The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in learning and memory. Recent studies show that painful stimuli activate the prefrontal cortex and that brain chemistry is altered in this area in patients with
chronic pain. Components of the CNS that are involved in
pain transmission and modulation, from the spinal cord to the ACC, are very
plastic and undergo rapid and long-term changes after injury. Patients suffering from
chronic pain often complain of memory and concentration difficulties, but little is known about the neural circuitry underlying these deficits. To address this question, we analyzed synaptic transmission in the ACC from mice with
chronic pain induced by hindpaw injection of complete
Freund's adjuvant (CFA). In vitro whole-cell patch-clamp recordings revealed a significant enhancement in
neurotransmitter release probability in ACC synapses from mice with
chronic pain. Trace fear memory, which requires sustained attention and the activity of the ACC, was impaired in CFA-injected mice. Using knock-out mice, we found that
calmodulin-stimulated
adenylyl cyclases, AC1 and/or AC8, were crucial in mediating the long-lasting enhanced presynaptic transmitter release in the ACC of mice with
chronic pain. Our findings provide strong evidence that presynaptic alterations caused by peripheral
inflammation contribute to memory impairments after injury.