Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain‐like state using fMRI and brain wave analysis

Abstract

Neuropathic pain is the most difficult pain to manage in the pain clinic, and sleep problems are common among patients with chronic pain including neuropathic pain. In the present study, we tried to visualize the intensity of pain by assessing neuronal activity and investigated sleep disturbance under a neuropathic pain-like state in mice using functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG)/electromyogram (EMG), respectively. Furthermore, we investigated the effect of gabapentin (GBP) on these phenomena. In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, fMRI showed that sciatic nerve ligation produced a significant increase in the blood oxygenation level-dependent (BOLD) signal intensity in the pain matrix, which was significantly decreased 2 h after the i.p. injection of GBP. Based on the results of an EEG/EMG analysis, sciatic nerve-ligated animals showed a statistically significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase, and the sleep disturbance was almost completely alleviated by a higher dose of GBP in nerve-ligated mice. These findings suggest that neuropathic pain associated with sleep disturbance can be objectively assessed by fMRI and EEG/EMG analysis in animal models. Furthermore, GBP may improve the quality of sleep as well as control pain in patients with neuropathic pain.

Central Sensitization and Descending Facilitation in Chronic Pain State

“…Cortical GABAergic neurons play important roles in sleep/wake regulation (Gottesmann, 2004;Kilduff et al, 2011), and disturbance of this system may lead to the pathogenesis of insomnia in these patients. In the experimental model mice for neuropathic pain, an increase in wakefulness and a decrease in non-rapid eye movement sleep during day time, in which mice are supposed to be drowsy or sleeping, have been demonstrated by means of EEG analysis (Takemura et al, 2011). Under these conditions, as mentioned above, GAT-3 on activated astrocytes were increased in the ACC, and extracellular GABA levels in this area after depolarization were rapidly decreased .…”

“…At the same time, thermal hyperalgesia these animals showed was also normalized by GBP. Changes in EEG patterns identified in these mice during light phase were also attenuated by GBP treatment (Takemura et al, 2011). The site of action of GBP is still obscure, although GBP was shown to block the function of voltage-gated calcium channels (VGCCs), by binding to the -1 subunits.…”

“…Recently brain hyperactivity in neuropathic pain model mice in response to painful thermal stimulation has been examined using functional MRI (fMRI) (Takemura et al, 2011). Compared to sham-operated animals, exaggerated BOLD signals in the brain regions, such as the S1, ACC and medial/lateral thalamus, of animals subjected to nerve ligation were observed.…”

Drug-induced sleep: theoretical and practical considerations

“…Gabapentin and pregabalin are employed by sleep medicine in the context of pain-related sleep disruption due to fibromyalgia [87] and other chronic pain syndromes [2,98].…”

Objective evaluation for venous leg ulcer-related nociceptive pain using thermography

“…6,7 However, these tools cannot be used for patients with cognitive impairment or disturbance of consciousness. Several methods that may be able to evaluate pain objectively have been reported, such as functional magnetic resonance imaging or brain wave that visualize brain function, [8][9][10][11][12] or alpha-amylase or skin conductance evaluations of autonomic function, [13][14][15] but these methods cannot be performed rapidly in clinical situations. One promising objective pain evaluation scale for cognitively impaired patients is the Abbey Pain Scale, which consists of subscales for vocalization, facial expression, change in body language, behavioral change, physiological change, and physical changes.…”