Xinzhong Dong (left) is testing compounds targeting an Mrg receptor that appears to dull pain. Gail Mandel discovered Nav1.7, a sodium channel involved in pain perception that drug companies are exploring.

Neuroscientists often use natural ingredients—like menthol, capsaicin, and wasabi extracts—that stimulate nerve cells to react just as they would in response to painful cold and heat, for example, or to inflammation and chemical irritants. Drawing on electrical recordings, imaging, molecular techniques, mouse models, and genetic studies, scientists can explore the nervous system as it reacts to “pain” at the subcellular level. Their studies have revealed many molecular pathways that regulate pain perception, including specialized ion channels that open and close to send pain signals along nerves to the spinal cord and brain. They have also begun to explain the systemic changes in response to pain sensation that can cause chronic disorders.

HHMI scientific officer Ed McCleskey, who spent much of his research career studying pain, believes such progress will translate into health care benefits. “We have been using more or less the same aspirin and morphine variants for centuries now. But a wave of recent basic science discoveries has begun to transform the pain field, and they are already yielding insights for finding new ways to treat pain.”

The Many Types of Pain

Aspirin and opiates work just fine for most of us most of the time. But plenty of people don’t benefit from either drug or can’t handle their serious drawbacks, which range from stomach irritation and excessive bleeding to addiction and respiratory suppression. The devastating daily reality of uncontrolled chronic pain far exceeds the ability of today’s medicines to help. Every year, at least 116 million adult Americans experience severe chronic pain—more than the number affected by heart disease, diabetes, and cancer combined—at a cost of $560 billion annually in direct medical expenses and $635 billion in lost productivity, according to a June 2011 report from the Institute of Medicine.

Researchers today recognize several pain subtypes, which develop via electrical signals running along a complex, interconnected neural perception system genetically encoded to detect and respond to painful stimuli.

The body detects and converts pain stimuli into electrical signals at the fine nerve endings of “nociceptors,” sensory neurons specialized to respond to pain. Their axons, which conduct electrical signals, are only a millionth of a meter in diameter but can be more than a meter long, with one end located where a stimulus is detected—at a fingertip, for example—and the other end in the spinal cord, where it forms a synapse, or communication junction, with a second cell that sends the signal to the brain. The nociceptor’s spinal synapse is highly sensitive to opiates and other agents that can alter pain perception. The cell bodies of nociceptors and other sensory neurons sit just outside the spinal cord in clumps called dorsal root ganglia; action potentials—short-term changes in electrical charge—pass through the ganglia on the way to the spinal cord.

To convey signals from a peripheral organ to the spinal cord, the axon depends on a variety of molecules. Some convert a physical or chemical event into a small electrical signal at the peripheral nerve ending; others amplify the signal and send it along the length of the axon. Molecules at the synapse convert the electrical signal into a chemical signal, triggering release of a neurotransmitter that activates the postsynaptic neuron. Other molecules tune transmission of pain signals. Various types of ion channels—proteins that create pores in cell membranes—serve as detectors, amplifiers, and electrical-to-chemical translators, while receptors for hormone-like molecules modulate the activity of the channels.

		The Synapse Revealed Thomas M. Jessell of Columbia University explains what happens at a synapse.

Photo: Bruce Forster

	PAGE 1 2 3 4	Go Back | Continue