Role of the Supraspinal Opioidergic Circuit in Left Prefrontal Repetitive Transcranial Magnetic Stimulation-Induced Analgesia

INTRODUCTION: The concurrent rise of undertreated pain and opiate abuse poses a unique challenge to physicians and researchers alike. A focal, noninvasive form of brain stimulation called transcranial magnetic stimulation (TMS) can produce analgesic effects on postoperative and laboratory-induced pain, but the anatomical and pharmacological mechanisms underlying this stimulation-induced analgesia remain unclear. The purpose of this project was to determine whether a 20-minute dose of 10 Hz left dorsolateral prefrontal cortex (DLPFC) repetitive TMS (rTMS) induces top-down analgesia via modulation of the supraspinal opioidergic circuit.;METHODS: In two separate studies, healthy volunteers were randomized to receive intravenous (I.V.) saline or naloxone immediately prior to sham or real left DLPFC rTMS. Using quantitative sensory testing (QST) on unadulterated skin and short sessions of heat on capsaicin-sensitized skin, acute pain and hot allodynia were respectively assessed before and after sham or real rTMS. This paradigm was implemented in a laboratory study prior to being adapted for use inside of a 3T magnetic resonance imaging (MRI) scanner.;RESULTS: In the laboratory, real rTMS reduced acute pain and hot allodynia to a greater degree than did sham rTMS. These analgesic effects were significantly reduced by pretreatment with naloxone. In the scanner, healthy volunteers who received a dose of real rTMS exhibited larger blood oxygen level-dependent (BOLD) signal response to painful stimuli in prefrontal cortex (PFC) and smaller BOLD signal response to painful stimuli in the anterior cingulate cortex (ACC), thalamus, midbrain and medulla than healthy volunteers who received sham rTMS. Naloxone pretreatment significantly reduced the analgesic effects and the BOLD signal changes exhibited by the group that received real rTMS. A preliminary dynamic causal modeling (DCM) analysis suggests that real rTMS enhanced the intrinsic connectivity within the network of DLPFC, thalamus, midbrain and medulla.;CONCLUSIONS: These results are consistent with the theory that left DLPFC rTMS induces a top-down opioidergic analgesia by enhancing the capacity for the prefrontal cortex to recruit and modulate subcortical opioidergic brain circuits.