The cellular basis of protease-activated receptor 2-evoked mechanical and affective pain

Area of Science:

• Neuroscience
• Pain research
• Molecular biology

Background:

• Protease-activated receptor 2 (PAR2) is linked to inflammatory and visceral pain.
• The precise cellular source of PAR2-evoked pain remains unclear, with conflicting data on sensory neuron expression.
• Existing PAR2 tools lack specificity, potentially interacting with Mas-related GPCRs (Mrg) in sensory neurons.

Purpose of the Study:

• To elucidate the cellular mechanisms underlying PAR2-evoked pain.
• To determine if PAR2 expression in sensory neurons is essential for PAR2-mediated pain behaviors.
• To identify the specific sensory neuron population responsible for PAR2-evoked pain.

Main Methods:

• Development of a PAR2-conditional knockout mouse model.
• Specific deletion of PAR2 in sensory neurons using the PirtCre mouse line.
• Behavioral analysis of PAR2 agonist-evoked pain responses (mechanical and thermal hyperalgesia, facial grimacing) in knockout and control mice.
• RNA sequencing to assess F2rl1 mRNA expression in sensory neurons.

Main Results:

• PAR2 agonist-induced mechanical hyperalgesia and facial grimacing were abolished in PAR2-conditional knockout mice lacking PAR2 in sensory neurons.
• Thermal hyperalgesia was not affected by the absence of PAR2 in sensory neurons.
• F2rl1 mRNA was detected in approximately 4% of small-diameter sensory neurons, co-expressing Nppb and IL31ra, a population previously linked to itch.
• Activation of PAR2 in this specific sensory neuron population elicited pain behaviors.

Conclusions:

• PAR2-dependent mechanical hyperalgesia and facial grimacing originate from sensory neurons projecting to the hind paw.
• A distinct subpopulation of dorsal root ganglion (DRG) sensory neurons, co-expressing Nppb and IL31ra, mediates PAR2-evoked pain.
• These findings identify a specific cellular substrate for PAR2-mediated pain, distinct from its previously suggested role in itch.