PAIN IS GOOD
One might envision that life would be lovely without pain. However, people born
with a congenital insensitivity for pain bear witness that this is not so. Such people lean on hot stoves and realize it only upon smelling their burning flesh, fail to pull away from sharp objects, and are unaware of bone breaks, infections, or internal injuries which become life threatening as a result. They learn only with great difficulty how to survive in a world full of danger.

Pain is good. Normal, everyday pain serves key biological functions. First, pain is a warning device, helping to prevent tissue damage. Pain signals carried by sensory nerves to the spinal cord trigger protective reflexes to rapidly withdraw your body from danger.

In turn, spinal cord neurons relay the pain message to the brain to organize adaptive behaviors, such as swatting the offending bee. Second, pain serves a recuperative function. After injury, pain motivates one to tend to the wound, and to enter a period of inactivity and behavior related to healing. Thus normal pain is highly adaptive for survival.

PAIN IS DYNAMIC
But there is more to pain. Pain is arguably the most dynamic of the senses. It is not passively relayed from the periphery to the brain. Rather, it is powerfully modulated at the first synapse, at which sensory nerves relay pain information to the spinal cord. Here, pain messages can be suppressed, relayed unaltered, or amplified.

The existence of neural circuitry that can suppress pain has long been recognized, with endorphins being the best known of the pain suppressing neurotransmitters. Painsuppression ("analgesia" meaning "without pain") is created by preventing sensory nerves from relaying pain information to spinal cord and by preventing spinal neurons from relaying pain information to the brain. Analgesia is adaptive under "fight/flight" situations where being oblivious to tissue damage facilitates defense and escape. Drugs such as morphine mimic the actions of endorphins by binding to their receptors (Millan, 2002).

Pain facilitation ("hyperalgesia" meaning "exaggerated pain") can also be adaptive. Hyperalgesia is created by enhancing sensory nerve excitability, enhancing release of "pain" neurotransmitters from sensory nerves to spinal cord and/or amplifYing pain messages relayed to the brain. The end result is that pain is greater than normal (Willis, 1992). This is good when you have tissue damage or infection. It increases your focus on the injury to ensure that you attend to the injury and learn to avoid such injuries.

Hyperalgesia is one of a constellation of physiological adaptations that is triggered by immune activation. Thus it is similar to fever, increased sleep, decreased appetite, decreased social interactions, and other sickness responses created by the central nervous system (CNS) in response to signals received from activated immune cells (Maier & Watkins, 2000).

PAIN CAN BECOME PATHOLOGICAL
Pain can turn bad. You expect that when an injury heals that the pain will stop. You expect that when you have no reason for pain, that you will have no pain. However, millions of Americans suffer from chronic, unremitting pain despite the fact that there is no current tissue damage. Whether this arises as a result of prior tissue or nerve injury, a minor procedure such as orthoscopic surgery, amputation, or for no apparent reason, the end result may be insufferable pain and misery (Watkins & Maier, 2002). A soothing hot shower is now perceived as pain. Clothing or a gentle breeze on the affected body part explodes into a fireball of pain. Indeed, affected individuals may become prisoners in their own homes, unable to wear clothing or encounter everyday environmental stimuli that we barely even notice. Such pain can expand over time. Pain arising from one hand, for example, may insidiously spread, progressing up the arm, jumping to the opposite arm, and even enveloping the entire body (Watkins & Maier, 2002).Pain can destroy lives. Pain is now pathological rather than physiological, as it no longer serves any biologically adaptive function.

So, why does pain turn bad? Until recently, the search to understand pathological pain focused exclusively on neurons. Sensory neurons relay pain to spinal cord neurons, which relay pain to the brain. Since this pathway is composed of neurons, they must be to blame. And indeed, the neural pain pathway is plastic. That is, this pathway can change in ways that will amplify pain messages. For example, traumatized sensory nerves can develop spontaneous activity such that they send pain messages to the spinal cord despite the fact that no painful stimulus exists. Furthermore, sensory nerves may begin expressing receptors that normal nerves never express. In this way, stress hormones, which never excite sensory nerves under normal conditions, now trigger pain. A wide array of such changes have been documented at various levels of the pain pathway (Woolf & Salter, 2000).

But doesn't that predict that pathological pain should be easily controlled? One would have thought so. Certainly, drug development for pain control has focused on such plastic changes in pain neurons and has brought a multitude of drugs to clinical trials. The sad conclusion, however, is that the definition of a good drug for pathological pain control is one that leaves 4 out of 5 patients with no pain relief (Watkins & Maier, 2002). How can this be? Why has rational drug development based on reducing neuronal plasticity failed? Could there be an as-yet-unrecognized player in pathological pain?

GLIA: NEW PLAYERS IN PAIN
Indeed, there is. Just as a seething crowd eggs on boxers in the ring, spinal cord cells called glia can egg on neurons in the pain pathway. This drives the creation and maintenance of pathological pain. Unlike neurons, glia do not have axons projecting to distant sites. Thus, glia act by influencing neurons in their neighborhood. Glia outnumber neurons 20: 1. Their sheer numbers predict that they do something important.

