Neuroscience 2005 Abstract
| Presentation Number: | 52.15 |
|---|---|
| Abstract Title: | Peripheral NMDA receptors: the role of glycine<sub>B</sub> site antagonists in visceral pain. |
| Authors: |
Sladek, M.*1,2
; Nagel, J.1
; Headley, P. M.2
; Parsons, C. G.1
1Preclinical Research & Development, Merz Pharmaceuticals GMBH, Frankfurt, Germany 2United Kingdom, Eckenheimer Landstrasse 100, 60318, |
| Primary Theme and Topics |
Sensory and Motor Systems - Pain -- Visceral pain |
| Session: |
52. Visceral Pain I Poster |
| Presentation Time: | Saturday, November 12, 2005 3:00 PM-4:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # V8 |
| Keywords: | BLOOD-BRAIN BARRIER, PATCH CLAMP, MICRODIALYSIS |
Peripheral NMDA receptors may be involved in visceral nociceptive processing. As shown at SFN 2002 (#451.3), the brain impermeant, selective glycineB antagonist MRZ 2/596 was anti-allodynic in a rat model of irritable bowel syndrome (IBS) at 0.1 mg/kg i.p. Low brain penetration was confirmed in an in vitro model of the blood-brain barrier (BBB). MRZ 2/596 showed a permeability coefficient similar to the BBB-impermeant marker sucrose, 1.11 ± 0.05 x 10-5 (SD) cm/s and 0.77 ± 0.02 x 10-5 cm/s respectively. The in vitro data were consistent with brain microdialysis studies in awake rats, where MRZ 2/596 at the very high dose of 30 mg/kg i.p. generated maximal brain concentrations of only 0.11 uM. This compound at 25 mg/kg i.p was also completely inactive against maximal electroshock-induced convulsions (MES) in mice. The related moderately brain permeant compound MRZ 2/576 was also far more active in the IBS model than following systemic administration against MES or micro-iontophoretic excitation of single spinal neurones in rats. These findings suggest that peripheral NMDA receptors might have a different pharmacology to those in the CNS.
The pharmacology of NMDA receptor in cultures of adult rat DRG neurons was therefore analysed using patch clamp experiments. Visceral DRG neurons were identified by retrograde staining with Fast DiI-oil. Steady-state inward current responses to NMDA (200 uM with glycine 10 uM) were antagonized by MRZ 2/576 and 2/596 with similar IC50s of 0.87 ± 0.14 uM (n=7) and 0.85 ± 0.11 uM (n=11). In cultured rat hippocampal neurons, MRZ 2/576 was weaker (IC50 of 3.08 ± 0.14 uM, n=8) under similar conditions, but was three fold more potent than MRZ 2/596.
The expression of NR1 and all NR2 subunits was shown by Western blotting, immunostaining, and RT-PCR of DRG cultures and cryosections. For all NR1/NR2 subunits examined, no difference in the expression pattern was detected that might explain the different pharmacology in DRG cells in comparison to the CNS.
The pharmacology of NMDA receptor in cultures of adult rat DRG neurons was therefore analysed using patch clamp experiments. Visceral DRG neurons were identified by retrograde staining with Fast DiI-oil. Steady-state inward current responses to NMDA (200 uM with glycine 10 uM) were antagonized by MRZ 2/576 and 2/596 with similar IC50s of 0.87 ± 0.14 uM (n=7) and 0.85 ± 0.11 uM (n=11). In cultured rat hippocampal neurons, MRZ 2/576 was weaker (IC50 of 3.08 ± 0.14 uM, n=8) under similar conditions, but was three fold more potent than MRZ 2/596.
The expression of NR1 and all NR2 subunits was shown by Western blotting, immunostaining, and RT-PCR of DRG cultures and cryosections. For all NR1/NR2 subunits examined, no difference in the expression pattern was detected that might explain the different pharmacology in DRG cells in comparison to the CNS.
<B>Conflict of Interest:</B> Pharmaceutical Employee
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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