Selective knockdown of NMDA receptors in primary afferent neurons decreases pain during phase 2 of the formalin test

McRoberts, JA; Ennes, HS; Marvizón, JCG; Fanselow, MS; Mayer, EA; Vissel, B

Selective knockdown of NMDA receptors in primary afferent neurons decreases pain during phase 2 of the formalin test

McRoberts, JA Ennes, HS Marvizón, JCG Fanselow, MS Mayer, EA Vissel, B

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Publication Type:: Journal Article
Citation:: Neuroscience, 2011, 172 pp. 474 - 482
Issue Date:: 2011-01-13

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Field	Value	Language
dc.contributor.author	McRoberts, JA	en_US
dc.contributor.author	Ennes, HS	en_US
dc.contributor.author	Marvizón, JCG	en_US
dc.contributor.author	Fanselow, MS	en_US
dc.contributor.author	Mayer, EA	en_US
dc.contributor.author	Vissel, B https://orcid.org/0000-0001-8860-8050	en_US
dc.date.available	2010-10-17	en_US
dc.date.issued	2011-01-13	en_US
dc.identifier.citation	Neuroscience, 2011, 172 pp. 474 - 482	en_US
dc.identifier.issn	0306-4522	en_US
dc.identifier.uri	http://hdl.handle.net/10453/117780
dc.description.abstract	The role of NMDA receptors (NMDARs) expressed by primary afferent neurons in nociception remains controversial. The aim of this study was to develop mice with a tissue selective knockdown of NMDARs in these neurons and to evaluate their behavioral responses to different types of painful stimuli. Mice with floxed NMDAR NR1 subunit gene (fNR1) were crossed with mice expressing Cre recombinase under the control of the peripherin promotor (Prph-Cre). Male Prph-Cre+ floxed NR1 mice were compared to Cre- littermates. Both quantitative RT/PCR and Western blotting indicated a ~75% reduction in NR1 expression in dorsal root ganglia (DRG) extracts with no effect on NR1 expression in spinal cord, brain or the enteric nervous system. Immunocytochemistry with antibodies to NR1 revealed decreased staining in all size classes of DRG neurons. NMDA produced a detectable increase in [Ca 2+] i in 60% of DRG neurons cultured from Cre- mice, but only 15% of those from Cre+ mice. Furthermore, the peak [Ca 2+] i responses were 64% lower in neurons from Cre+ mice. There was no significant difference between Cre+ and Cre- mice in response latencies to the hotplate or tail withdrawal tests of thermal nociception, nor was there a difference in withdrawal thresholds to mechanical stimuli of the tail or paw. However, compared to Cre- littermates, Cre+ knockdown mice had a 50% decrease in the phase 2 response to formalin injection (P<0.001). There was no effect on phase 1 responses. These results suggest that NMDA receptors expressed by primary afferent nerves play an important role in the development of sensitized pain states. © 2011 IBRO.	en_US
dc.relation.ispartof	Neuroscience	en_US
dc.relation.isbasedon	10.1016/j.neuroscience.2010.10.045	en_US
dc.subject.classification	Neurology & Neurosurgery	en_US
dc.subject.mesh	Ganglia, Spinal	en_US
dc.subject.mesh	Afferent Pathways	en_US
dc.subject.mesh	Nociceptors	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Transgenic	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Pain	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Receptors, N-Methyl-D-Aspartate	en_US
dc.subject.mesh	Pain Measurement	en_US
dc.subject.mesh	Down-Regulation	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Sensory Receptor Cells	en_US
dc.title	Selective knockdown of NMDA receptors in primary afferent neurons decreases pain during phase 2 of the formalin test	en_US
dc.type	Journal Article
utslib.citation.volume	172	en_US
utslib.for	1701 Psychology	en_US
utslib.for	1109 Neurosciences	en_US
utslib.for	1702 Cognitive Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.publication-status	Published	en_US
pubs.volume	172	en_US

Abstract:

The role of NMDA receptors (NMDARs) expressed by primary afferent neurons in nociception remains controversial. The aim of this study was to develop mice with a tissue selective knockdown of NMDARs in these neurons and to evaluate their behavioral responses to different types of painful stimuli. Mice with floxed NMDAR NR1 subunit gene (fNR1) were crossed with mice expressing Cre recombinase under the control of the peripherin promotor (Prph-Cre). Male Prph-Cre+ floxed NR1 mice were compared to Cre- littermates. Both quantitative RT/PCR and Western blotting indicated a ~75% reduction in NR1 expression in dorsal root ganglia (DRG) extracts with no effect on NR1 expression in spinal cord, brain or the enteric nervous system. Immunocytochemistry with antibodies to NR1 revealed decreased staining in all size classes of DRG neurons. NMDA produced a detectable increase in [Ca 2+] i in 60% of DRG neurons cultured from Cre- mice, but only 15% of those from Cre+ mice. Furthermore, the peak [Ca 2+] i responses were 64% lower in neurons from Cre+ mice. There was no significant difference between Cre+ and Cre- mice in response latencies to the hotplate or tail withdrawal tests of thermal nociception, nor was there a difference in withdrawal thresholds to mechanical stimuli of the tail or paw. However, compared to Cre- littermates, Cre+ knockdown mice had a 50% decrease in the phase 2 response to formalin injection (P<0.001). There was no effect on phase 1 responses. These results suggest that NMDA receptors expressed by primary afferent nerves play an important role in the development of sensitized pain states. © 2011 IBRO.

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http://hdl.handle.net/10453/117780