Despite advances in understanding the acute pain pathways, the neural mechanisms underlying chronic or severe pain remain poorly understood. While neurons responding to transient pain are known throughout the nervous system, identifying those that are active specifically in long-term pain is crucial. A recent study published in Nature identifies a group of neurons in the lateral parabrachial nucleus (IBPN) that stay active during chronic pain. These neurons express the neuropeptide Y1 receptor (Y1R) and are implicated in transmitting long-term pain signals. But these neurons can be influenced by competing need states.
In this study, adult female and male mice (aged = least 8 weeks old) were used. Mice of various transgenic strains (Npy1r-Cre, Npy-Flp, Pdyn-IRES-Cre, Penk-IRES2-Cre, Vglut2-IRES-Cre, Y1-lox/lox, Lbx1-Cre, Npy-IRES-Cre, NPY-hrGFP, and C57BL/6J) were group-housed under 12-hour light and 12 hr dark cycles with humidity of 50±15% and temperature of 21.5- 22.3 °C, as well as free access to water and food. Various transgenic strains were used. Experiments were blinded, randomized, and counterbalanced.
Mouse brains were collected, sectioned, and processed for CosMx spatial transcriptomics. Neuronal subpopulations in the lPBN were visualized using a high-resolution transcriptomic imaging technique. Mice underwent stereotaxic viral injections and fiber-optic or cannula implantation. Post-surgery pain, hunger, and thirst, as well as behavioral patterns, were assessed for neuronal activity, pain modulation, and conditioned responses. Various compounds like polyethylene glycol (PEG), clozapine-N-oxide (CNO), complete Freund’s adjuvant (CFA), formalin, diphtheria toxin, ghrelin, and lithium chloride (LiCl) were administered via intramuscular, subcutaneous, or intraperitoneal injections. Calcium imaging (Fiber photometry and microendoscopy) recorded neuronal activity during behavioral assays. All statistical analyses were conducted using Prism 10 (GraphPad) software.
Transcriptomic imaging method revealed a total of 14 neuronal clusters, including neuropeptide Y (Npy1r [Y1R])–expressing neurons. These neurons were activated and spatially during the persistent pain. Chemogenetic inhibition of lPBN Y1R neurons reduced chronic pain, whereas activation induced pain responses.
Calcium activity of IPBN Y1R neurons during chronic pain showed that the bilateral activation during formalin-induced pain, behavior-linked responses with slower and sustained activity, which offer persistent pain. Neuropathic and inflammatory models enhanced excitatory sensitization and pain intensity. Correlational analysis identified that 40% of IPBN Y1R neurons were active during licking and 16% were elevated after injection of formalin, independent of pain-related behaviors.
NPY release in the IPBN attenuates persistent neuropathic and inflammatory pain. Needs like Hunger, fear, and thirst increased the NPY, which reduced the sustained pain through postsynaptic Y1R neurons. Blocking of YIR in the IPBN prevents analgesia, whereas acute pain remains unaffected.
Reinforcement learning models demonstrated that NPY gates ascending nociceptive inputs, reducing both licking behavior and internal pain perception. Neuronal recordings confirm that NPY suppresses tonic Y1R activity during chronic pain without affecting acute nociceptive responses. All these findings establish YIR neurons as a key hub for integrating pain and analgesic signals, offering therapeutic potential.
Reference: Goldstein N, Maes A, Allen HN, et al. A parabrachial hub for need-state control of enduring pain. Nature. 2025. doi:10.1038/s41586-025-09602-x
