Distinct Roles of Astrocytes and GABAergic Neurons in the Paraventricular Thalamic Nucleus in Modulating Diabetic Neuropathic Pain

Abstract

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain (NP). The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 days after streptozotocin (STZ) injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.Significance Statement Some studies have focused on the role of paraventricular thalamic nucleus (PVT) glutamatergic neurons in neuropathic pain (NP) and anxiety. However, the role of PVT astrocytes and GABAergic neurons in diabetic neuropathic pain (DNP) has not been studied. We used chemogenetic techniques to bidirectionally regulate the activity of PVT astrocytes or GABAergic neurons and found that PVT astrocyte activation promotes NP, while PVT GABAergic neuron activation may mediate antinociceptive effects. These findings clarify the critical roles of PVT astrocytes and GABAergic neurons in modulating DNP, providing insight for the development of new strategies for the prevention and treatment of DNP and revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.