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 CM CaMKIIα neurons simultaneously projecting to both the BLA CaMKIIα and BLA VGAT1 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-BLA CaMKIIα pathway or CM-BLA VGAT1 pathway also showed similar behaviors. In addition, results from fiber photometry also confirmed that the BLA‑projecting CM CaMKIIα 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. • The CM-BLA pathway suppresses acute itch while facilitating acute pain. • CM input engages both CaMKIIα and VGAT1 neurons in the BLA during itch and pain. • Postsynaptic BLA neurons show different response biases during acute itch and pain.
Liu et al. (Fri,) studied this question.