An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in

Itch is an unpleasant sensation that provokes the desire to scratch.While acute itch serves as a protec-tive system to warn the body of external irritating agents,chronic itch is a debilitating but poorly-treated clinical dis-ease leading to repetitive scratching and skin lesions.How-ever,the neural mechanisms underlying the pathophysiol-ogy of chronic itch remain mysterious.Here,we identified a cell type-dependent role of the anterior cingulate cortex(ACC)in controlling chronic itch-related excessive scratch-ing behaviors in mice.Moreover,we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area(VTA)that was critically involved in chronic itch.Furthermore,we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch.Finally,the ACC neurons were shown to predomi-nantly innervate the non-dopaminergic neurons of the VTA.Taken together,our findings uncover a cortex-midbrain cir-cuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

Chemokine Receptor CXCR3 in the Spinal Cord Contributes to Chronic Itch in Mice

Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis （ACD）. CXCR3 in the spinal cord also con- tributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3-/- mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund＇s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3-/- mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water （AEW）. Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Further- more, touch-elicited itch （alloknesis） after compound 48/80 or AEW treatment was suppressed in Cxcr3-/- mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3-/- mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.

Modulation of Pain and Itch by Spinal Glia

Chronic pain and itch are a pathological operation of the somatosensory system at the levels of primary sensory neurons, spinal cord and brain. Pain and itch are clearly distinct sensations, and recent studies have revealed the separate neuronal pathways that are involved in each sensation. However, the mechanisms by which these sensations turn into a pathological chronic state are poorly understood. A proposed mechanism underlying chronic pain and itch involves abnormal excitability in dorsal horn neurons in the spinal cord. Furthermore, an increasing body of evidence from models of chronic pain and itch has indicated that synaptic hyperexcitability in the spinal dorsal horn might not be a consequence simply of changes in neurons, but rather of multiple alterations in glial cells. Thus, understanding the key roles of glial cells may provide us with exciting insights into the mechanisms of chronicity of pain and itch, and lead to new targets for treating chronic pain and itch.