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

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

115 genes are being assessed for altered pain susceptibility phenotypes. To date, the following 86 unique candidate genes have entered Pain Phenotyping.

Abhd13 Acod1 Acox3 Adamtsl3 Agbl1 Alad Alg6 Aqp1
Atf3 AU040320 Avpr1a BC048562 Bdkrb1 Bloc1s6 C4b Cacna2d4
Cdk2ap2 Cgnl1 Cnrip1 Cntnap2 Col20a1 Col9a3 Cp Dguok
Dnmt3b Dusp16 Eif2d Emp1 Esd Exoc2 Ficd Gabr2a
Gapvd1 Gria1 Grm1 Hmgb4 Htr3a Lamb3 Lgals4 Lrrc55
Maged1 Mkrn3 Mme Mmp16 Myh10 Myom2 Nav2 Npy1r
Nrxn2 Nt5dc2 Nup155 Olfr1006 Pah Pdcd6ip Pdpn Piezo2
Pink1 Pip4k2c Polr1d Ppp2r5c Ptprk Rex1bd Rnpepl1 Scrn2
Sez6l Shisa6 Slc17a8 Slc24a4 Slc30a4 Slc9a9 Stk36 Taf13
Tecpr2 Tedc1 Timp1 Trak2 Trappc1 Trim14 Trpm3 Tspan17
Tubb6 Utp4 Ypel2 Zfp236 Zfp597 Zfp91

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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