When patients complain of pain, doctors reach for remedies on a rather dusty shelf. Opium and salicylic acid, discovered centuries ago, have fundamentally shaped practically every pain reliever on the market. Though treatment options for pain have not changed much since the ancient Greeks, an understanding of pain's basic mechanisms has progressed rapidly in the last decade. The optimism among researchers is palpable. "I think it's been unbelievable," says Frank Porreca, professor of pharmacology at the University of Arizona in Tucson. "We've had tremendous breakthroughs."
Yet none of these breakthroughs has translated to new clinical treatments. "The findings add to the burgeoning body of disparate facts pertaining to pain, but are unlikely to trigger new analgesics any time soon," writes pharmacologist Alan Cowan of Temple University in Philadelphia, in an E-mail. Not a single novel class of drugs has emerged from nearly 25 years of bench work, he adds.
It's not an uncommon lament among pain researchers, both basic scientists and clinicians. "It's depressing," says Jeff Mogil, professor of pain studies at McGill University in Montreal. He recounts the high-profile failures of "drugs that worked really well in animals, really ought to have worked, and didn't have any efficacy in humans at all." He cites the neurokinin antagonists that block receptors for substance P, a neuropeptide believed to alert neurons to tissue damage. The drugs weren't effective in humans. "We're still living that one down," he says. "Was it the fault of the basic science? Was it the fault of the clinical trials? What went wrong?"
These past failures have pushed researchers to be more innovative in their approaches to pain. Recent work has ventured into such new areas as growth factors and cytokines, which may be dynamically involved in the adaptive state that occurs with chronic pain. Others have shifted their focus away from traditional sites in the periphery and spinal cord to molecular targets in higher brain centers.
ADAPTING TO THE ACHE Chronic pain remains a big problem, affecting one in five Americans, according to the American Pain Society. Many patients do not get adequate relief with the current armamentarium of pain drugs. "We really shouldn't accept the idea that we've solved this problem of managing pain," acute or otherwise, says Porreca. "We medicate people so that they're not really conscious."
When pain is persistent, numerous adaptations occur at every level of the pain pathway--the periphery, the spinal cord, and the brain. These changes are long-lasting; they are maintained after the initiating event has healed, and they can persist for years. Because of this, clinicians and researchers consider chronic pain a disease state rather than a symptom. Neuropathic pain, resulting from nerve injury, is of particular interest because it is the most resistant to treatment. "It's clearly the biggest mystery," says Mogil.
The pain message begins with nociceptors, sensory afferent nerves with specialized receptors that are triggered only by high-intensity (painful) stimuli. Nerve morphology and function radically change in response to nerve injury. In addition to changes in pain receptor sensitivity, nerve membrane excitability increases, sometimes to the point of spontaneous discharge. The result: spontaneous pain and hypersensitivity to both painful and harmless stimuli. "The question is, how do you turn that off?" says Alan Lichtman, a pharmacologist at the Medical College of Virginia in Richmond.
Blocking sodium channels with agents such as lidocaine, a local anesthetic, will prevent the abnormal discharge of injured afferent nerves. "But you can't really use [lidocaine]," says Porreca, because the dose required to relieve neuropathic pain would be toxic.
Nonetheless, sodium channels remain a target of interest because of their heterogeneity. Tetrodotoxin-resistant sodium channels are selectively expressed in nociceptive neurons. From the perspective of pain transmission, this presents an attractive opportunity, but as yet, researchers have not found any highly selective ligands for these types of channels, says Porreca.
Targeting the source, the actively maintained state of pain sensitization, rather than the symptom, pain, forces a strategic change. Porreca's group hypothesized that the morphological changes in neuropathic pain implicated a role for growth factors. The current focus is artemin, an endogenous protein from the family of glial cell line-derived neurotrophic factors (GDNF). Specific receptors for artemin are selectively expressed on nociceptors.
To model neuropathic pain in rats, spinal nerves are constricted with surgical ties. The nerve swells "and basically chokes itself," says Porreca, which causes degeneration of some of the afferent fibers. The rats' behavior reflects hypersensitivity to painful stimuli for months. Neurochemically, transmitter release and the density of specific neuronal markers become altered. Porreca reports in a recent paper that systemic administration of artemin prevented and reversed both the behavioral and neurochemical changes in rats.1 Reversal is vital for treatment; patients generally don't seek help until after the process triggered by nerve damage has occurred.
