63: KNX Compounds Reduce Thermal Hypersensitivity in Chronic Neuropathic Pain: A Preclinical Study

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

Background and Aims: Chronic neuropathic pain is maintained by dysregulated central circuits and neuronal hyperexcitability that remain inadequately targeted by current therapies[1,2]. KNX100 is a novel non-opioid compound targetting nucleus accumbens, which is recognised as modulators of central pain processing[3 ,4]; KNX101 is an analogue designed for longer duration and enhanced efficacy. This study tested whether these compounds could treat established neuropathic pain in the chronic constriction injury (CCI) model. We aimed to (1) characterise thermal hypersensitivity, (2) determine whether repeated KNX dosing reduces hind paw withdrawals compared with vehicle and gabapentin, and (3) assess whether any effects persist after washout.

Methods: Forty-two Sprague–Dawley rats received vehicle (n=8), gabapentin 40mg/kg i.p. (n=8), KNX101 7.46mg/kg i.p. (n=10), KNX100 7.38mg/kg i.p. (n=8) or KNX100 3.7mg/kg i.p. (n=8); doses expressed as free base equivalents. Testing comprised 2 min cold plate (5°C) then 2 min hot plate (46°C); outcomes were hind paw withdrawals (HPW). Assessments occurred pre-CCI and for three post-CCI weeks. From week 4, rats received thrice-daily dosing for 12days with testing at peak effect (gabapentin 60min; vehicle/KNX 25min). Week 6 followed 48h washout. Negative binomial mixed-effects models tested group×week effects with sex covariate, subject random intercept and Dunnett comparisons versus vehicle during Weeks 4–5.

Results: A significant group×week interaction was observed for both cold (p=3.8×10⁻⁶) and hot plate (p=0.0014) HPW. On the cold plate at Week 4, KNX101 produced the largest reduction vs vehicle (log −1.23, p<0.0001), followed by KNX100 high (−0.76, p=0.0046) and KNX100 low (−0.61, p=0.029), while gabapentin showed no effect (p=0.90). Effects persisted at Week 5 for KNX101 (p=0.026) and KNX100 high (p=0.007). Hot plate responses showed a similar pattern: Week 4 KNX101 (−1.31, p<0.0001) and Week 5 KNX100 high (−0.87, p=0.0023) and KNX101 (−0.65, p=0.019). All groups returned to vehicle levels after 48-h washout.

Conclusions: Repeated dosing with KNX101 and KNX100 reduced temperature-evoked hind paw withdrawals in rats with CCI, with the clearest effects observed during the active treatment phase and diminishing after 48-hour washout. A dose-related trend was evident, with KNX101 showing the largest reductions, followed by the higher and then lower KNX100 dose. These findings suggest that targeting nucleus accumbens may offer a non-opioid strategy for modulating chronic neuropathic pain behaviour. Effects were observed across both cold- and hot-plate modalities, while gabapentin provided a clinical benchmark under matched testing conditions. Overall, the data support further translational development of KNX compounds for chronic pain.

References: 1. Woolf, C.J., Central sensitization: implications for the diagnosis and treatment of pain. Pain, 2011. 152(3 Suppl): p. S2-s15.
2. Finnerup, N.B., R. Kuner, and T.S. Jensen, Neuropathic Pain: From Mechanisms to Treatment. Physiol Rev, 2021. 101(1): p. 259-301.
3. Baliki, M.N. and A.V. Apkarian, Nociception, Pain, Negative Moods, and Behavior Selection. Neuron, 2015. 87(3): p. 474-91.
4. Tracy, L.M., et al., Oxytocin and the modulation of pain experience: Implications for chronic pain management. Neurosci Biobehav Rev, 2015. 55: p. 53-67.

Presenting Author: Zeynab Alshelh
Submitting Author: Zeynab Alshelh

Senior Author: Michael Bowen

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Zeynab Alshelh: PhD - University of Sydney
• Yiyang Wang: BS - University of Sydney
• Stela Petkova: PhD - University of Sydney
• Neda Assareh: PhD - University of Sydney
• Jackson McPartland: BS - University of Sydney
• Luke Henderson: PhD - University of Sydney
• Michael Bowen: PhD - University of Sydney