Antinociceptive Effect of the Polygala sabulosa Hydroalcoholic Extract in Mice: Evidence for the Involvement of Glutamatergic Receptors and Cytokine Pathways

: This study investigated the role of the glutamatergic system on the antinociception caused by Polygala sabulosa hydroalcoholic extract (HE). The systems mediated by substance P, capsaicin, interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) were also investigated. P. sabulosa HE given orally produced a significant inhibition of glutamate‐induced paw licking [ID50 = 530.3 (416.7–674.8) mg/kg and inhibition of 79 ± 6% at 1000 mg/kg]. The plant derivatives α‐spinasterol, scopoletin and styryl‐2‐pyrones (compound 1 and 3) (10 mg/kg, intraperitoneally) inhibited 80 ± 7%, 46 ± 11%, 45 ± 11% and 35 ± 13% the nociceptive response caused by glutamate, respectively. Furthermore, P. sabulosa HE (500 mg/kg, orally) caused marked inhibition of nociceptive response induced by intrathecal injection of glutamate, N‐methyl‐d‐aspartic acid, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid, kainate, TNF‐α and IL‐1β, with inhibitions of 44 ± 7%, 55 ± 4%, 38 ± 10%, 61 ± 7%, 76 ± 9% and 100%, respectively. In contrast, P. sabulosa HE (500 mg/kg, orally) did not affect the biting response induced by the metabotropic glutamatergic receptor agonist (±)‐1‐aminocyclopentane‐trans‐1,3‐dicarboxylic acid, substance P and capsaicin. The locomotor activity was altered only in mice treated with a very high dose (1000 mg/kg) of P. sabulosa HE. Our results showed that the antinociceptive effects of P. sabulosa HE are associated with an inhibition of glutamatergic transmission and an inhibition of pathways dependent on pro‐inflammatory cytokines. The plant derivatives α‐spinasterol, scopoletin and styryl‐2‐pyrones play an important role on the antinociceptive effects of P. sabulosa HE.