982). Controllability, coping behavior, and stress-induced analgesia in the rat. Pain, 12, 47-56.
Will, M. J., Watkins, L. R., & Maier, S. F. Uncontrollable stressors potentiate the rewarding properties of morphine. Pharmacology, Biochemistry, & Behavior, 60, 655-664.
Bolles, R. C., & Fanselow, M. S. (1980). A perceptual-defensive-recuperative model of fear and pain. Behavioral and Brain Sciences, 3, 291-301.
Fanselow, M. S. (1986). Conditioned fear-induced opiate analgesia: a competing motivational state theory of stress analgesia. Annals of the New York Academy of Sciences, 467, 40-54.
Grau, J. W. (1987). The central representation of an aversive event maintains the opioid and nonopioid forms of analgesia. Behavioral Neuroscience, 101, 272-288.
Grau, J. W. (1987). The variables which control the activation of analgesic systems: Evidence for a memory hypothesis and against the coulometric hypothesis. Journal of Experimental Psychology: Animal Behavior Processes, 13, 215-225.
Meagher, M. W. and Grau, J. W, & King, R. A. . (1989). Prefrontal cortex lesions block the opioid and nonopioid hypoalgesia elicited by brief shocks, but not long shock-induced hypoalgesia. Behavioral Neuroscience, 103, 1366-1371.
Meagher, M. W., Grau, J. W., & King, R. A. (1990). The role of supraspinal systems in analgesia: The impact of spinalization and decerebration on the analgesia observed after very brief versus long shocks. Behavioral Neuroscience, 104, 328-338.
Helmstetter, F. J. (1992). The amygdala is essential for the expression of conditioned hypoalgesia. Behavioral Neuroscience, 106, 518-528.
Meagher, M. W., Chen, P., Salinas, J. A., & Grau, J. W. (1993). Activation of the opioid and nonopioid hypoalgesic systems at the level of the brainstem and spinal cord: Does a coulometric relation predict the emergence or form of environmentally-induced hypoalgesia? Behavioral Neuroscience, 107, 493-505.
Fanselow, M. S. (1994). Neural organization of the defensive behavior system responsible for fear. Psychonomic Bulletin & Review, 1, 429-438.
Grau, J. W., Burks, K., Kallina, C. F., King, T. E., & Meagher, M. W. (1996). Activation of the opioid and nonopioid antinociceptive systems in pentobarbital anesthetized rats: Assessing the role of shock severity. Psychobiology, 24, 71-84.
Illich, P. A., King, T. E., & Grau, J. W. (1995). Impact of shock on pain reactivity: I. Whether hypo- or hyperalgesia is observed depends on how pain reactivity is tested. Journal of Experimental Psychology: Animal Behavior Processes, 21, 331-347.
King, T. E., Joynes, R. L., Meagher, M. W., & Grau, J. W. (1996). Impact of shock on pain reactivity: II. Evidence for enhanced pain. Journal of Experimental Psychology: Animal Behavior Processes, 22, 265-278.
King, T. E., Joynes, R. L., & Grau, J. W. (1997). The Tail-Flick Test II: The role of supraspinal systems and avoidance learning. Behavioral Neuroscience, 111, 754-767.
Prentice, T. W., Joynes, R. L., Meagher, M. W., & Grau, J. W. (1996). Impact of shock on pain reactivity: III. The magnitude of hypoalgesia observed depends on test location. Behavioral Neuroscience, 109, 528-541.
Grau, J. W., King, T. E., Joynes, R. L., & Meagher, M. W. (1998). Using nociceptive reflexes to measure pain: Methodological issues and interpretative problems. In M. Kavaliers, K-P. Ossenkopp, & P. R. Sandberg (Eds.), Nociception and pain in animals: Measurement techniques and procedures. Autsin, TX: Landes.
Maier, S. F. (1990). Role of fear in mediating shuttle escape learning deficit produced by inescapable shock. Journal of Experimental Psychology: Animal Behavior Processes, 16, 137-149.
Shors, T. J., Weiss, C., & Thompson, R. F. (1992). Stress-induced facilitation of classical conditioning. Science, 257, 537-539.
Rosen, J. B., & Schulkin, J. (1998). From normal fear to pathological anxiety. Psychological Review, 105, 325-350.
King, T. E., Crown, E. D., Sieve, A. N., Joynes, R. L., Grau, J. W., & Meagher, M. W. (1999). Shock-Induced Hyperalgesia: I. Evidence Forebrain Systems Play an Essential Role. Behavioral Brain Research, 100, 33-42.
McLemore, S., Crown, E. D., Meagher, M. W., & Grau, J. W. (1999). Shock-induced hyperalgesia: II. Role of the dorsolateral periaqueductal gray. Behavioral Neuroscience, 113.
Crown, E. D., King, T. E., Meagher, M. W., & Grau, J. W. (in review). Shock-induced hyperalgesia: IV. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei. Behavioral Neuroscience.
Davis, M. (1989). Sensitization of the acoustic startle reflex by footshock. Behavioral Neuroscience, 103, 495-503.
Meagher, M. W., McLemore, S., King, T. E., Sieve, A. N., Crown, E. D., & Grau, J. W. (in review). Shock induced hyperalgesia: III. Generality. Journal of Experimental Psychology: Animal Behavior Processes.
Rhudy, J. L., & Meagher, M. W. (in press). Fear and anxiety: Divergent effects on thermal pain thresholds in humans. Pain.
Woolf, C. J., & Thompson, S.W.N. (1991). The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain, 44, 293-299.
Coderre, T. J., Katz, J., Vaccarino, A. L., & Melzack, R. (1993). Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain, 52, 259-285.
Wiertelak, E. P., Smith, K. P., Furness, L., Mooney-Heiberger, K., Mayr, T., Maier, S. F., & Watkins, L. R. (1994). Acute and conditioned hyperalgesic resposnes to illness. Pain, 56, 227-234.
Wiertelak, E. P., Furness, L. E., Watkins, L. R., Maier, S. F. (1994). Brain Research, 664, 9-16.
Willis, W. D., & Westlund, K. N. (1997). Neuroanatomy of the pain system and of the pathways that modulate pain. Journal of Clinical Neurophysiology, 14, 2-31.
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