N -Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain

Abstract

Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund's adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCgamma and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal-glial-cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCgamma and pERK2 are increased. At 96h the expression of the proinflammatory cytokine, IL-1beta, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCgamma and the induction of pERK2 and IL-1beta in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies.

Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice

“…p-ERK is sequentially activated in neurons, microglia, and astrocytes after spinal nerve ligation (Zhuang et al, 2005) and is also induced in spinal astrocytes in the late phase after CFA injection (Weyerbacher et al, 2010). P-p38 is expressed in spinal microglia after nerve injury (Clark et al, 2007;Jin et al, 2003) and acute inflammation (Svensson et al, 2003).…”

Hydrogen-rich saline controls remifentanil-induced hypernociception and NMDA receptor NR1 subunit membrane trafficking through GSK-3β in the DRG in rats

“…Proinflammatory cytokines are associated with spinal NMDARcontaining nociceptive neurons activation and the maintenance of inflammatory pain (Weyerbacher et al, 2010;Ian et al, 2004;Zhang et al, 2008). It is convinced that inhalation of H 2 efficiently suppresses proinflammatory cytokines release (Huang et al, 2011;Ji et al, 2010), however, in clinical application, inhalation of H 2 gas is not convenient and is dangerous because of its flammable and explosive nature even at a concentration of 4.7% in air (Ohsawa et al, 2007).…”

“…IL-6 was shown to be implicated in the initiation of inflammatory and neuropathic pain (Cui et al, 2000). It is demonstrated that proinflammatory cytokines have an excitatory action on the glutamatergic synaptic transmission and activation of NMDAR NR1 and NR2B subunits in the dorsal horn (Weyerbacher et al, 2010;Ian et al, 2004). IL-1␤ was indicated to be one of the crucial mediators of neuropathic pain acting through an acute modulation of NR1 activity (Zhang et al, 2008;Fukuoka et al, 1994).…”

Activation of Mas Oncogene-Related G Protein–Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

“…These increases were inhibited by intrathecal BAM8-22. Given that ERK (Wei et al, 2006;Weyerbacher et al, 2010) and PKC (Malmberg et al, 1997;Polgar et al, 1999) transduction pathways play a critical role in the hypersensitivity of spinal dorsal horn and/ or DRG neurons in peripheral inflammation, the above results may suggest that the activation of MrgC receptors inhibited central and peripheral sensitization.…”

“…PKCg is the major isoform of PKC in the spinal dorsal horn and is expressed in nociceptive neurons in lamina II (Malmberg et al, 1997;Polgar et al, 1999). The injection of CFA in the periphery increases the expression of PKC in the spinal dorsal horn (Martin et al, 1999;Honore et al, 2000;Weyerbacher et al, 2010), whereas the inhibition of PKC reduces CFA-induced miniature excitatory postsynaptic currents and c-Fos expression in dorsal horn neurons (Giles et al, 2007). PKCg knockout mice display a reduced pain behavior and c-Fos expression in the spinal dorsal horn following formalin injection (Malmberg et al, 1997).…”