A GABAergic neuronal thalamocortical circuit mediates the relief of diabetic neuropathic pain.

Abstract

Diabetic neuropathic pain (DNP) is a severe and clinically common form of neuropathic pain. Ventral posterolateral nucleus (VPL) glutamatergic neurones are reportedly involved in the development of neuropathic pain. However, the roles and mechanism of VPL GABAergic neurones and neural circuits in DNP remain unclear. After constructing a streptozotocin (STZ)-induced DNP model in male rats, we assessed VPL neuronal activity by immunofluorescence staining and von Frey test. Moreover, the roles of VPL GABAergic neurones and that projected to the forelimb primary somatosensory cortex (S1FL) were investigated using optogenetic and chemogenetic approaches, viral tracing, and behavioural tests. Optogenetic (F_2,18=376.155, P<0.001) and chemogenetic (F_2,16=226.340, P<0.001) activation of VPL GABAergic neurones relieved mechanical allodynia in male DNP model rats, which revealed that VPL GABAergic neurones mediated antinociceptive effects. We identified a GABAergic thalamocortical circuit in the VPL that projected to the S1FL and revealed that the thalamocortical circuit mediated antinociceptive effects (optogenetic: F_2,20=303.807, P<0.001; chemogenetic: F_2,15=62.008, P<0.001) in the context of DNP. These findings identify a GABAergic neuronal thalamocortical circuit associated with pain processing, reveal the mechanism of diabetic neuropathic pain pathogenesis and the role of thalamocortical pain circuits in analgesia, and provide new insights for the development of analgesics.