Completed Brain & Nervous System Mental Health

Spinal circuits underlying pathological pain

Funder Wellcome Charity-funded
Recipient organisation University of Glasgow
Funding £2.0M
Period Mar 2020 — Mar 2025

In plain English

AI plain-English summary

Spinal cord cells that normally process light touch can be hijacked to produce pain signals after nerve injury, and researchers are now tracing the exact wiring diagram of these circuits to find where the system goes wrong. Chronic pain affects one in five UK adults, yet many existing treatments are ineffective or addictive because they target pain broadly rather than the specific spinal circuits that generate it. The problem is that the spinal cord contains dozens of distinct types of excitatory interneurons—cells that amplify or relay signals—and scientists do not know which ones actually drive pathological pain. This project will use genetic tools to switch off specific cell populations in mice, then test whether the animals still feel pain from normally harmless stimuli. The team will focus on cells expressing GRPR, neuropeptide FF, and PKCγ, and map how these cells connect to each other and to the projection neurons that send pain signals to the brain. This is fundamental science. It will not produce a drug or device. But by identifying the precise cellular players in the pain circuit, it gives other researchers molecular targets to aim at. Similar mapping of spinal circuits in the past has led to the development of drugs that block pain without affecting normal sensation—a distinction that current painkillers often fail to make.

View original technical description
Allodynia and hyperalgesia occur in neuropathic and inflammatory pain states, and depend on circuits involving dorsal horn excitatory interneurons. Recent studies have identified several neurochemical/transcriptomic populations among these cells. We will use a multi-disciplinary approach, involving molecular-genetic targeting of these populations, to investigate their involvement in pain mechanisms at circuit and behavioural levels. We have found that neurons expressing gastrin releasing peptide receptor (GRPR) correspond to vertical cells, which transmit information to lamina I projection neurons, and are implicated in both neuropathic and inflammatory pain. We will use anatomical, electrophysiological and behavioural approaches to determine whether the GRPR cells fulfil this role. If not, we will investigate another population defined by expression of neuropeptide FF. Cells with PKCγ are critical for neuropathic allodynia, but these can be assigned to two populations that express neurotensin or cholecystokinin. We will determine whether these are functionally different, and whether both contribute to allodynia. Finally, we will establish whether any other excitatory interneurons are interposed between PKCγ cells and vertical cells in the pathway for tactile allodynia. The study will provide important information about synaptic circuits for pain, and the roles of different interneuron populations. Keywords: pain, spinal cord, neuronal silencing, chemogenetics, optogenetics

View the original record at the funder ↗

Researchers

Andrew Todd (EPMC Awardee)

Related Research

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The roles of functionally defined populations of lamina I projection neurons
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Original classification

Investigator Award in Science

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