Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

Abstract

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.

Fig. 1.

Group activations in response to punctate mechanical stimulation of the right leg. Brain areas significantly activated (red) or deactivated (blue) by stimulation of normal skin (Upper) or of the area of secondary hyperalgesia (Lower), after placebo (upper row) or a single dose (1,800 mg) of gabapentin (gbp, lower row). Note the drug-induced reduction in activation within the “pain matrix” (e.g., right and left insular cortex, brainstem, thalamus) and in deactivation outside the “pain matrix” (e.g., occipital, frontal and temporal cortex).

Fig. 2.

Paired group comparison of whole-brain activity during central sensitization between placebo (period 3) and gabapentin (period 4). (Upper) Voxels with a significant fMRI signal increase during period 4. (Lower) The same voxels, color-coded according to their response to stimulation in the two periods. Blue voxels showed deactivation in period 3 and reduced deactivation in period 4; yellow voxels showed deactivation in period 3 and activation in period 4; red voxels showed activation in period 3 and increased activation in period 4. Note that most of the voxels (94%) are blue and yellow, indicating that the fMRI signal increase during period 4 was mostly the result of drug-induced reduction of brain deactivations in response to punctate mechanical stimulation.

Fig. 3.

ROI analysis. Plots showing fMRI signal changes for the four study periods (1, normal state/placebo; 2, normal state/drug; 3, central sensitization/placebo; 4, central sensitization/drug) in a priori selected ROIs. Blue and red lines indicate the stimulation of the right and left leg, respectively. ROIs were anatomically defined on the high-resolution structural image of each subject. For each ROI, the number of subjects showing spatial overlap is color coded from red to yellow. Note the main effect of gabapentin in the right and left insula (after stimulation of both legs, P < 0.02), the main effect of central sensitization in the anterior cingulate cortex (P = 0.054), right (P = 0.058) and left (P = 0.031) thalamus (after right leg stimulation), and the interaction between central sensitization and drug effect in the brainstem after right leg stimulation, i.e., greater evidence of central sensitization effect during placebo (P = 0.013) than during drug (P = 0.401). A systematic description of the ROI analysis results is shown in Table 1.