Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia

Abstract

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 repetitive transcranial magnetic stimulation (rTMS) has been shown to produce acute and chronic analgesic effects when applied to dorsolateral prefrontal cortex (DLPFC), but the anatomical and pharmacological mechanisms by which prefrontal rTMS induces analgesia remain unclear. Data suggest that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit. This potential pathway might explain how prefrontal rTMS reduces pain. The purpose of this sham-controlled, double-blind, crossover study was to determine whether left DLPFC rTMS-induced analgesia was sensitive to μ-opioid blockade. Twenty-four healthy volunteers were randomized to receive real or sham TMS after either intravenous saline or naloxone pretreatment. Acute hot and cold pain via quantitative sensory testing and hot allodynia via block testing on capsaicin-treated skin were assessed at baseline and at 0, 20, and 40 minutes after TMS treatment. When compared to sham, real rTMS reduced hot pain and hot allodynia. Naloxone pretreatment significantly reduced the analgesic effects of real rTMS. These results demonstrate that left DLPFC rTMS-induced analgesia requires opioid activity and suggest that rTMS drives endogenous opioidergic pain relief in the human brain. Further studies with chronic dosing regimens of drugs that block or augment the actions of opiates are needed to determine whether TMS can augment opiates in chronic or postoperative pain management.

Conflict of interest statement

The authors declare no conflict of interest related to this study.

Copyright © 2012 International Association for the Study of Pain. All rights reserved.

Figures

Figure 1

Comparison of hot pain thresholds (mean percent change from baseline ± SEM) over time. The black line represents saline-real TMS while the gray line represents naloxone-real TMS. Asterisks (* p < 0.05, ** p < 0.001) indicate significant baseline comparisons within-groups (immediately above data series) and between-groups (immediately above SEM bars).

Figure 2

Comparison of block pain intensity ratings (mean ± SEM). Twenty-two (22) sec blocks of a fixed temperature reported as an intensity of “7” on a VAS (1-10) at baseline were applied to capsaicin-sensitized skin in three consecutive trials at 0, 20 and 40 min after TMS with pretreatment. Asterisks (* p < 0.05, ** p < 0.001) indicate significant baseline comparisons within groups (immediately above data series) and between-groups (immediately above brackets).