Sleep fragmentation by brief awakenings as a surrogate to measure neuropathic spontaneous pain

项目总结/文摘

Project Summary/Abstract Most preclinical research on neuropathic pain has focused almost exclusively on mechanical allodynia and thermal hyperalgesia as endpoint readouts. While these are pertinent to assess stimulus-evoked hypersensitivity, they leave out the two top complaints reported by neuropathic pain patients: spontaneous pain and sleep disturbances. There is currently no technique to measure spontaneous pain reliably in rodents, limiting our study of the mechanisms responsible, and the nature of the sleep disturbances in neuropathic pain states are not known. We analyzed sleep and pain responses in two mouse models of peripheral neuropathic pain and found that while peripheral nerve trauma did not change total sleep amount, it caused a severe non-rapid eye movement sleep (NREMS) fragmentation in both models, which was only detected when mice also displayed signs of abnormal pain hypersensitivity and resolved when evoked pain sensitivity returned to pre-injury values. The temporal profile of the wake episodes that fragment sleep fits with the very brief sharp pain burst reported in patients with traumatic neuropathic pain (1), and also with the rare occurrence of spontaneous pain-like behavior observed in awake rodents after trigeminal nerve injury (2-4). In our pilot data, we used a combination of genetic and pharmacological approaches and found that the increase in sleep fragmentation after nerve injury originates from injured peripheral sensory neurons, does not appear to be caused by peripheral inputs and can be blocked by analgesics. In this project we hypothesize that sleep fragmentation caused by nerve injury is causally linked to the spontaneous activity in sensory fibers that activates pain pathways, and that therefore it could be used as a surrogate readout for quantifying neuropathic spontaneous pain. We propose 3 Specific Aims to test if sleep fragmentation after nerve injury is caused by ectopic activation of injured sensory neurons that activates ascending pain pathways, while it does not involve innocuous stimuli or require evoked noxious stimuli. Aim 1: Identify which peripheral sensory neurons drive NREMS fragmentation after nerve injury. Aim 2: Determine if the neural activity responsible for NREMS fragmentation is generated spontaneously at the injury site or requires external stimuli. Aim 3: Test if the spino-parabrachial pathway contributes to nerve injury-induced NREMS fragmentation Because we cannot measure spontaneous pain in live animals it has been impossible to perform mechanistic studies. Identifying a novel readout measure for neuropathic spontaneous pain would represent a fundamental breakthrough to study the underlying mechanisms and test the efficacy of potential novel analgesics.