61: Preclinical Behavioural Investigation of Nucleus Accumbens Modulation in Chronic Neuropathic Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Behavioral studies

Background and Aims: Chronic neuropathic pain is associated with maladaptive changes in central pain circuitry, yet current treatments remain limited with side effects. The nucleus accumbens (NAc) shell has been increasingly implicated in chronic pain processing, but its key role in modulating pain-related behaviour remains unclear. KNX100 is a novel small molecule compound developed by Kinoxis Therapeutics that modulate NAc shell activity and is therefore promising in targeting pain circuitry. This study aimed to investigate whether pharmacological modulation of NAc shell activity alters behavioural hypersensitivity in a rat model of chronic neuropathic pain.

Methods: This study used chronic constriction injury (CCI) model to induce neuropathic pain on the sciatic nerve. Twenty-nine rats (14 male, 15 female) were randomly assigned to one of three groups: chronic KNX100 treatment, saline control, or delayed acute KNX100 treatment. Behavioural hypersensitivity was assessed across six post-surgical cold/hot plate sessions using hind-paw withdrawal frequency (HPW). From the fourth testing session onwards, animals received intraperitoneal injections of KNX100 or saline three times daily. Negative binomial mixed-effects models tested group × week effects with sex covariate, subject random intercept and Dunnett comparisons versus vehicle during Weeks 4–6.

Results: A significant group × week interaction was observed for cold (p = 1.3×10⁻¹⁴) and hot (p < 2.2×10⁻¹⁶) HPW following CCI. For cold HPW, no group differences were observed during Weeks 1–3; significant reductions in the drug-treated group emerged at Weeks 4 and 5 (p < 0.0001) and Week 6 (p = 0.0004) versus vehicle, while the vehicle-to-drug group showed a delayed reduction at Week 6 (p < 0.0001). Hot HPW showed a similar time-dependent pattern, with significant reductions in the drug-treated group at Weeks 4–6 (p < 0.0001) and in the vehicle-to-drug group at Week 6 (p < 0.0001).

Conclusions: These findings suggest that KNX100 effectively reduces behavioural hypersensitivity in a rat model of chronic neuropathic pain. The results support a critical role for NAc shell modulation in pain-related behaviour and provide a foundation for subsequent translational investigations.

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Liu, D., Xu, F.-X., Yu, Z., Huang, X.-J., Zhu, Y.-B., Wang, L.-J., Wu, C.-W., Zhang, X., Cao, J.- L., & Li, J. (2025). Distinct nucleus accumbens neural pathways underlie
separate behavioral features of chronic pain and comorbid depression. Journal of Clinical Investigation, 135(15). https://doi.org/10.1172/jci191270

Ren, W., Centeno, M. V., Berger, S., Wu, Y., Na, X., Liu, X., Kondapalli, J., Apkarian, A. V., Martina, M., & Surmeier, D. J. (2015). The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nature Neuroscience, 19(2), 220–222. https://doi.org/10.1038/nn.4199

Presenting Author: Yiyang Wang
Submitting Author: Yiyang Wang

Senior Author: Michael T Bowen

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Zeynab Alshelh: PhD - Kinoxis Therapeutics, Australia. Brain and Mind Centre, The University of Sydney, Australia.
• Stela Petkova: PhD - Kinoxis Therapeutics, Australia. Brain and Mind Centre, The University of Sydney, Australia.
• Neda Assareh: PhD - Kinoxis Therapeutics, Australia. Brain and Mind Centre, The University of Sydney, Australia.
• Jackson McPartland: MRes - Brain and Mind Centre, The University of Sydney, Australia
• Luke Henderson: PhD - Brain and Mind Centre, The University of Sydney, Australia
• Michael T Bowen: PhD - Kinoxis Therapeutics, Australia. Brain and Mind Centre, The University of Sydney, Australia.