One size doesn’t fit all: towards optimising the therapeutic potential of endogenous pain modulatory systems

Abstract

Introduction. Top–down processing pathways modulate neuronal transmission at the level of the spinal cord dorsal horn and thus govern, in part, the percept of pain. In health, these descending control systems can give rise to a naturally occurring form of pain inhibition. Despite a high therapeutic potential, the clinical applicability of harnessing such endogenous systems has not been fully realised. We propose that this is due to several complicating issues. First, the descending pain modulatory system (DPMS) is influenced by sensory as well as affective brain circuits. Thus, because of the bidirectional nature of the DPMS, pain may be facilitated or inhibited in a manner that corresponds not only to the degree of injury but also to the emotional status of the individual. This relates to the second issue; the DPMS, traditionally viewed as an encompassed “whole” for top–down processing, is in fact comprised of distinct neuronal networks. Emerging data highlight that a blanket pharmacological approach does not consider that diverse circuits, despite overlapping functionality and neurochemistry, require unique intervention. Meaning that, for DPMS-targeted analgesia, activity must be altered in the relevant pathway where cortical influences must also be considered. Here, we review what is known about the neuroanatomical framework by which distinct descending pathways are subserved, citing evidence from both preclinical (animal) and clinical (human) studies. This is timely because movement towards selective therapeutic intervention (ie, relevant to specific features of pathological pain conditions and their comorbidities) will depend on recognition of top–down controls within the DPMS as functionally unique systems that are engaged by specific environmental or affective “drivers.” For this to occur, studies that define the anatomical and pharmacological nature of the circuits therein, and translational delineation of the mechanisms underlying key descending control pathways, are key.