Lateral Habenula Astrocyte Activation in Paclitaxel-Induced Peripheral Neuropathy

The painful neuropathy induced by paclitaxel (PIPN) significantly impacts the quality of life for cancer patients and may lead to the cessation of the chemotherapy and poor clinical outcomes. The importance of spinal glia pathophysiology to the etiology of chronic pain has been investigated in multiple pain models; however, less is understood regarding its regulation at the supraspinal level. The lateral habenula (LHb), which is responsible for coding aversion signals, has emerged as a key region of pain signal processing. Whether activated astrocytes in LHb are responsible for pain signaling is not yet understood. In the current study, we investigated the astrocyte activation in LHb, evoked hypersensitivity, spontaneous pain and comorbid anxiety-like behaviors in a mouse model of PIPN. We first demonstrated the existence of astrocyte activation in LHb during the late phase of PIPN, as indicated by the enhanced immunoreactivity of GFAP and cellular hypertrophy. We then inhibited LHb astrocyte activation by microinjections of L-a-aminoadipic acid (L-a-AA), an astrocyte-specific cellular toxin. L-a-AA selectively attenuated the spontaneous pain but not the evoked hyperalgesia in a lateralized manner, supporting the hypothesis that the activated astrocytes contribute differently to sensory and affective pain in PIPN. Furthermore, we induced PIPN-like behaviors in naive mice by transplantation of activated astrocytes treated by paclitaxel and by in vivo chemogenetic activation of astrocytes through AAV-GFAP-hM3Dq. Taken together, our results showed the contributions of astrocyte activation in LHb to the development of pain and associated affective changes and its unilateral regulation of spontaneous pain, deepening our understanding of the functional asymmetry of LHb.