Calcium Calmodulin-Stimulated Adenylyl Cyclases Contribute to Activation of Extracellular Signal-Regulated Kinase in Spinal Dorsal Horn Neurons in Adult Rats and Mice

Abstract

The extracellular signal-regulated kinase (Erk) cascades are suggested to contribute to excitatory synaptic plasticity in the CNS, including the spinal cord dorsal horn. However, many of their upstream signaling pathways remain to be investigated. Here, we demonstrate that glutamate and substance P (SP), two principal mediators of sensory information between primary afferent fibers and the spinal cord, activate Erk in dorsal horn neurons of both adult rat and mouse spinal cord. In genetic knock-out mice of calcium calmodulin-stimulated adenylyl cyclase subtypes 1 (AC1) and 8 (AC8), activation of Erk in dorsal horn neurons were significantly reduced or blocked, either after peripheral tissue inflammation or by glutamate or SP in spinal cord slices. Our studies suggest that AC1 and AC8 act upstream from Erk activation in spinal dorsal horn neurons and the calcium-AC1/AC8-dependent Erk signaling pathways may contribute to spinal sensitization, an underlying mechanism for the development of persistent pain after injury.

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…18 In AC knockout (isoforms 1, 8, and 1 and 8) mice, forskolin-induced nociception was reduced. 19,20 Morphine-induced antinociception was not different between wild-type and AC knockout (isoforms 1, 8, and 1 and 8) mice. However, as expected, tolerance to morphine was blunted in the knockout compared to wildtype mice.…”

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

“…The mechanism of LTP induction involves the activation of NMDA receptors, neurokinin 1 receptors, and the downstream mitogen-activated protein kinase (MAPK) pathway. 24,25 In addition, in vivo LTP of C-fiber-evoked responses could also be induced by low-frequency or high-frequency stimulation of sciatic nerve fibers. 24 The LTP induction is also dependent on NMDA receptor activation.…”

Role of Extracellular Signal-Regulated Kinase in Synaptic Transmission and Plasticity of a Nociceptive Input on Capsular Central Amygdaloid Neurons in Normal and Acid-Induced Muscle Pain Mice

“…At some cortical synapses, LTP induction requires activation of extracellular signal-regulated kinase (ERK) (Impey et al, 1999;Giovannini et al, 2001;Lin et al, 2003Lin et al, , 2006. Since a biochemical hallmark of chronic pain is increased levels of phosphorylated ERK (pERK) in the DH (Ji et al, 1999;Garry et al, 2005;Wei et al, 2006) (for review, see , it is likely that ERK activity triggered by repeated and excessive noxious stimuli might induce LTP of nociceptive inputs onto DH neurons, thereby resulting in central sensitization.…”