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.
Highlights
Research focused on the intersection between circadian rhythms and pain has revealed numerous bidirectional interactions among the processes underlying both systems
Immune cells and mediators can lead to disinhibition in the central nervous system (Latremoliere, 2016), notably by T cells and microglia (Watkins et al, 2007; Old et al, 2016). These cells release mediators that play an active role in central sensitization, including IL-1β and IL-6 which inhibit the frequency of inhibitory post synaptic currents (IPSC’s) in lamina 2 neurons, and IL-1β which decreases the amplitude of IPSC’s on the post synaptic cell (Kawasaki et al, 2008)
When GABAergic neurons in the lateral parabrachial (LPB) are stimulated for the first 7 days of common peroneal nerve ligation, they can completely stop the development of neuropathic pain (Sun et al, 2020). This is achieved through a monosynaptic connection of LPB inhibitory neurons onto LPB excitatory neurons. These findings show that the LPB can exhibit a gain in excitability and disinhibition, the hallmarks of central sensitization, and that increasing its inhibitory tone relieves pain
Summary
Research focused on the intersection between circadian rhythms and pain has revealed numerous bidirectional interactions among the processes underlying both systems. These cells release mediators that play an active role in central sensitization, including IL-1β and IL-6 which inhibit the frequency of inhibitory post synaptic currents (IPSC’s) in lamina 2 neurons, and IL-1β which decreases the amplitude of IPSC’s on the post synaptic cell (Kawasaki et al, 2008).
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