They were ignored by pain researchers as they were not thought to influence neuronal function. This view is changing. New research implicates two types of spinal cord glia, called microglia and astrocytes, in the creation and maintenance of pathological pain. This newly recognized role of glia as powerful modulators of pain has major implications for developing drugs for controlling clinical pain (Watkins, Milligan, & Maier, 2003).

Normally, glia are quiet. Under basal conditions, they regulate extracellular ions,
metabolites, and neurotransmitters, scavenge dead cells, etc. Glia do not contribute to normal everyday pain. However, glia do become activated under select conditions, as when immune cells signal the CNS to trigger sickness responses (Maier & Watkins, 2000). While this is a normal, physiological, survival-oriented response, there simply is more than one way to activate glia. As will be discussed below, we believe that pathological pain can be created by viruses, nerve damage, or other pathological processes "tapping into" this ancient glially-driven pain facilitation pathway, driving it in a perseverative, non-adaptive direction. Such conditions trigger spinal cord glia to become activated and to release substances that amplify pain (Watkins & Maier, 2002).

There are a number of situations in which activated glia may contribute to pain. First is in infectious .diseases, such as AIDS, in which pathogens (viruses or bacteria) "home" to the CNS and take up residence. This is especially insidious in AIDS as the drugs used to treat this disease do not cross the blood-brain barrier so the virus is safely out of reach. Once in the CNS, the AIDS virus activates glia. This is because glia are "immunocompetent", meaning that they recognize, and become activated in response to, pathogens. In AIDS, upwards of 90% of patients suffer from pain, yet no bodily source of the pain can be identified in a surprisingly large number of patients. This suggests that activated glia may be the cause.

Second, pathological pain arising from traumatized or inflamed nerves may be perceived not only from the body region normally innervated by the damaged nerve but also from body regions innervated by nearby healthy, uninvolved nerves. Such pain is called "extra-territorial pain" as it is perceived as arising from tissues outside the territory innervated by the damaged nerve.

Third is "mirror" pain. This is a fascinating phenomenon wherein pain is not only perceived as arising from an area of trauma (e.g. left hand) but is also perceived as arising from the healthy, mirror-image body part (e.g. right hand). Classically, patients reporting extra-territorial pain or mirror image pain were referred to psychiatrists rather than neurologists, as such "impossible" sensations could not be readily accounted for by neuronal models of pain. New studies point to spinal cord glia as key players in all of these pain phenomena (Watkins, Milligan, & Maier, 2001). This is a dramatic departure from the classical view that pathological pain is created and modulated solely by neurons.

Considering glia as dynamic modulators of pain may appear to be an odd concept as glia have been considered to merely serve "housekeeping" functions in the CNS. However, glia are perfectly positioned to regulate pain. First, glia can release classical neuroactive substances (reactive oxygen species, nitric oxide, prostaglandins, excitatory amino acids, etc.) that enhance the excitability of pain-responsive spinal cord neurons.

These glially derived substances can also enhance the release of neurotransmitters from sensory nerves that relay pain information to the spinal cord. In addition, glia express receptors not only for viruses and bacteria, but also for a variety of neurotransmitters and neuromodulators. Hence they can become activated in response to chemical signals that are released by neurons under conditions that create pathological pain. Indeed, microglia and astrocytes are now known to become activated in response to a wide array of conditions that create pathological pain. Once activated, microglia and astrocytes form positive feedback loops, creating perseverative release of pain enhancing substances (Watkins et aI., 2001).

Importantly, glial activation is causal, rather than being merely correlated with
exaggerated pain states. Glial activation is both necessary and sufficient for such changes to occur. Glial activation is necessary since pharmacologic blockade of glial activation blocks pathological pain (Meller, Dykstra, Grzbycki, Murphy, & Gebhart, 1994; Milligan et aI., 2000). The strategy for examining whether glial activation is sufficient rests on the fact that, as noted above, glia are similar to immune cells in that they become activated by viruses and bacteria. Indeed, immune activation of glia creates exaggerated pain responses (Meller et aI., 1994; Milligan et aI., 2000).

Activated glia do not just communicate with neurons using classical
neurotransmitters. Rather, they (like other immune cells) release a family of proteins called pro-inflammatory cytokines: tumor necrosis factor, interleukin-l, and interleukin 6. These alter the function of both glia and neurons, as each express cytokine receptors. Glia do not tonically release pro inflammatory cytokines. Pharmacologic blockade of pro inflammatory cytokine receptors leaves normal everyday pain unaltered (Milligan et all., 2001; Sweitzer, Martin, & DeLeo, 2001).

This supports that glia are not involved in pain modulation except under conditions leading to pathological pain. Indeed, pro inflammatory cytokines are critically involved in the creation and maintenance of exaggerated pain responses. The administration of pro inflammatory cytokines over spinal cord creates exaggerated pain responses (DeLeo, Colburn, Nichols, & Malhotra, 1996; Reeve, Patel, Fox, Walker, & Urban, 2000). Alternatively, the blockade of proinflammatory cytokine receptors prevents and reverses pathological pain (Milligan et al., 2001; Sweitzer et aI., 2001). Thus pro inflammatory cytokines are both necessary and sufficient for such pain changes to occur.

