N-Methyl-d-Aspartate Antagonists and Neuropathic Pain:  The Search for Relief

A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain

“…The role of glutamate in the physiology of normal pain sensing and transmission, and in chronic pain phenomena, was originally established in the late 1980s (Davies and Lodge, 1987; Dickenson and Sullivan, 1987; Childers and Baudy, 2007). NMDA receptors are intimately involved in both the initiation of a pain sensation and its transmission into the CNS, as well as the phenomenon termed “wind up”, wherein the transmission of signal between primary and second order sensory neurons is amplified in conditions of repetitive sensory input as seen after nerve injury (Davies and Lodge, 1987; South et al, 2003).…”

“…There is increasing evidence for the role of peripheral mechanisms in chronic pain syndromes (e.g., Parada et al, 2003; Christoph et al, 2005; Villarreal et al, 2005; Staud, 2010; Ferrari et al, 2014; Ma and Quirion, 2014; Yang et al, 2014; Boada et al, 2015), and some of the most well-established peripheral changes are up-regulation of the NMDA subtype of glutamate receptors (Du et al, 2003; Jang et al, 2004; Childers and Baudy, 2007), and of voltage sensitive sodium channels (Wang et al, 2002; Black et al, 2004; Coggeshall et al, 2004; Lai et al, 2004; Dib-Hajj et al, 2007; Levinson et al, 2012). Such neuroadaptive events provide candidate targets for development of multi-target medications for treatment of chronic pain.…”

Magnetic resonance and optical imaging probes for NMDA receptors on the cell surface of neurons: synthesis and evaluation in cellulo

“…Each contrast agent will bind to the protein to some extent, disrupting its rotational dynamics and leading to an enhancement of the longitudinal relaxation rate of the water protons. As a control experiment, the effect of added HSA on the measured relaxivity of [Gd·L [1][2][3][4][5][6] ] (each at 1 mM) was assessed at 1.4 T following incremental addition of up to 1.6 mM HSA. Increases in r 1p were observed and association constants were estimated by assuming a 1 : 1 stoichiometry of interaction.…”

“…18 The expression of functional NMDA receptors on differentiated NSC-34 cells was demonstrated as reported earlier using immuno-fluorescence techniques with primary antibodies. 13 The labelling of differentiated NSC-34 cells with [Gd·L [1][2][3][4][5][6] ] was assessed by measuring the longitudinal relaxation times, T 1 , of the water signal in cell suspensions using a Siemens human whole body MR scanner, equipped with a head coil operating at 3 T. These measurements allowed the calculation of cellular relaxation rates, R 1,cell . Differentiated cells were incubated for 45 min with 200 μM [Gd·L [1][2][3][4][5][6] ] (37°C, 5% CO 2 ), washed with Hank's Buffered Saline Solution (HBSS) to remove unbound complex, re-suspended in fresh buffer and R 1 was determined in cell suspensions using an inversion recovery sequence (Fig.…”

“…d For [Gd·L 7 ] 2− , the relaxivity value in water was 7.23 mM −1 s −1 (310 K, 60 MHz). [1][2][3][4][5][6] ] for 45 minutes. Under the same conditions, the Gd 3+ complexes of L a -L d gave corresponding changes of +18, +70, −9 and +76% respectively.…”