Sci. Aging Knowl. Environ., 26 February 2003
Gain on Pain
Scientists identify portion of molecule that relays pain from damaged nerves
Key Words: CaM kinase II hyperalgesia allodynia CCI
Some people feel stabbing pain even though they have no obvious injury. This so-called neuropathic pain afflicts the elderly disproportionately and appears to result from nerve damage. Researchers have been unable to separate the signals for neuropathic pain from those for other types of chronic pain, such as that caused by long-lasting inflammation (see "The Burden of Pain on the Shoulders of Aging"). New results home in on part of a protein that's required to convey neuropathic pain specifically, providing a possible therapeutic target.
Unlike other types of chronic pain, neuropathic pain renders skin hypersensitive to light touch, lowers a person's threshold for pain, and rebuffs analgesics such as aspirin and morphine. Older people are prone to at least two diseases that involve neuropathic pain. Trigeminal neuralgia jabs the face because of damage to the facial nerves, and postherpetic neuralgia nettles the skin after a bout of shingles. A molecule called the NMDA receptor, which juts out from neurons in the brain and spinal cord, transmits neuropathic and inflammatory pain, and a protein called PSD-95 docks with the receptor in cell membranes. Previously, researchers showed that decreasing the amount of PSD-95 in mice delays the onset of neuropathic pain due to nerve injury. This observation suggests that PSD-95 conveys neuropathic pain--but not whether it conveys neuropathic pain specifically.
To probe this issue, Garry and colleagues created mice that carried a shortened version of PSD-95: The mutant molecule retained its ability to bind the NMDA receptor, but it lacked a segment that might be responsible for sending the pain message.
Mice with the clipped PSD-95 did not appear to have general neurological problems--they had no trouble walking, for example. Then, the researchers injected the caustic chemical formalin into their paws, and the mice licked and shook the irritated appendage, indicating that intact PSD-95 is not required for inflammatory pain. The researchers provoked neuropathic pain by cutting the pelvic nerve in one leg of the animals. In tests conducted a week later, normal animals withdrew their injured paws from a warm plate, a prickly brush, and cold water faster than they withdrew their healthy paws, indicating that they were suffering from neuropathic pain. The mutant mice, however, did not react to the irritants; without PSD-95's tail, the mice were not hypersensitive to these innocuous stimuli. In addition, injection of NMDA caused neuropathic pain in normal animals but not in the altered rodents, suggesting that trimmed PSD-95 prevents the NMDA receptor from forwarding neuropathic signals. Additional biochemical tests revealed that less of a known signal-passing enzyme bound to the NMDA receptor in the mutant mice than in the normal mice, hinting that full-length PSD-95 is required for the enzyme and the NMDA receptor to interact properly.
Molecular pharmacologist Roger Johns of The Johns Hopkins University in Baltimore, Maryland, calls the result "a wonderful advance," because it clarifies the role of PSD-95 in neuropathic pain. Biochemist Yuan-Xiang Tao at the same university says he would like to see additional data to confirm that loss of PSD-95 alters the signals that the NMDA receptor passes on. In the meantime, the new results might help researchers stab back at this uncomfortable sensation.
February 26, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150