Qualification of fMRI as a biomarker for pain in anesthetized rats by comparison with behavioral response in conscious rats

fMRI can objectively measure pain-related neural activities in humans and animals, providing a valuable tool for studying the mechanisms of nociception and for developing new analgesics. However, due to its extreme sensitivity to subject motion, pain fMRI studies are performed in animals that are immobilized, typically with anesthesia. Since anesthesia could confound the nociceptive processes, it is unknown how well nociceptive-related neural activities measured by fMRI in anesthetized animals correlate with nociceptive behaviors in conscious animals. The threshold to vocalization (VT) in response to an increasing noxious electrical stimulus (NES) was implemented in conscious rats as a behavioral measure of nociception. The antinociceptive effect of systemic (intravenous infusion) lidocaine on NES-induced fMRI signals in anesthetized rats was compared with the corresponding VT in conscious rats. Lidocaine infusion increased VT and suppressed the NES-induced fMRI signals in most activated brain regions. The temporal characteristics of the nociception signal by fMRI and by VT in response to lidocaine infusion were highly correlated with each other, and with the pharmacokinetics (PK) of lidocaine. These results indicate that the fMRI activations in these regions may be used as biomarkers of acute nociception in anesthetized rats. Interestingly, systemic lidocaine had no effect on NES-induced fMRI activations in the primary somatosensory cortex (S1), a result that warrants further investigation.