Pain

The IMPC is hunting unknown genes responsible for pain sensitivity by screening knockout mice

  • One-third of the global population suffers from chronic pain, including 100 million people in the USA 1
  • Basic science estimates that 30-80% of the variance in pain responses can be explained by genetic factors 1
  • The search for novel mechanisms and targets for pain therapeutics is an urgent priority due to the current opiate use and overdose epidemic

Find out more in these IMPC Publications:

 

  • Machine learning-based automated phenotyping of inflammatory nocifensive behavior in mice. Molecular Pain 2020. DOI: 10.1177/1744806920958596

Approach

In order to identify the function of genes, the consortium is piloting a series of protocols as described in IMPReSS (International Mouse Phenotyping Resource of Standardised Screens).

Protocol name IMPReSS ID Protocol purpose
Formalin Challenge In development Assess the tonic phase of response to inflammatory pain through manual and automated scoring of video collected up to 90 minutes post-challenge.
Complete Freund’s Adjuvant (CFA) Challenge JAX_EDM_001 CFA is not a standalone assessment, but instead is an inflammatory stimulus that can be administered prior to assessing mechanical and thermal nociception. Edema is also collected as a quantitative measure of localized inflammation
Von Frey HRWL_VFR_001 JAX_VFR_001 TCP_VFR_001 UCD_VFR_001 Assess mechanical hypoalgesia, hyperalgesia and allodynia in naive or CFA challenged animals
Hargreaves’ JAX_HRG_001 TCP_HRG_001 UCD_HRG_001 Assess thermal nociception in CFA challenged animals
Hot Plate HRWL_HOT_001 Assess thermal nociception in naïve animals
Cage Lid Interaction In development Novel, passive measurement of pain behavior in mice challenged with CFA. Non-invasive, wireless capacitance measuring device is used to detect cage-lid contact time in the home-cage environment.
Dynamic Weight Bearing In development Quantify evoked pain by assessing postural equilibrium in unrestrained mice.

Gene list

110 genes are being assessed for altered pain susceptibility phenotypes. To date, the following candidate genes have entered Pain Phenotyping.

AU040320 Abhd13 Acod1 Acox3 Adamtsl3
Agbl1 Akr1b3 Alad Alg6 Aqp1
Atf3 Avpr1a BC048562 Bdkrb1 Bloc1s6
C4b Cacna2d4 Cd2ap Cdk2ap2 Cenpt
Cgnl1 Cnrip1 Cntnap2 Col20a1 Col9a3
Cp Dnmt3b Dusp16 Eif2d Emp1
Esd Exoc2 Ficd Foxn3 Gabra2
Gapvd1 Gria1 Grik1 Grm1 Hmgb4
Htr3a Ipo9 Lamb3 Lats1 Lgals4
Lrrc55 Maged1 Mdh1 Med27 Mkrn3
Mme Mmp16 Mrps12 Mtg2 Myh10
Myom2 Nars Nav2 Ndufa6 Nrxn2
Nsmce2 Nt5dc2 Nup155 Ola1 Olfr1006
Otud7a Oxa1l Pah Pdcd6ip Pex14
Piezo2 Pink1 Pip4k2c Polr1d Ppp2r5c
Ptprk Rex1bd Rnpepl1 Rps20 Rsad2
Scrn2 Sez6l Shank3 Shisa6 Slc17a8
Slc24a4 Slc30a4 Slc7a14 Slc9a7 Slc9a9
Stk36 Taf13 Tecpr2 Tedc1 Timp1
Trak2 Trappc1 Trim14 Trim2 Trpc1
Trpm3 Tspan17 Tspoap1 Tubb6 Unc13c
Utp4 Ypel2 Zfp236 Zfp597

These genes were selected via a diverse range of discovery partners including nominations from the IMPC Portal and through synergistic interactions with an existing NIH funded Addiction Supplement. The remaining genes are extant IMPC lines highlighted as potentially pain related based on Gene Weaver selection criteria.

P2rx4 and Trpa1 knockout mice are being tested by all centres as positive controls. Existing null alleles of these genes are published as presenting with decreased pain sensitivity.

Request mouse lines

Vignettes

Reduced mechanical nociception following inflammatory stimulus using Complete Freund’s Adjuvant (CFA)

Htr3aem1(IMPC)J

Females average von Frey thresholds, baseline, 24 and 48 hrs post CFA challenge

An ethical approach

IMPC Centres breeding mice and collecting phenotyping data are guided by their own ethical review panels and licensing and accrediting bodies, reflecting the national legislation under which they operate. All phenotyping procedures were examined for potential refinements that were disseminated throughout the Consortium. Animal welfare was assessed routinely for all mice involved.

The IMPC will make experimental data freely available without restriction to facilitate research and minimize duplication. In addition, the IMPC will continue to apply the Animal Research: Reporting of In Vivo Experiments (ARRIVE) to ensure analyses can be reproduced.

[1] – Tsang et al., The Journal of Pain, 9(10) pp883-891 (2008)

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