Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA
Ying Yu
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA
Sekun Park
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA
Feng Cao
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA
Jordan L. Pauli
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA
Tyler S. Nelson
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Richard D. Palmiter
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, WA 98195, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, USA; Corresponding author
Summary: Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury, collectively referred to as nociplastic pain, are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN Calca neurons from releasing neurotransmitters, we demonstrate that activation of Calca neurons is necessary for the manifestation and maintenance of chronic pain. Additionally, by directly stimulating Calca neurons, we demonstrate that Calca neuron activity is sufficient to drive nociplasticity. Aversive stimuli of multiple sensory modalities, such as exposure to nitroglycerin, cisplatin, or lithium chloride, can drive nociplasticity in a Calca-neuron-dependent manner. Aversive events drive nociplasticity in Calca neurons in the form of increased activity and excitability; however, neuroplasticity also appears to occur in downstream circuitry.
