Authors
Babcock, L. A., Gunawardena, M., Lowrey, P. E., Pangeni, R., Hall, M., Taylor, M., Chethan, S., Herz, S. M., Adeso, D. A., Murtagh, O. L., Xu, Q., Hsu, K.-L., Lichtman, A. H.
Abstract
Diacylglycerol lipase-beta (DAGL{beta}), a biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), is highly expressed in macrophages and serves as a potential contributor to inflammatory and hypernociceptive responses. Moreover, the DAGL{beta} inhibitor KT109 produces antinociceptive effects in various rodent pain models, and its liposome formulation dramatically increases its antinociceptive potency in a lipopolysaccharide mouse model of inflammatory pain compared to free KT109. Here, we further optimized the liposomal KT109 formulation through adjustment of lipid composition and improved processing, achieving 100-fold higher drug encapsulation efficiency than the previous formulation, uniform size distribution, and excellent storage stability. Further, the second generation liposomal KT109 showed remarkable potency (ED50 [95% CL] = 0.226 [0.113-0.454] mg/kg) in a mouse model of paclitaxel-induced neuropathic pain, compared to free KT109 (ED50 [95% CL] = 31 [21-46] mg/kg). Liposomal KT109 (0.4 mg/kg) fully reversed paclitaxel-induced mechanical hypersensitivity for up to 24 hours, and its antinociceptive effects were sustained following a week of daily injections, with no detectable tolerance. In addition, the adenosine monophosphate-activated protein kinase (AMPK) inhibitor, dorsomorphin, prevented the antinociceptive effects of KT109, which is consistent with previous work demonstrating AMPK activation mediates the antinociceptive phenotype of DAGL{beta} knockout mice.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 22 Oct 2026.
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