WHY IS THIS IMPORTANT?
The emerging story is that the pain pathway can no longer be envisioned as a simple chain of neurons. Rather, microglia and astrocytes within the spinal cord can dramatically amplify neuronal signaling, thereby creating pathological pain. These glia become activated by immune challenges and by substances released by neurons. Upon activation, glia release an array of substances that leads to amplification of pain. Of these, the pro inflammatory cytokines appear to be common spinal mediators of pathological pain.

This scenario may explain the mysteries of extra territorial and mirror-image pains, wherein pain is perceived from sites distant from the original site of trauma. First, pro inflammatory cytokines act in a paracrine fashion, diffusing away from their site of release to effect distant cells. Given the exquisite somatotopic organization of the spinal cord, a spread of proinflammatory cytokines from their site of release would be expected to amplify pain perceived from body regions beyond the site of injury.

Second, in addition to a chemical spread of excitation via proinflammatory cytokine release, glia can also create an electrical spread of excitation. Glia are interconnected into widespread networks by gap junctions. These physical "pores" between adjoining glia allow waves of excitation to rapidly spread to distant sites. Distant glia, newly activated by this wave of excitation, can now begin releasing pain-enhancing substances including pro inflammatory cytokines (Araque, Parpura, Sanzgiri, & Haydon, 1999). Indeed, proinflammatory cytokines and gap junctions have now been implicated in both extraterritorial and mirror image pain (Watkins et aI., 2003).Involvement of glia in pain regulation may also have major implications for clinical pain control. Pathological pain is poorly managed, if at all, by currently available drugs.

These drugs were not developed with glia as a target since glia were not thought to be a source of pathological pain. The involvement of glia in exaggerated pain responses is exciting because it predicts whole new approaches for the control of human pathological pain. It predicts that preventing glial activation or the action of unique glial products such as pro inflammatory cytokines may provide a solution for the devastating effects of human pathological pain. Indeed studies with laboratory animals have already identified a series of compounds that may be worth evaluating for their ability to control clinical pain (Watkins et aI., 2003).

Lastly, it is unlikely that glia regulate only pain. Glial regulation of pain is an
excellent model system for examining glial-neuronal interactions given the multi
disciplinary approaches that can be brought to bear, from behavior to molecular biology.

However, the discovery of powerful glial-neuronal interactions in the pain system
predicts that similar interactions may well be found for other sensory systems as well.

Acknowledgements
This work was supported by NIH grants MH01558, DA015642, DA015656, NS40696
and NS38020.

References
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Milligan, E. D., Mehmert, K. K., Hinde, J. L., Harvey, L. O. J., Martin, D., Tracey, K. J., Maier, S. F., & Watkins, L. R. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the Human Immunodeficiency Yirus-l (illY-I) envelope glycoprotein, gp120. Brain Res. 2000;861:105-116.

Milligan, E. D., O'Connor, K. A., Nguyen, K. T., Armstrong, C. B., Twining, c., Gaykema, R., Holguin, A., Martin, D., Maier, S. F., & Watkins, L. R. Intrathecal illY-l envelope glycoprotein gp120 enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci. 2001;21:2808-2819.

Reeve, A. J., Patel, S., Fox, A., Walker, K., & Urban, L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain. 2000;4:247-257.

Sweitzer, S. M., Martin, D., & DeLeo, J. A. Intrathecal interleukin-l receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neurosci. 2001;103:529539.

Watkins, L. R., & Maier, S. F. Beyond neurons: Evidence that immune and glialcells contribute to pathological pain states. Physiol Rev. 2002;82:981-1011.

Watkins, L. R., Milligan, E. D., & Maier, S. F. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24,450-455.

Watkins, L. R., Milligan, E. D., & Maier, S. F. Immune and glial involvement in physiological and pathological exaggerated pain states. In J. O. Dostrovsky, Carr, D.E. & Koltzenberg, M. (Ed.), Advances in Pain Research and Therapy (pp. in press). Seattle: IASP Press; 2003.

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Recommended Readings
1. DeLeo, I.A. & Yezierski. The role of neuroinflammation and neuroimmune activation in persistent pain, Pain. 2001;90:1-6.
2. Maier, S.F. & Watkins, L.R. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition, Psychol Rev. 1998;105:83-107.
3. Watkins, L.R., Hansen, M.K., Nguyen, K.T., Lee, J.E. & Maier, S.F. Dynamic regulation of the proinflammatory cytokine, interleukin-l beta: molecular biology for non-molecular biologists, Life Science. 1999;65:449-481.
4. Watkins, L.R. & Maier, S.F. The pain of being sick: Implications of immune-to-brain communication for understanding pain, Ann Rev Psychol. 2000;51:29-57.
5. Watkins, L.R. & Maier, S.F. (Ed.) Cytokines and Pain, Basel: Birkhauser; 1999.

Corresponding author
Linda Watkins
Dept of Psychology
Campus Box 345
University of Colorado at Boulder Boulder, CO 80309-0345
Email: Lwatkins@psych.Colorado.edu
Phone: 303-492-7034
Fax: 303-492-2967