A Sketch of the Subjective

WHEN PAIN IS PROTECTIVE

Source: http://www.biolib.dew

The opium poppy, Papaver somniferum, has been known to have pain-relieving properties.

Nociception is a normal nervous system function – perhaps the primary one, evolutionarily speaking. It is a warning system of danger or credible threat. Those few who feel no pain serve as a reminder as to the benefits of pain (see Life Without Pain, p. 8).

Pain generally begins with the nociceptors, the free nerve endings of small, myelinated A-δ fibers and smaller, unmyelinated C fibers. When local injury unleashes inflammatory mediators – including Cox-2, interleukins, leukotrienes hydrogen and potassium ions, histamine, and bradykinin – the nearby nociceptors depolarize transmitting the message toward the dorsal horn. Here, they secrete various neuropeptides, such as substance P, and excitatory amino acids, such as glutamate and aspartate, which in turn stimulate dorsal horn neurons to continue the message.

But nociception does not become pain until the brain adds layers of meaning to the input from the trigeminal and spinothalamic tract. "These messages are sent to the limbic system, the site of emotions and feeling; to the cortex for cognitive appraisals; and to the big frontal lobes, where we can see the past through memories and project into the future. Pain is never just a signal," explains Richard Chapman, director of the Pain Research Center at the University of Utah in Salt Lake City.

Ronald Melzack and Patrick Wall framed the idea of the central nervous system (CNS) and filtering, assessing modulating sensory information 40 years ago with their "gate-control" theory.¹ Melzack, a psychologist at McGill University, and Wall, a physiologist at University College London, realized they shared interpretations of experiments and observations on the nature of pain and put their thoughts together in 1962, publishing in the journal Brain.² The response was under-whelming, but when they published in Science three years later, the world was apparently ready for their insights.¹

Melzack and Wall pointed out the inadequacies of the specificity theory, which envisioned a direct line from receptors in the periphery, and the pattern theory, which proposed a summation of equal inputs. Their gate-control mechanism better fit observations. Here, dorsal horn cells modulate patterns of incoming information to the brain, which produces the response and perception. The idea of gate control "transformed the understanding of the pain process," wrote Mary Galea, professor of neuroscience at the University of Melbourne, in Wall's obituary in 2001.³

Courtesy of the John C. Liebeskind History of Pain Collection, History & Special Collections Division, Louise M. Darling Biomedical Library, UCLA.

Case notes from William K. Livingston on a WWII soldier with peripheral nerve injury, 1945.

Gate control clearly implicated the brain, which can counter nociception. One way it does this is via the release of opioid peptides that bind μ-opioid receptors in the brain and spinal cord. "The rapid activation of this system suppresses an individual's perception of a stressful event and the accompanying emotions. It kicks in when pain is sustained and stressful and regulates responses to maintain homeostasis," says Jon-Kar Zubieta, director of the psychiatry division at the Depression Center, University of Michigan, Ann Arbor. Descending pathways also bring the inhibitory neurotransmitters gamma-aminobutyric acid (GABA), serotonin, and noradrenaline to the dorsal horn.

Nociceptive pain feels different depending upon whether it emanates from the periphery or internal organs. Somatic pain, felt at the surface, tends to be sharp, defined, and localized and limited. Visceral pain is diffuse, dull, and can be referred. University of Utah's Chapman compares the two: "Gas in the bowel is a nasty pain caused by distension of the tissues. You can stretch skin a lot before it hurts, but a burn hurts right away. Adequate stimulation differs for internal organs and skin, and the nature of the pain is different. That is a real problem for identifying the source of pain, such as in the emergency department or in sports injuries."

Sometimes the brain's modulation of nociception does not precisely counter the stimulation. "Pain is an unusual perception," says J. Timothy Cannon, director of the neuroscience program at the University of Scranton, Pa. "It does not show a good one-to-one relationship with noxious input. Pain can occur without any obvious noxious input or greatly out of proportion to observable noxious input," he adds. And that is when the experience of pain segues from protective to pathological.

WHEN PAIN IS PATHOLOGICAL

Pain can linger once nociception ebbs. It can also arise without obvious stimulus. "Acute pain directs attention at something going wrong. Chronic pain is more complex. We often know what causes it, but we can't necessarily fix it," says Timothy E. Quill, director of the Palliative Care Program at Strong Memorial Hospital in Rochester, NY. The acute/chronic distinction transcends the literal definition of short versus long term. Although described as "continual" and "persistent," chronic pain more accurately reflects disturbed homeostasis.

And chronic pain is common. Researchers in Finland surveyed 6,500 members of the general population and found that 35.1% reported such pain at the time of questioning. Chronic pain was daily for 14.3% of the respondents, and 40% of primary care visits concerned chronic pain.⁴ Statistics are similar in other nations.

When chronic pain is not simply nociceptive, it falls under the umbrella of neuropathy. Damage to the nervous system confers a constant painful state. In effect, one sees a maiming of the messenger.

Neuropathic pain may be an overreaction (hyperalgesia) or follow an innocuous stimulus, such as touch (allodynia). Subtypes include diabetic neuropathy, which arises from the peripheral nervous system (PNS), and phantom limb pain, which stems from both the PNS and the CNS. Neuropathic pain can be intense: many people with diabetes cannot stand the feel of blankets on their feet.

A type of neuropathic pain most vividly noted on the battlefield is causalgia, described by Union Army Surgeon S. Weir Mitchell during the American Civil War as "the most terrible of all tortures." Harvard neurologist W. K. Livingston reiterated Mitchell's findings during the Second World War, keeping meticulous case histories. The intense burning of causalgia, later named reflex sympathetic dystrophy, is usually felt in a hand or foot, even if said extremity is paralyzed or missing.

