20 November 2002 17:00 EST

by Apoorva Mandavilli

Two methods now used interchangeably to test for pain sensitivity in mice can give directly contradictory results, a team of neuroscientists has discovered. The news may send pain researchers scurrying to redo old experiments and re-test once-discarded drug candidates.

The shock sensitivity test, commonly used as for a surrogate for pain sensitivity, is "not reflective at all" of a commonly used alternative, the tail-flick latency test (which measures the time taken for a mouse to flick its tail away from a heat source), said Joseph Buxbaum, associate professor of psychiatry at the Mount Sinai School of Medicine in New York. He was speaking today at a meeting organized by the New York Academy of Sciences.

"Shock sensitivity was considered to be identical to tail-flick latency - they've always been considered analogous," said Buxbaum. "But practically, they're very different."

Buxbaum tested shock sensitivity in mice lacking the protein calsenilin, a protein implicated in Alzheimer's disease (AD). The knockout mice were more sensitive to shock, the researchers found.

But earlier this year, a rival team reported that the same mice were less sensitive to pain, prompting Buxbaum to revisit his experiments.

Buxbaum first identified calsenilin a few years ago as a protein that interacts with presenilin, a key player in AD. Calsenilin has since made an appearance in the scientific literature under at least two other names - Potassium Channel Interacting Protein 3 (KChIP3) and downstream regulatory element antagonistic modulator (DREAM).

A team led by Josef Penninger at the Amgen Institute in Toronto reported in Cell earlier this year that mice lacking DREAM, or calsenilin, have a diminished response to heat, pressure, chronic pain, and even neuropathic pain.

"We were just flabbergasted because, when we looked at shock sensitivity, the mice were more sensitive," Buxbaum recalled.

This time, Buxbaum and his collegaues tested for pain sensitivity using the tail-flick latency test, and confirmed that the mice were indeed less sensitive to pain. The results have been submitted for publication.

Although shock sensitivity and tail-flick latency have always been considered to be analogous, "they're clearly very divergent in this model," said Buxbaum.

"The take home is that shock sensitivity is not reflective at all of tail-flick latency," he added. "In the same animal, there can be increased sensitivity to one and decreased sensitivity to another."

One possible explanation for the conflicting results is that one test probes the peripheral sensory pathway while the other works through the central pain pathway, suggests Sam Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.

In any case, "this is a big deal in the analgesic community," Gandy told BioMedNet News. Pain researchers will have to decide which test is more useful for their purposes, or choose to use both, he said.

While most drug candidates are tested on humans before they are used in the clinic, he added, the finding "means that there may have been some promising compounds that were discarded prematurely."

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See also:
Biochemical and immunocytochemical characterization of calsenilin in mouse brain
N. Zaidi, O. Berezovska, E. Choi, et al.
Neuroscience, 2002 114:247

DREAM is a critical transcriptional repressor for pain modulation
H.Y. Cheng, G.M. Pitcher, S.R. Laviolette, et al.
Cell, 2002 Jan 108:31-43

Neurophysiological evaluation of pain
[Invited review]
Burkhart Bromm and Jürgen Lorenz
Electroencephalography and Clinical Neurophysiology, 1998, 107:4:227-253

Pathobiology of neuropathic pain
[Review]
Manfred Zimmermann
European Journal of Pharmacology, 2001, 429:1-3:23-37
 

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