Definition of the operational principles of a brainstem opioid circuit
Lead Research Organisation:
University of Bristol
Department Name: Physiology and Pharmacology
Abstract
Available in the lab of Tony Pickering as part of a collaboration with Graeme Henderson (Bristol) and Dave Spanswick (Neurosolutions & Warwick University).
Project Description
Opioid drugs, like morphine, are extensively used as analgesics to treat pain but their utility is compromised by risks of addiction, tolerance and respiratory depression. The brain releases opioid peptides, such as *-endorphin, to produce analgesia appropriate to the behavioural context. This *-endorphin originates from just two small clusters of pro-opioimelanocortin (POMC) neurons in the brain and brainstem. Although much is known about the receptors and signalling of the opioid system, the details of the neural circuit mechanisms and their functional role are still being elucidated. In part this is because of the challenge of targeting the small numbers of neurones that are relatively inaccessible.
We have recently successfully applied opto- and chemo-genetic methods to control the activity of the brainstem POMC neurons in GM mice (Balthasar 2004 Neuron). Such activation produced opioid-mediated analgesia and substantial actions on respiration and vagal control of heart rate (Cerritelli et al 2016 PlosOne). This opioid effect did not desensitise, involves discrete inhibitory and excitatory actions and our pilot data shows direct opioidergic synaptic actions. This study will examine the neural organisation and synaptic transmission in this brainstem opioidergic circuit.
The student will make patch clamp recordings of visually identified neurones in medullary slices along with viral vector-mediated optogenetics to selectively evoke activity and manipulate these circuits. It will also progress to use similar opto- and chemo-genetic methods in vivo enabling behavioural assays. The industrial collaboration will involve a placement at Neurosolutions in Warwick implementing a translational optogenetic assay and adopting single cell PCR for genetic profiling of the targets of the POMC neurones. We are seeking to identify the receptor, synaptic and circuit mediation of these actions on autonomic and pain control centres in the brainstem. The student will receive training in electrophysiology, stereotaxic vector injection and recovery surgery, optogenetics, in vivo behavioural assays and in single cell genetic profiling alongside transferrable skills in the translational neurosciences.
Project Description
Opioid drugs, like morphine, are extensively used as analgesics to treat pain but their utility is compromised by risks of addiction, tolerance and respiratory depression. The brain releases opioid peptides, such as *-endorphin, to produce analgesia appropriate to the behavioural context. This *-endorphin originates from just two small clusters of pro-opioimelanocortin (POMC) neurons in the brain and brainstem. Although much is known about the receptors and signalling of the opioid system, the details of the neural circuit mechanisms and their functional role are still being elucidated. In part this is because of the challenge of targeting the small numbers of neurones that are relatively inaccessible.
We have recently successfully applied opto- and chemo-genetic methods to control the activity of the brainstem POMC neurons in GM mice (Balthasar 2004 Neuron). Such activation produced opioid-mediated analgesia and substantial actions on respiration and vagal control of heart rate (Cerritelli et al 2016 PlosOne). This opioid effect did not desensitise, involves discrete inhibitory and excitatory actions and our pilot data shows direct opioidergic synaptic actions. This study will examine the neural organisation and synaptic transmission in this brainstem opioidergic circuit.
The student will make patch clamp recordings of visually identified neurones in medullary slices along with viral vector-mediated optogenetics to selectively evoke activity and manipulate these circuits. It will also progress to use similar opto- and chemo-genetic methods in vivo enabling behavioural assays. The industrial collaboration will involve a placement at Neurosolutions in Warwick implementing a translational optogenetic assay and adopting single cell PCR for genetic profiling of the targets of the POMC neurones. We are seeking to identify the receptor, synaptic and circuit mediation of these actions on autonomic and pain control centres in the brainstem. The student will receive training in electrophysiology, stereotaxic vector injection and recovery surgery, optogenetics, in vivo behavioural assays and in single cell genetic profiling alongside transferrable skills in the translational neurosciences.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/P016049/1 | 01/10/2017 | 02/02/2022 | |||
| 1955498 | Studentship | MR/P016049/1 | 01/10/2017 | 23/12/2021 | Rebecca Tench |