Antisense oligonucleotide of cargo adaptor BICD2 long-term effectively alleviates neuropathic pain via activation of PSD95 in the mouse spinal dorsal horn.

The involvement of Bicaudal D2 (BICD2), a dynein motor adaptor protein, in neuropathic pain pathogenesis remains unexplored. This study investigated the role of spinal BICD2 and its interaction with postsynaptic density protein 95 (PSD95) in neuropathic pain using Western blotting, immunofluorescence staining and reverse transcription quantitative polymerase chain reaction. We further evaluated the long-term analgesic efficacy of intrathecally (i.t.) administered Bicd2-specific antisense oligonucleotide (ASO) in male murine models of nociceptive hypersensitivity induced by spared nerve injury (SNI), cisplatin chemotherapy, and streptozotocin (STZ)-induced diabetes. Results demonstrated that BICD2 expression was selectively upregulated in the spinal dorsal horn following SNI. Both Bicd2 siRNA and Bicd2 ASO delivered via i.t. injection significantly suppressed BICD2 overexpression and attenuated mechanical/thermal hyperalgesia across all neuropathic pain etiologies (trauma, chemotherapy, diabetes). Critically, immunofluorescence staining confirmed co-expression of BICD2 and PSD95. Nerve injury-induced PSD95 elevation in the dorsal horn was abolished by Bicd2 siRNA or ASO treatment. Moreover, PSD95 inhibitor NA-1 not only alleviated SNI-induced the hyperalgesia, but also reversed mechanical/thermal hyperalgesia evoked by BICD2 overexpression. These findings reveal a novel mechanism wherein BICD2 alleviates neuropathic pain through PSD95 activation in the spinal dorsal horn, and establish the therapeutic potential of spinally targeted Bicd2 ASO for sustained pain management.