Modeling the daily rhythm of human pain processing in the dorsal horn

PLoS Comput Biol. 2019 Jul 11;15(7):e1007106. doi: 10.1371/journal.pcbi.1007106. eCollection 2019 Jul.


Experimental studies show that human pain sensitivity varies across the 24-hour day, with the lowest sensitivity usually occurring during the afternoon. Patients suffering from neuropathic pain, or nerve damage, experience an inversion in the daily modulation of pain sensitivity, with the highest sensitivity usually occurring during the early afternoon. Processing of painful stimulation occurs in the dorsal horn (DH), an area of the spinal cord that receives input from peripheral tissues via several types of primary afferent nerve fibers. The DH circuit is composed of different populations of neurons, including excitatory and inhibitory interneurons, and projection neurons, which constitute the majority of the output from the DH to the brain. In this work, we develop a mathematical model of the dorsal horn neural circuit to investigate mechanisms for the daily modulation of pain sensitivity. The model describes average firing rates of excitatory and inhibitory interneuron populations and projection neurons, whose activity is directly correlated with experienced pain. Response in afferent fibers to peripheral stimulation is simulated by a Poisson process generating nerve fiber spike trains at variable firing rates. Model parameters for fiber response to stimulation and the excitability properties of neuronal populations are constrained by experimental results found in the literature, leading to qualitative agreement between modeled responses to pain and experimental observations. We validate our model by reproducing the wind-up of pain response to repeated stimulation. We apply the model to investigate daily modulatory effects on pain inhibition, in which response to painful stimuli is reduced by subsequent non-painful stimuli. Finally, we use the model to propose a mechanism for the observed inversion of the daily rhythmicity of pain sensation under neuropathic pain conditions. Underlying mechanisms for the shift in rhythmicity have not been identified experimentally, but our model results predict that experimentally-observed dysregulation of inhibition within the DH neural circuit may be responsible. The model provides an accessible, biophysical framework that will be valuable for experimental and clinical investigations of diverse physiological processes modulating pain processing in humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Validation Study

MeSH terms

  • Circadian Rhythm / physiology*
  • Computational Biology
  • Ganglia, Spinal / physiopathology
  • Humans
  • Interneurons / physiology
  • Models, Neurological*
  • Nerve Net / physiology
  • Neuralgia / physiopathology
  • Nociception / physiology
  • Nociceptive Pain / physiopathology
  • Pain / physiopathology*
  • Pain Perception / physiology
  • Spinal Cord Dorsal Horn / physiopathology*

Grants and funding

The authors were funded by the National Institute for Mathematical and Biological Synthesis, sponsored by the National Science Foundation through NSF Award DBI-1300426, with additional support from The University of Tennessee, Knoxville (JC, SHP, MHH, VB) This work was also partially supported by the following sources: NSF Mathematical Sciences PostDoctoral Research Fellowship DMS-1703761 (JC), University of Michigan (SHP), NSF Award DMS-1412119 (VB), and the Pritzker Neuropsychiatric Disorders Research Consortium (MHH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.