CNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesics

Abstract

AbstractfMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system‐specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are “normal.” Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential “translational tool” in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23–41, 2007. © 2007 Wiley‐Liss, Inc.