In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons

Abstract

The persistent increase in pain sensitivity observed after injury, known as hyperalgesia, depends on synaptic plasticity in the pain pathway, particularly in the spinal cord. Several potential mechanisms have been proposed, including post-synaptic exocytosis of the AMPA subclass of glutamate receptors (AMPA-R), which is known to play a critical role in synaptic plasticity in the hippocampus. AMPA-R trafficking has been described in spinal neurons in culture but it is unknown if it can also occur in spinal neurons in vivo, or if it can be induced by natural painful stimulation. Here we have induced referred mechanical hyperalgesia in vivo by intracolonic instillation of capsaicin in mice and have observed a recruitment of GluR1 AMPA-R subunits to neuronal plasma membranes in the lumbar spinal cord. Intracolonic capsaicin induced a rapid (10 min) increase in GluR1, but not GluR2/3 in the synaptosomal membrane fraction which lasted at least 3 h and a decrease in GluR1 subunit in the cytosolic fraction. Capsaicin treatment also provoked CaMKII activation and pre-treatment with a specific CaMKII inhibitor prevented the GluR1 trafficking. Brefeldin-A, an antibiotic that inhibits exocytosis of proteins, not only prevented GluR1 trafficking to the membrane but also inhibited referred hyperalgesia in capsaicin-treated mice. Our results show that delivery of GluR1 AMPA receptor subunits to the cell membrane through a CaMKII activity-dependent exocytotic regulated pathway contributes to the development of hyperalgesia after a painful stimulus. We conclude that AMPA-R trafficking contributes to the synaptic strengthening induced in the pain pathway by natural stimulation.

Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

“…It has been reported that painful stimuli can recruit AMPA receptor GluR1 subunits to neuronal plasma membranes in the lumbar spinal cord (Galan et al, 2004). We next investigated the distribution of AMPA receptor subunits in the ACC after nerve ligation.…”

Pathway-Specific Bidirectional Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II at Spinal Nociceptive Synapses after Acute Noxious Stimulation

“…CaMKII has been implicated in the induction of NMDA receptor-dependent sensitization of neurons in the spinal cord dorsal horn (Fang et al, 2002;Garry et al, 2003;Galan et al, 2004). This central sensitization is a likely mechanism underlying certain forms of hyperalgesia, the enhanced sensation of painful stimuli that may arise after intense noxious stimulation, and is commonly believed to involve LTP-like strengthening of primary afferent transmission that depends on activation of NMDA receptors and CaMKII (Kolaj et CaMKII autophosphorylated at Thr 286/287 (pCaMKII) would be expected at synapses from primary afferent fibers supplying the noxiously stimulated tissue.…”

Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits

“…Postsynaptic AMPA receptor subunit trafficking, especially GluA1 and GluA2, in the development of synaptic plasticity under pathophysiological conditions may be associated with chronic pain (4, 8 -10). For example, in the anterior cingulate cortex and spinal cord, GluA1 was recruited to the plasma membrane under pain conditions to enhance glutamatergic transmission, leading to a behavioral state of sensitized pain (11)(12)(13). However, the molecular mechanism underlying dynamic distribution of GluA1 after inflammation in the descending pain modulatory circuitry remains unclear.…”