The Modulation of Pain by Circadian and Sleep-Dependent Processes: A Review of the Experimental Evidence

Abstract

This proceedings paper is the first in a series of three papers developing mathematical models for the complex relationship between pain and the sleep-wake cycle. Here, we briefly review what is known about the relationship between pain and the sleep-wake cycle in humans and laboratory rodents in an effort to identify constraints for the models. While it is well accepted that sleep behavior is regulated by a daily (circadian) timekeeping system and homeostatic sleep drive, the joint modulation of these two primary biological processes on pain sensitivity has not been considered. Under experimental conditions, pain sensitivity varies across the 24 h day, with highest sensitivity occurring during the evening in humans. Pain sensitivity is also modulated by sleep behavior, with pain sensitivity increasing in response to the build up of homeostatic sleep pressure following sleep deprivation or sleep disruption. To explore the interaction between these two biological pro- The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/098269 doi: bioRxiv preprint first posted online Jan. 9, 2017; 2 Hagenauer, Crodelle, Piltz, Toporikova, Ferguson and Booth cesses using modeling, we first compare the magnitude of their effects across a variety of experimental pain studies in humans. To do this comparison, we normalize the results from experimental pain studies relative to the range of physiologicallymeaningful stimulation levels. Following this normalization, we find that the estimated impact of the daily rhythm and of sleep deprivation on experimental pain measurements is surprisingly consistent across different pain modalities. We also review evidence documenting the impact of circadian rhythms and sleep deprivation on the neural circuitry in the spinal cord underlying pain sensation. The characterization of sleep-dependent and circadian influences on pain sensitivity in this review paper is used to develop and constrain the mathematical models introduced in the two companion articles.

Investigating circadian rhythmicity in pain sensitivity using a neural circuit model for spinal cord processing of pain

“…Experiments on pain in neuropathic patients suggest that neuropathic pain has a circadian rhythm as well, having its peak in the afternoon, see Figure 2 in [8]. An afternoon peak in pain sensitivity is opposite of the daily rhythm in pain sensitivity under normal conditions [9]. We use our model to further investigate this phenomenon and propose that a possible mechanism for this shift in rhythm is due to the interaction between the Aβ and C fibers.…”

“…Neuropathic conditions are characterized by an 8-12 hour shift in the phasing of daily rhythms in pain sensitivity [37,31,15,8]. As an application of the model, we investigate whether a large phase shift could be produced by a combination of deregulated neural inhibition, and differentially-phased rhythmic afferent input from Aβ and C fibers [24], see [9].…”

“…We are particularly interested in using the model to investigate mechanisms for circadian and sleep-dependent modulation of pain sensitivity. As reviewed in [9], pain sensitivity exhibits a daily rhythm with a trough in the late afternoon and a peak sometime after midnight for humans. There are several hypotheses for the source of this circadian rhythm, including the sensory afferent fibers, and the top-down inhibition.…”

A Two-Process Model for Circadian and Sleep-dependent Modulation of Pain Sensitivity

“…While there is strong experimental evidence that increased homeostatic sleep drive that occurs due to sleep deprivation increases pain sensitivity (as reviewed in [7]), the correlation between pain sensitivity and the homeostatic sleep drive under normal sleep conditions has not been determined. To construct our model, we assume that pain sensitivity exhibits increases and decreases throughout the 24 h day that follow the increases and decreases of the homeostatic sleep drive.…”

“…Pain sensitivity is strongly modulated by time of day and by prior sleep behavior. As reviewed in the preceding chapter [7], in humans highest sensitivity to painful stimuli occurs during the night and lowest sensitivity occurs in the late afternoon. Additionally, sleep deprivation increases pain sensitivity.…”