Upregulation of Forebrain NMDA NR2B Receptors Contributes to Behavioral Sensitization after Inflammation

Abstract

Transgenic overexpression of NMDA NR2B receptors in forebrain regions increased behavioral responses to persistent inflammatory pain. However, it is not known whether inflammation leads to the upregulation of NR2B receptors in these regions. Here, we show that peripheral inflammation increased the expression of NMDA NR2B receptors and NR2B receptor-mediated synaptic currents in the anterior cingulate cortex (ACC). In freely moving mice, the increase in NR2B receptors after inflammation contributed to enhanced NMDA receptor-mediated responses in the ACC. Inhibition of NR2B receptors in the ACC selectively reduced behavioral sensitization related to inflammation. Our results demonstrate that the upregulation of NR2B receptors in the ACC contributes to behavioral sensitization caused by inflammation.

Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain

“…This implies that morphological changes appear rapidly after the injury. These data are reminiscent of the increase in NR2B subunits described in the cingulate cortex of mice exposed to inflammatory pain (15). In that case, NR2B expression increase became evident already at 1 day, and remained elevated at 1 week.…”

“…Neurochemical and morphological rearrangement of the spinal cord are well known to be present in animal models of chronic pain (20)(21)(22)(23) and functional changes have been previously described in association with pain in primary somatosensory cortex (24) as well as in the anterior cingulate cortex, where up-regulation of NMDA NR2B subunits after peripheral inflammation has been recently shown (15). To our knowledge, however, morphological changes associated with pain have been described.…”

“…Synaptic currents were elicited by electrical stimulation of the afferent fibers; this was obtained by using a large patch pipette (Ϸ1 M⍀) filled with Hepes-buffered ACSF (pH 7.4) placed in layer 5 (15). EPSCs were evoked by extracellular stimulation by using a 200-s-long pulse delivered with an isolation unit (A360 WPI).…”

“…Moreover, overexpression of the NR2B subunit of the NMDA receptor in mouse forebrain resulted in increased sensitivity to inflammatory pain (14) and, conversely, inflammatory pain leads to up-regulation of NR2B subunit expression in the anterior cingulate cortex (15). In line with these findings, a recent study conducted on a rat model of chronic pain showed that injection of D-cycloserine, a partial agonist of the NMDA receptor (16), in mPFC has potent analgesic effect, which is maximum for injections 1-2 mm away from CG1 area and decays at further distance (17).…”

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…These phenomena can be caused by the upregulation of AMPA-type glutamate receptors and phosphorylation of several other ion channels leading to postsynaptic hyperexcitability (Ikeda et al, 2006;Latremoliere and Woolf, 2009;Sandkühler, 2007). Other aspects of NP involve somatosensory processing, which occurs in cerebral cortical areas, such as the anterior cingulate cortex (ACC), where protein kinase M zeta (PKMζ) is activated, excitatory neurotransmission at pyramidal neurons is potentiated (LTP), glutamate receptors are upregulated and decreases in long-term depression (LTD) lead to disinhibition and reorganization of neural networks (Li et al, 2010;Vogt, 2005;Wu et al, 2005). NP, therefore, can be viewed as a spectrum of disorders with mechanistically-related, but distinct, aetiologies.…”