Differential Regulation of the Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Acute Itch and Acute Pain
Brain Res Bull. 2026 May 4:111916. doi: 10.1016/j.brainresbull.2026.111916. Online ahead of print.
ABSTRACT
As core aversive somatosensory sensations, itch and pain rely on precise central modulation, in which the central medial thalamic nucleus (CM) and basolateral amygdala (BLA) are critically involved. However, the involved regulatory circuits remain unclear. c-Fos staining showed that CM and BLA neurons were activated by Chloroquine (CQ)-, and Histamine (His)-induced acute itch and Formalin-induced acute pain. Subsequently, morphological tracing results confirmed the CM-BLA pathway, with CMCaMKIIα neurons simultaneously projecting to both the BLACaMKIIα and BLAVGAT1 neurons. Furthermore, behavioral data revealed that CM-BLA pathway exerts differential regulation with anti-pruritic effects on acute itch and pronociceptive effects on acute pain. Accordingly, selective activation of either CM-BLACaMKIIα pathway or CM-BLAVGAT1 pathway also showed similar behaviors. In addition, results from fiber photometry also confirmed that the BLA‑projecting CMCaMKIIα neurons exhibited significantly enhanced activity under both acute itch and nociceptive stimuli. Notably, postsynaptic BLA neurons in the CM-BLA pathway displayed differential functional predominance upon co-activation: VGAT1-positive neurons responded more robustly to acute itch than CaMKIIα-positive neurons, whereas CaMKIIα-positive neurons exhibited greater activation by acute pain stimuli than VGAT1-positive neurons. We therefore infer that during acute itch, CM neurons may suppress itch by activating BLA GABAergic interneurons to indirectly modulate local excitatory glutamatergic circuits, whereas in acute pain, CM neurons may facilitate pain via BLA glutamatergic principal neurons, while co‑activating GABAergic interneurons to synergistically enhance pain facilitation in the CM‑BLA pathway. These findings delineate a critical supraspinal circuit that differentially modulates acute itch and pain, providing novel mechanistic insights into somatosensory integration.
PMID:42092703 | DOI:10.1016/j.brainresbull.2026.111916