Anti-hyperalgesic effects of two sphingosine derivatives in different acute and chronic models of hyperalgesia in mice

The study evaluated the effects of two sphingosine derivatives N-(2-tert-butoxycarbamylhexadecyl)glutaramide (AA) and N-(1-benzyloxyhexadec-2-yl)glutaramide (OA) in different models of hypersensitivity in mice. Male Swiss mice were orally pre-treated with AA or OA (0.3–3mg/kg). After 1h, they received λ-carrageenan (300μg/paw), lipopolysaccharide (LPS; 100ng/paw), bradykinin (BK; 500ng/paw) or prostaglandin E2 (PGE2; 0.1nmol/paw) or epinephrine (100ng/paw), and the mechanical withdrawal thresholds were evaluated using von Frey filament (0.6g) at different time points. The effect of the compounds against inflammatory and neuropathic pain was also evaluated using complete Freund’s adjuvant (CFA), or by performing partial sciatic nerve ligation (PSNL). Animals pre-treated with AA and OA reduced hypersensitivity induced by carrageenan, LPS and BK, and modest inhibition of PGE2-induced hypersensitivity and carrageenan-induced paw oedema were observed in mice treated with OA. Though the partial effect presented by AA and OA, when dosed once a day, both compounds were able to significantly reduce the persistent inflammatory and neuropathic pain induced by CFA and PSNL, respectively. These results demonstrate that the sphingosine derivatives AA and OA present important anti-hypersensitive effects, suggesting a possible interaction with the kinin signalling pathway. This may represent an interesting tool for the management of acute and chronic pain, with good bioavailability and safety.