A descending posterior insular pathway drives sensory hypersensitivity in neuropathic pain

Descending cortical control plays a critical role in shaping neuropathic pain. However, how specific circuits within the insular cortex (IC), a critical cortical hub that integrates the sensory and affective dimensions of pain, contribute to this process remains poorly understood. Here, we show that posterior IC glutamatergic (pICGlu) neurons are selectively and contralaterally activated in a chronic constriction injury (CCI) model and bidirectionally regulate pain sensitivity, whereas anterior IC glutamatergic (aICGlu) neurons preferentially mediate CCI-induced anxiety-like behaviors. Circuit mapping revealed that pICGlu neurons project to rostral ventromedial medulla GABAergic (RVMGABA) neurons, particularly a Slc32a1+/Penk- subpopulation, which in turn innervate spinal dorsal horn GABAergic (DHGABA) interneurons. Consistent with this organization, pathway-specific manipulations demonstrated that activation of the pIC-RVM-DH circuit enhances nociceptive hypersensitivity, whereas its inhibition alleviates CCI-induced allodynia. Together, these findings identify a previously uncharacterized pICGlu-RVMGABA-DHGABA circuit that mediates the sensory dimension of neuropathic pain and provides a circuit-level framework for descending cortical control of pain hypersensitivity.