Central circuits underlying conditioned pain modulation

Abstract

Conditioned pain modulation (CPM) is a phenomenon whereby an initial painful stimulus is reduced by the application of a second painful stimulus, i.e. pain inhibits pain. The variability of an individuals CPM capacity is important clinically, as reduced CPM ability is associated with increased postoperative pain, the presence of persistent pain conditions and the efficacy of analgesic medications. Experimental animal investigations and human lesion studies suggest that the brainstem is critical for CPM expression, in particular the subnucleus reticularis dorsalis (SRD). The aims of this thesis were to employ high resolution functional magnetic resonance imaging to define the central circuits responsible for CPM in humans, and whether these changes reflect differences at rest, i.e. in the absence of a CPM paradigm. The results presented in this thesis show, for the first time, that CPM analgesia in healthy individuals is associated with reduced activity within the primary synapse that is significantly influenced by the SRD. Furthermore, our data suggest that the engagement of higher brain sites prevents the generation of this analgesic mechanism, raising the raising the possibility that altered responsiveness in these cortical regions may underlie the reduced CPM observed in individuals with chronic pain. Finally, we have shown that these group differences exhibit similar alterations in the pain-free state, and that on-going activity and connections of certain brain regions can predict the effectiveness of an individuals’ endogenous analgesic brain circuitry. Overall, these data reveal that CPM responsiveness is underpinned by differences in the pain-free state, which in turn could influence an individuals’ propensity for developing chronic pain following injury. This body of work sets the precedence for future investigations to determine whether individuals with chronic pain syndromes displayed similar differences in resting state brain activity and provides a framework for future development of analgesic medications to target this circuitry.