Chemogenetic silencing of nociceptor populations (360G-Wellcome-109116_Z_15_A)

£31,040

Nociceptors are heterogeneous sensory neurons and due to single cell sequencing, our understanding of their diversity is expanding. To understand which nociceptor populations are responsible for different pain-related behavioural phenotypes, we aim to employ a chemogenetic silencing tool to allow reversible inhibition of selected cells in vivo. Our chemogenetic tool of choice is the mutated glutamate-gated chloride channel (GluCl). Initially, we expressed the channel in cultured DRG neurons and using patch-clamp recordings observed dose dependent silencing upon application of the agonist ivermectin (IVM). We have optimised the channel and assessed channel functionality in vitro and in vivo following AAV-mediated delivery. Behavioural assays suggest IVM treated animals had significantly elevated pain thresholds compared to vehicle treated mice. Using rodent pain models (SNI, CCI) in conjunction with conditioned place preference tasks, we aim to further establish this method of nociceptor silencing as a potential therapeutic. Furthermore, to understand nociceptor heterogeneity our first target population will be the A-delta nociceptors. Using transgenic strategies we hope to selectively express GluCl in A-delta nociceptors and perform electrophysiological and sensitive behavioural assays pre and post IVM treatment. Ultimately this project aims to facilitate the discovery of novel nociceptor populations, their roles and their therapeutic potential.

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Grant Details

Amount Awarded 31040
Applicant Surname Middleton
Approval Committee Internal Decision Panel
Award Date 2017-01-31T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title PhD Studentship (Basic)
Internal ID 109116/Z/15/A
Lead Applicant Mr Steven Middleton
Partnership Value 31040
Planned Dates: End Date 2019-09-30T00:00:00+00:00
Planned Dates: Start Date 2016-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East