Extracellular matrix protein fibulin-2 limits GABAB-mediated inhibition of pain sensitization in the spinal cord of neuropathic rats
Marie-Amelie
Papon1, 2*,
Yves
Le Feuvre1, 2,
Alexandre
Favereaux1, 2,
G.
Barreda-Gomez3,
Claire
Leger1, 2,
R.
Rodriguez-Puertas3,
Frédéric
Nagy1, 2 and
Marc
Landry1, 2
-
1
University of Bordeaux, INSERM U862, France
-
2
University of Bordeaux, France
-
3
Universidad del Pais Vasco, Department of Pharmacology, Spain
GABAB receptor activation has a well-known anti-nociceptive action in acute pain but only limited effects in pathological states. We consider a possible impairment of GABAB signalling resulting in disinhibition processes in the rat spinal cord. We hypothesize that receptor activation is altered by interactions with partner proteins such as the extracellular matrix protein (MEC) fibulin-2 (Fbln2). We propose that Fbln2 exerts a permanent modulation of GABAB activation. Moreover, we show that this Fbln2 modulation is altered in neuropathic pain conditions, thus contributing to sensitization processes. Using qRT-PCR, we showed that Fbln2 was overexpressed in neuropathic rats. Next, we demonstrated that the repeated injection of anti-Fbln2 siRNA in the spinal dorsal horn of neuropathic rats potentiated the anti-nociceptive effect of Baclofen treatment. Hence, Fbln2 decreased the GABAB functionality in neuropathic rats. Next, we used FRET/FLIM imaging in neuronal cultures to monitor Baclofen-induced interaction between B1 and B2 subunits, an index of GABAB receptor activation. We showed that Baclofen-induced B1-B2 interaction decreased upon Fbln2 overexpression, and increased upon anti-Fbln2 siRNA treatment. Moreover, direct Fbln2 protein application dose-dependently decreased Baclofen-induced B1-B2 interaction. Thus, Fbln2 prevents ligand-induced activation of the receptor, possibly by reducing ligand affinity. Finally, we explored this possibility by using weak (Saclofen) or strong (CGP) affinity competitive antagonists. Baclofen effect was tested by FRET/FLIM and patch clamp. Baclofen effect was partially reversed by Saclofen and totally by CGP. Importantly, application of anti-Fbln2 siRNA suppressed the Saclofen induced reversion, but did not change CGP effect. It may thus possible that, in absence of Fbln2, the increase in Baclofen affinity hampered binding of the low-affinity antagonist Saclofen. Altogether, our data show that an overexpressed MEC protein modulates metabotropic receptor pharmacological sensitivity. This mechanism may be critically involved in disinhibition causing pain sensitization.
Conference:
3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009.
Presentation Type:
Poster Presentation
Citation:
Papon
M,
Le Feuvre
Y,
Favereaux
A,
Barreda-Gomez
G,
Leger
C,
Rodriguez-Puertas
R,
Nagy
F and
Landry
M
(2009). Extracellular matrix protein fibulin-2 limits GABAB-mediated inhibition of pain sensitization in the spinal cord of neuropathic rats.
Front. Neurosci.
Conference Abstract:
3rd Mediterranean Conference of Neuroscience .
doi: 10.3389/conf.neuro.01.2009.16.167
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Received:
26 Nov 2009;
Published Online:
26 Nov 2009.
*
Correspondence:
Marie-Amelie Papon, University of Bordeaux, INSERM U862, Bordeaux, France, amelie_pap@hotmail.com