Central plasticity in pathological pain

Abstract

Neurons and synapses in the central nervous systems are very dynamic and plastic, and can undergo changes throughout life. Studies of molecular and cellular mechanisms of such changes not only provide important insight into how we learn and store new knowledge in our brains, but also reveal the mechanisms of pathological changes occurring following an injury. Here, we propose that while neuronal mechanisms underlying physiological functions such as learning and memory may share some common signalling molecules with abnormal or injury-related changes in the brain, distinct synaptic mechanisms are involved in pathological pain as compared with that of cognitive learning and memory. Using genetically altered mice and classic physiological approaches, we showed that N-methyl-D-aspartate (NMDA) receptor-dependent, calcium-calmodulin- activated adenylyl cyclases (AC1 and AC8) in the anterior cingulate cortex (ACC) play important roles in the induction and expression of persistent inflammatory and neuropathic pain. In contrast, acute pain was not significantly affected. Calcium-calmodulin-dependent protein kinase IV, which is widely expressed in central areas related to pain and memory, primarily contributes to injury-related fearful memory and emotional responses. Our studies suggest distinct signalling pathways are responsible for physiological responses to the injury, including behavioural, emotional and memory.