MOVING UP THE SPINE Normally, nociceptors relay pain messages to second-order neurons in the dorsal horn of the spinal cord. In neuropathic pain, connections form between non-nociceptive and nociceptive neurons such that innocuous stimuli are perceived as painful. Further, loss of inhibitory interneurons leads to enhanced transmission of pain signals.
Linda Watkins and her colleagues at the University of Colorado, Boulder, target glia in the spinal cord, rather than neurons, which she says "opens up whole new avenues to approach human clinical pain." Glia do not send signals to the brain--they don't have axons--but they do release substances that modulate the pain message. "They're an outside instigator, like the crowd egging a bully on."
Proinflammatory cytokines appear to be the key mediator in the glial-induced pain changes, and anti-inflammatory cytokines such as interleukin-10 (IL-10) check those changes. Because this homeostatic mechanism occurs through cell signaling, the effects are specific with regard to timing and site of action. "IL-10 is like Valium for glia," says Watkins. In a recent publication, they report progress using gene therapy to deliver IL-10 epidurally.2
Adaptations in the brain contribute to the sensitization in chronic pain states by means of a "descending facilitation system," says Min Zhuo, Canadian Research chair and professor of physiology at the University of Toronto. Following the trend towards reductionism in pain research, his team focused on targeting molecules in specific cortical regions. This "top-down" approach might allow effective therapies to target sensitized pain states regardless of their peripheral sources.
The neurotransmitter N-methyl-D-aspartate (NMDA) has been implicated in centrally mediated sensitization. In a study published last year, Zhuo reported that inhibiting the enzyme adenylyl cyclase (AC), which links NMDA receptors to cyclic AMP, alleviated symptoms of chronic pain but not acute pain.3 This result occurred in AC knockout mice and in wild-type mice after microinjection of an inhibitor into the anterior cingulate cortex. Because only chronic pain was affected, Zhuo suggests that AC is critical in the sensitization process.
Higher brain functions such as mood and attention can influence the perception of pain. Both the anterior cingulate cortex and insular cortex receive pain messages and are thought to process motor and emotional responses to pain.
Neurosurgeon Luc Jasmin and his team at the University of California, San Francisco, study the output of the insular cortex. By increasing local levels of gamma aminobutyric acid (GABA), either by inhibiting its degradation or by implanting a viral vector, analgesia is induced in rats.4 Further, an adrenergic blocker reversed the effect, indicating a role for descending norepinephrine pathways. The team was surprised to find that cortical output affected spinal sensory components in addition to higher cognitive functions.
Brain targets aren't ideal, however; the widespread distribution of the molecules that Zhuo and Jasmin targeted creates a major hurdle. Adenylyl cyclase is second messenger to a whole family of G protein-coupled receptors, crucial signaling proteins in the brain and elsewhere. And, GABA has been implicated in as many as one-third of the synapses in the brain. Success in these studies depends largely on local administration of drugs or gene manipulation.
"Drugs affect multiple components, most of which have nothing to do with pain," says Jasmin. Even though pain is likely a diffuse phenomenon, his work supports the idea that "nodal points" in the brain can drastically affect the pain response. "With gene therapy, you will be able to target brain dysfunction in [specific] areas."
While pain researchers are following new leads and identifying novel mechanisms, the value of these discoveries for clinical application remains unclear. "There are hundreds and hundreds of molecules that are going to play important roles in pain," says Mogil. "Do we not have to identify all those molecules? Of course we do. And so people are putting bricks up on the wall, and the faster those bricks go up the sooner the house is built."
Given the heterogeneity of pain, its etiology, mechanisms, and time course, it may take a village.
Jill U. Adams (firstname.lastname@example.org) is a freelance writer in Albany, NY.
1. L.R. Gardell et al., "Multiple actions of systemic artemin in experimental neuropathy," Nat Med, 9: 1383-9, November, 2003.
2. L.R. Watkins, S.F. Maier, "Glia: a novel drug discovery target for clinical pain," Nat Rev Drug Discov, 2:973-85, December 2003.
3. F. Wei et al., "Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases," Neuron, 6:713-26, 2002.
4. L. Jasmin et al., "Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex," Nature, 424:316-20, July 17, 2003.