Concurrent activation of the somatosensory forebrain and deactivation of periaqueductal gray associated with diabetes-induced neuropathic pain

Abstract

We combined behavioral testing with brain imaging using (99m)Tc-HMPAO (Amersham Health) to identify CNS structures reflecting alterations in pain perception in the streptozotocin (STZ) model of type I diabetes. We induced diabetic hyperglycemia (blood glucose >300 mg/dl) by injecting male Sprague-Dawley rats with STZ (45 mg/kg i.p.). Four weeks after STZ-diabetic rats exhibited behaviors indicative of neuropathic pain (hypersensitivity thermal stimuli) and this hypersensitivity persisted for up to 6 weeks. Imaging data in STZ-diabetic rats revealed significant increases in the activation of brain regions involved in pain processing after 6 weeks duration of diabetes. These regions included secondary somatosensory cortex, ventrobasal thalamic nuclei and the basolateral amygdala. In contrast, the activation in habenular nuclei and the midbrain periaqueductal gray were markedly decreased in STZ rats. These data suggest that pain in diabetic neuropathy may be due in part to hyperactivity in somatosensory structures coupled with a concurrent deactivation of structures mediating antinociception.

Figure 1

Graphs showing the blood glucose levels (A) and body weights (B) of control (black circles) and diabetic (open circles) rats. Differences in blood glucose (Beyer Elite™ Glucometer) before and after injection with vehicle (saline) or STZ are shown in Panel A. Note that diabetic rats developed a relatively stable level of hyperglycemia approximately 3 days after injection with STZ. Panel B shows the mean body weight for control and STZ-D groups over the six weeks following injection. STZ-D animals had a significantly lower weight gain than control animals, but did not lose weight. Asterisks indicate a significant difference between groups, determined using a repeated measures mixed model ANOVA (SPSS for Windows) with Dunnetts T3 for post-hoc analysis (* = p < .05; ** = p < .005; *** = p< .0001).

Figure 2

Graph showing changes in behavioral response to thermal stimuli applied to the plantar surface of the left hind foot in STZ-D (open circles) and control (black circles) rats. Differences in behavioral responsiveness to noxious heat between control and STZ injected rats developed by four weeks after induction of diabetes. All values are expressed as the group means at four time points: baseline, and 4, 5 and 6 weeks after confirmed diabetes. Asterisks indicate a significant difference between groups, determined using a repeated measures mixed model ANOVA (SPSS for Windows) with Dunnetts T3 for post-hoc analysis (* = p < .05).

Figure 3

Sample colorized coronal sections showing differences in resting brain activation between non-diabetic control and STZ-D rats, at three A–P levels: −2.3, −3.3 and −6.3. Note: each image is taken from a single brain section in individual animals and therefore may not accurately depict group means presented in the table and graphs.

Figure 4

The bar graphs compare the mean basal (unstimulated) bilateral level of activation (AI) in somatosensory and endogeneous antinociceptive ROIs for control (black circles) and diabetic experimental (open circles) groups six weeks after injection of vehicle or STZ. Data are shown only for ROIs showing a significant difference in activation between the two groups. Significant differences in AI between groups were determined using a mixed-model repeated measures ANOVA corrected for multiple comparisons (SPSS for Windows). Line drawings of sampled brain regions were modified from the stereotaxic atlas of the rat brain (Paxinos and Watson, 1998) to show the approximate Anterior-Posterior (AP) level where each brain region was sampled. Asterisks indicate: * = p < .05; ** = p < .005; *** = p< .0001.