Injury to the peripheral nervous system can provoke recurring pain and negative affect comorbidity, an explicit burden of chronic pain patients. In humans and preclinical models, neuropathic pain involves the sensitization of peripheral and central circuits that underlie ongoing pain and produce allodynia, in which innocuous stimuli are now painful. Although we understand much of the anatomy and physiology of the processing of injury information from the periphery to the brain, our knowledge of how forebrain circuits generate the pain percept and its affective component is limited. Our recent studies indicate that afferent activity within the mediodorsal thalamus (MD) connection to the anterior cingulate cortex (ACC) selectively drives aversive conditioning in chronic pain states. The conditioning results from a plasticity mechanism in the ACC, one that increases the correlation between MD activity and aversive behavior. These findings are the basis of our hypothesis that MD- ACC neuronal activity, in chronic pain states, is a determinant of aversiveness, and that it is separate from nociception. To challenge our hypothesis, we propose an innovative combination of in vivo microendoscopy and circuit-specific labeling to measure MD-ACC activity at baseline, in response to investigator-evoked stimuli and in an operant environment, using two nerve-injury induced preclinical pain models.
Our specific aims focus on 1. Determining if MD-ACC activity specifically encodes pain-related states, rather than acute nociception; 2. Testing whether inhibition of MD-ACC activity attenuates pain aversiveness selectively in chronic pain conditions; and 3. Assessing if analgesics interact differentially with MD-ACC activity in connection with their potency against pain aversiveness. Information gained from these studies will highlight the therapeutic potential of targeting the MD (e.g., with novel pharmacotherapeutics) in ongoing pain states and elaborate our knowledge of when and where brain activity becomes abnormal after an injury to the peripheral nervous system.
The aversive component of the pain experience, which is a significant contributor to reduced quality of life for millions of chronic pain patients in the United States, depends on the transmission of injury messages from the periphery to the cerebral cortex and generation of pain by the brain. To study the circuits that process pain aversiveness, here we propose an in vivo imaging approach that examines the mediodorsal thalamus (MD) to anterior cingulate cortex (ACC) pathway in preclinical models of chronic neuropathic pain. Our studies will distinguish neuronal activity biomarkers of pain-associated negative affect at baseline, in behavioral settings of pain aversiveness and in response to first-line and novel analgesics.
