Curcumin is a naturally occurring
polyphenol compound with potential
analgesic effects. It has been shown to improve
pain-like behaviors in numerous models of
pain. Despite its potential,
curcumin exhibits poor physicochemical and pharmacokinetic properties, which hinder its oral therapeutic efficacy.
Curcumin diethyl γ-aminobutyrate (CUR-2GE), a
carbamate prodrug of
curcumin, was designed to overcome these limitations and demonstrated greater anti-neuroinflammatory effects compared to
curcumin in vitro. Thus, this study evaluated the effect of CUR-2GE and its parent compound on
pain-like behaviors in
carrageenan- and LPS-induced mouse models. The possible side effects of CUR-2GE were also assessed by exploring its effects on motor coordination and spontaneous locomotor activity after acute and chronic treatments. The results showed that CUR-2GE improved mechanical and
thermal hyperalgesia and locomotor activity to a greater extent than
curcumin in
carrageenan-induced mice. These results are in line with the ability of CUR-2GE to suppress peripheral
inflammation in the paw tissue of
carrageenan-induced mice, indicated by a significant decrease in TNF-α and
IL-6 expression levels. Similarly, in LPS-induced mice, CUR-2GE improved sickness and
pain-like behaviors (exploratory behaviors and long-term locomotor activity) to a greater extent than
curcumin. Furthermore, CUR-2GE significantly reduced the level of proinflammatory
cytokines in both the plasma and spinal cord tissue of LPS-induced mice, exhibiting significantly higher inhibition than
curcumin. Moreover, the motor coordination, and locomotive behaviors of mice were not affected by both acute and chronic administration of CUR-2GE, indicating no potential CNS side effects. Thus, CUR-2GE demonstrated enhanced therapeutic efficacy in mouse models of inflammatory
pain without any possible CNS side effects, suggesting its potential to be developed as an
analgesic agent against inflammatory
pain.