Because neuropathic pain is not well understood, treatments tend not to be targeted, and therefore fall short. Neuropathic pain's otherness plays out in the different drugs known to treat it; it is more responsive to anticonvulsants, steroids, and tricyclic anti-depressants than to the opiates and nonsteroidal anti-inflammatory drugs (NSAIDs) used for acute pain. And gene-expression profiling is beginning to describe such pain types at the molecular level. Researchers at Neurogen in Branford, Conn., for example, are investigating waxing and waning gene expression among 104 candidate genes in a rat model for neuropathic pain. Michael Costigan, an instructor in the neural plasticity research group at Harvard Medical School, is looking at expression of 240 genes in dorsal root ganglia following peripheral nerve damage. So far, they've found that genes whose products facilitate neurotransmission are down-regulated, whereas genes involved in the immune response and inflammation are upregulated.

IN SEARCH OF RELIEF

Discovery of the mechanisms of pain relievers has taught us much about pain biology. Aspirin and other NSAIDs dampen prostaglandin synthesis by blocking cyclooxygenase, with the newer Cox-2 inhibitors doing so more selectively. Opiate drugs tap into our endogenous opiate system. Anti-inflammatories and opiates were widely use for centuries before their mechanisms were recognized. The analgesic effects of tricyclic antidepressants, although not completely understood, Cannon says, might bolster descending pathways by increasing availability of serotonin. But despite all the research, the medicine cabinet still offers mostly variations on a few themes. "Poppies gave us opium and its grandchildren; willow bark gave us aspirin and the NSAIDs. We have precious little else," says Chapman.

Katz cites side effects as a tremendous barrier. "We do not treat pain adequately because we are unable to clearly separate the anatomy and physiology of pain from normal anatomy and physiology." It's a sore subject with patients who'd found relief from arthritis with the Cox-2 inhibitors.

Of the 89 current NIH clinical trials for pain relievers, most investigate new ways to deliver old standards (capsaicin, morphine, and lidocaine) or alternative approaches (acupuncture, massage, chamomile tea, music therapy, and shamanic healing). A promising new type of painkiller, like the old, comes from nature. Ziconotide, a synthetic version of cone snail venom approved by the US Food and Drug Administration in late 2004, blocks calcium channels.

INDIVIDUAL DIFFERENCES

Courtesy of the John C. Liebeskind History of Pain Collection, History & Special Collections Division, Louise M. Darling Biomedical Library, UCLA.

A draft diagram of the presynaptic "gate control" mechanism with notes on orientation. The image was later published in Science (150:171–9, 1965).

The fact that painkillers are not uniformly effective echoes the extreme variability of the pain experience. No two people experience identical nociceptive input the same way. "You've got neurophysiological, hormonal, cultural, situational, and psychological factors," says Katz.

Context is crucial. During World War II, Harvard anesthesiologist Henry K. Beecher noted that injured soldiers reported less pain than civilians at Massachusetts General Hospital with the same problems. The soldier is not surprised by injury, whereas his hospitalized counterpart has just been in an accident. Beecher termed the overlaid cognitive and emotional responses to nociception the "reaction component" of pain.

Clinicians use several methods to assess pain. Most familiar is the numbered pain scale, with zero indicating no pain and 10 indicating the worst imaginable. Children are asked to point to cartoon faces to communicate the level of their distress. And the detailed McGill Pain Questionnaire computes a "present pain intensity" from zero to five.

But self-assessment fails for the unconscious or dying. Quill relies on facial expression, even though he knows the person may not feel pain at all. "It is hard to know with 100% certainty, so we try to interpret nonverbal cues," he says. If a patient grimaces, the staff increases the pain medication.

Health care workers have long noted differences in response to painkillers. "Some people are hypersensitive to a standard dose of morphine.... Another group doesn't respond unless we give an industrial strength dose," Chapman says. What's new is stamping genetic explanations on these distinctions.

One gene, for example, encodes the liver enzyme CYP2D6. A person with a deficiency of the enzyme cannot metabolize codeine.⁵ For another gene, COMT, three common haplotypes correlate to low, average, and high pain sensitivity. The encoded protein metabolizes dopamine and noradrenaline. People with the most active version of the enzyme do not metabolize these neurotransmitters rapidly, which allows enkephalins to accumulate and modulate pain. People with the least active enzyme have higher levels of the neurotransmitters, less enkephalin release, and lower pain thresholds.⁶

Microarray studies are fleshing out the cascades of gene action that cause and accompany a painful experience. For example, Sox11 mRNA floods the dorsal root ganglia cells in mice with heat-injured footpads. Microarray analysis of such cells reveals the genes whose expression changes in response to the increased Sox11 – and they are reminiscent of developmental pathways.⁷ The findings are consistent with those of Yves De Koninck at McGill University, who used a peripheral nerve injury rat model to show that GABA, which is normally inhibitory in the adult, is excitatory in the spinal cord after peripheral nerve injury – just as it is during development.⁸ Nociception, then, may reawaken certain long-dormant processes or mimic them.

Despite exciting studies that dissect pain at the molecular level, understanding the experience may require a unique fusion of observations at different levels. Says Chapman, "Pain cannot be reduced simply to neurophysiology or pharmacogenomics. Pain is at the other end, the whole human being. It is a conscious experience that emerges from our very complex brains. People suffer in complicated ways."