Insular balance of glutamatergic and GABAergic signaling modulates pain processing.

Abstract Neuroimaging studies of patients with chronic pain have shown that neurotransmitter abnormalities, including increases in glutamate and decreases in GABA, could be responsible for the cortical hyperactivity and hyperalgesia/allodynia observed in some pain conditions. These finding are particularly evident in the insula, a brain region known to play a role in both the sensory-discriminative and the affective-motivational aspects of pain processing. However, clinical studies are not entirely able to determine the directionality of these findings, nor whether they are causal or epiphenomenon. Thus, a set of animal studies was performed to determine whether alterations in glutamate and GABA are the result of injury, the cause of augmented pain processing, or both. Compared with controls, the excitatory neurotransmitters glutamate and aspartate are significantly higher in the rat insula after chronic constriction injury of the sciatic nerve (CCI). The CCI also produced significant increases in allodynia (mechanical and cold), thermal hyperalgesia, and nociceptive aversiveness. Unilateral microinjection of ionotropic glutamate receptor antagonists restored these nociceptive behaviors to preinjury values. Increasing endogenous levels of GABA or enhancing signaling at inhibitory glycinergic receptors had similar effects as the glutamate receptor antagonists. In naive rats, increasing endogenous levels of glutamate, decreasing endogenous levels of GABA, or blocking strychnine-sensitive glycine receptors in the insula significantly increased thermal hyperalgesia and mechanical allodynia. These data support the hypothesis that an altered balance of excitatory and inhibitory neurotransmitters in brain regions such as the insula occurs in chronic pain states and leads to augmented central pain processing and increased pain sensitivity.