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Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Neely, GG and Rao, S and Costigan, M and Mair, N and Racz, I and Milinkeviciute, G and Meixner, A and Nayanala, S and Griffin, RS and Belfer, I and Dai, F and Smith, S and Diatchenko, L and Marengo, S and Haubner, BJ and Novatchkova, M and Gibson, D and Maixner, W and Pospisilik, JA and Hirsch, E and Whishaw, IQ and Zimmer, A and Gupta, V and Sasaki, J and Kanaho, Y and Sasaki, T and Kress, M and Woolf, CJ and Penninger, JM (2012) Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception. PLoS Genetics, 8 (12). ISSN 1553-7390

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The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. © 2012 Neely et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Neely, GG
Rao, S
Costigan, M
Mair, N
Racz, I
Milinkeviciute, G
Meixner, A
Nayanala, S
Griffin, RS
Belfer, Iinb6@pitt.eduINB6
Dai, Ffed1@pitt.eduFED1
Smith, S
Diatchenko, L
Marengo, S
Haubner, BJ
Novatchkova, M
Gibson, D
Maixner, W
Pospisilik, JA
Hirsch, E
Whishaw, IQ
Zimmer, A
Gupta, V
Sasaki, J
Kanaho, Y
Sasaki, T
Kress, M
Woolf, CJ
Penninger, JM
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 December 2012
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 8
Number: 12
DOI or Unique Handle: 10.1371/journal.pgen.1003071
Schools and Programs: School of Medicine > Anesthesiology
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 01 Jul 2014 16:15
Last Modified: 02 Feb 2019 16:58


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