Astrocytes in the ventral posterolateral nucleus modulate diabetic neuropathic pain in male rats and are inhibited by the analgesic koumine.

Diabetic neuropathic pain (DNP) is a common and intractable complication of diabetes mellitus that is relatively poorly managed by current pharmacotherapies. The ventral posterolateral nucleus (VPL) is a key thalamic subnucleus involved in nociceptive transmission, but the role of VPL astrocytes in DNP remains unclear. In this study, we observed a significant increase in VPL astrocyte activity 14 days after injections of streptozotocin in male rats. Short-term inhibition of VPL astrocytes with designer receptors exclusively activated by designer drugs (DREADDs) alleviated mechanical allodynia in DNP model rats, whereas astrocyte activation induced mechanical allodynia in control rats. To further explore the therapeutic potential of the modulation of VPL astrocyte activity, we examined the effects of koumine (KM), an alkaloid derived from Gelsemium. Notably, KM administration not only alleviated mechanical allodynia but also attenuated VPL astrocyte hyperactivity in DNP model rats. Moreover, prolonged activation of VPL astrocytes via DREADDs induced chronic pain-like behaviours in control rats, while subsequent KM administration reversed mechanical allodynia. Importantly, compared with DREADD-induced inhibition alone, prolonged inhibition of VPL astrocytes via DREADDs combined with KM administration induced great antiallodynic effects in DNP model rats. Collectively, these findings demonstrate that VPL astrocyte activation leads to neuropathic pain, providing a novel strategy for DNP intervention, and support the use of KM as a potential clinical therapy for DNP.