Systems and Circuits Linking Chronic Pain and Circadian Rhythms

Abstract

Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy.

Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal, and analgesia

“…Hallmarks of opioid dependence and opioid use disorder are profound disruptions to sleep and circadian rhythms that persist during abstinence and withdrawal [4][5][6][7] . In line with this, previous evidence suggests opioid tolerance, dependence, and analgesia [8][9][10][11][12] are modulated by sleep and circadian rhythms. Altered circadian rhythms and sleep disruptions are commonly observed in patients being treated with opioids 13 .…”

“…Previous studies implicated circadian regulation of pain, tolerance, and physical dependence 11,12 , suggesting bidirectional interactions between circadian rhythms and opioids 9 . NPAS2 is a circadian gene enriched in brain regions and spinal cord involved in pain and opioids, and previously shown to be involved in psychostimulant reward 44,45 .…”

Sleep phase and pre-sleep arousal predicted co-developmental trajectories of pain and insomnia within adolescence

“…In addition, pharmacological, social or psychological interventions may be effective in treating the conjoint development of pain and insomnia, including melatonin 7 , synchronizing adolescents’ school time with their biological clock 59 , and CBT 60 . The current results may indicate that the effect of melatonin on pain is mediated through insomnia symptoms, practically meaning that advancing adolescents’ sleep phase may lead to a reduction in insomnia symptoms, which, in turn, may reduce pain 56 .…”

“…This is in line with previous research suggesting that cognitive-emotional arousal may delay sleep onset and lower sleep quality 24 , and that worry, rumination and emotional distress are associated with the sleep-pain relationship 3 , 55 . Additionally, stress responses or arousal has been proposed to explain the sleep-pain relationship 5 , as well as influencing melatonin secretion 56 . Pre-sleep arousal may have both a moderating and a mediating effect on comorbid pain and insomnia.…”

The Diurnal Profile of Human Basal Pain Sensitivity and Skin Sympathetic Nerve Activity: A Healthy Volunteer Study

“…And the mechanism of diurnal rhythm in pain remains unclear. A recent report has simply summarized the interaction between chronic pain and circadian rhythm ( Warfield et al, 2021 ), including the effect of interrupting circadian clock gene expression after injury and its role in the induction and maintenance of chronic pain, and the effect of chronic pain on peripheral and central circadian rhythm.…”