CE14 - Physiologie et physiopathologie

Unrevealing the neuronal circuits underlying chronic pain – PaiNetWork

Unrevealing the neuronal circuits underlying chronic pain

This project tests the hypothesis that chronic pain is mediated by different neuronal circuits in the spinal cord dorsal horn, depending on pain etiology.

Study of neuronal circuits underlying inflammatory and neuropathic chronic pain

The goal of the PaiNetWork project is to characterize the phenotype, the function, and the synaptic connectivity of the neural microcircuits underlying mechanical allodynia at the peripheral, segmental, and supra segmental levels, under neuropathic or inflammatory conditions.

We combine state-of-the-art techniques - calcium imaging with multiphoton microscopy on an innovative ex vivo somatosensory preparation, viral transynaptic tracers, and chemogenetic - in transgenic mouse lines to identify and characterize these microcircuits from a synaptic and functional point of view.

Behavioral results measured so far confirm and extend our understanding of the role of CR and PKCg neurons of the spinal dorsal horn in the somatosensory system and chronic pain. Furthermore, calcium imaging of the dorsal horn activity revealed important differences between neuronal circuits engaged by peripheral stimuli in inflammatory versus neuropathic pain conditions.

Identification of the neurons and interneurons involved in these microcircuits underlying mechanical allodynia under neuropathic or inflammatory conditions, will allow the development of targeted therapies.

1. “Mare de souffrir, mais que font les chercheurs ?!”. March 2021. Semaine du cerveau, Clermont-Ferrand, France

2. “Heterogeneity in Dorsal Horn Circuits that Mediate Persistent Pain”. June 2021. Pain 2021 Workshop: Genetic Interrogation of Spinal Cord Circuits, Houston, USA (invited)

Unrevealing the neuronal circuits underlying chronic pain:

Unlike acute pain, which alerts and protects the body from imminent or potential dangers, chronic pain does not serve the biological interest and instead causes distress and suffering. Chronic pain manifests by several symptoms: spontaneous pain, exacerbation of pain sensation (hyperalgesia), and pain caused by normally innocuous stimulations (allodynia). Usual painkillers prescribed to treat chronic pain are rarely effective and associated with numerous side effects. An impediment to the identification of better therapies is the lack of fundamental knowledge about persistent pain circuits, including the identity and the connectivity of the neurons that transmit or modulate the pain.

Mechanical allodynia, when touch becomes painful, is one of the most prevalent symptoms in chronic pain patients. Normally, tactile or painful sensations are independent. The nerves carrying pain messages terminate in the superficial layers of the spinal cord dorsal horn, and those transmitting touch in the deep layers. However, in pathological conditions, tactile information can access nociceptive-specific neurons in the superficial dorsal horn, thus turning touch into pain (i.e. mechanical allodynia). The organization of the neural circuits involved in this mechanism is mostly unknown.

We recently found that the phenotype of neurons activated during mechanical allodynia is closely related to the pain etiology, whether it is neuropathic or inflammatory. A small number of the neurons that belong to these microcircuits has been identified, and the lack of information about the whole network and its specific features constitutes a major barrier against the implementation of a targeted and effective therapy. What are the other neurons? How does tactile information spread through these circuits?

The goal of the PaiNetWork project is to characterize the phenotype, the function, and the synaptic connectivity of the neural microcircuits underlying mechanical allodynia at the peripheral, segmental, and supra segmental levels, under neuropathic or inflammatory conditions.
Here, we will combine state-of-the-art techniques - calcium imaging with multiphoton microscopy on an innovative ex vivo somatosensory preparation, viral transynaptic tracers, and chemogenetic - in transgenic mouse lines to identify and characterize these microcircuits from a synaptic and functional point of view. Identification of the neurons and interneurons involved in these microcircuits underlying mechanical allodynia under neuropathic or inflammatory conditions, will allow the development of targeted therapies.


Keywords: Pain; Allodynia; Circuits; Dorsal horn; Transynaptic virus; Calcium imaging Chemogenetic;

Project coordination

Cedric Peirs (Inserm U1107, NEURO-DOL, Laboratoire de Pharmacologie fondamentale et clinique de la douleur)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

NEURO-DOL - Inserm U1107 Inserm U1107, NEURO-DOL, Laboratoire de Pharmacologie fondamentale et clinique de la douleur

Help of the ANR 315,036 euros
Beginning and duration of the scientific project: December 2019 - 36 Months

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