fMRI investigation of the effect of local and systemic lidocaine on noxious electrical stimulation-induced activation in spinal cord.
Spinal cord fMRI offers an excellent opportunity to quantify nociception using neuronal activation induced by painful stimuli. Measurement of the magnitude of stimulation-induced activation, and its suppression with analgesics can provide objective measures of pain and efficacy of analgesics. This study investigates the feasibility of using spinal cord fMRI in anesthetized rats as a pain assay to test the analgesic effect of locally and systemically administered lidocaine. Blood volume (BV)-weighted fMRI signal acquired after intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles was used as an indirect readout of the neuronal activity. Transcutaneous noxious electrical stimulation was used as the pain model. BV-weighted fMRI signal could be robustly quantified on a run-by-run basis, opening the possibility of measuring pharmacodynamics (PD) of the analgesics with a temporal resolution of approximately 2 min. Local administration of lidocaine was shown to ablate all stimulation-induced fMRI signals by the total blockage of peripheral nerve transmission, while the analgesic effect of systemically administered lidocaine was robustly detected after intravenous infusion of approximately 3mg/kg, which is similar to clinical dosage for human. This study establishes spinal cord fMRI as a viable assay for analgesics. With respect to the mode of action of lidocaine, this study suggests that systemic lidocaine, which is clinically used for the treatment of neuropathic pain, and believed to only block the peripheral nerve transmission of abnormal neural activity (ectopic discharge) originating from the damaged peripheral nerves, also blocks the peripheral nerve transmission of normal neural activity induced by transcutaneous noxious electrical stimulation.
Zhao
Fuqiang
F
Department of Imaging, Merck Research Laboratories, West Point, PA 19486, USA. fuqiang_zhao@merck.com
Williams
Mangay
M
Welsh
Denise C
DC
Meng
Xiangjun
X
Ritter
Amy
A
Abbadie
Catherine
C
Cook
Jacquelynn J
JJ
Reicin
Alise S
AS
Hargreaves
Richard
R
Williams
Donald S
DS
D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004558:Electric Stimulation / Q000009:adverse effects; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008012:Lidocaine / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods; D010100:Oxygen / Q000097:blood; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects*; D013997:Time Factors
D000779:Anesthetics, Local; D008012:Lidocaine; D010100:Oxygen