Bovine lactoferrin-induced antinociception through 5-HT1A/1D receptors in formalin-induced tonic pain

Bovine lactoferrin (bLF) is a multifunctional glycoprotein that displays modulatory effects on pain through pathways not fully known. Therefore, we determined the role of the serotonergic system as a potential mechanism underlying the antinociceptive effect of bLF on formalin-induced tonic nociception. The formalin test was used to assess the antinociceptive effect-pain-like behaviour (flinching) at 1 h. The bLF-induced antinociceptive effect was prevented by the intrathecal (3 µg/rat), but not the intraplantar (30 µg/rat) administration of methiothepin, a non-selective 5-hydroxytryptamine (5-HT) antagonist. Moreover, intrathecal administration of WAY-100635 (6 µg/rat; selective 5-HT1A receptor antagonist) and BRL1555724 (4 µg/rat; selective 5-HT1D receptor antagonist) prevented the bLF-induced antinociceptive effect. However, intrathecal administration of SB-224289 (5 µg/rat; selective 5-TH1B receptor antagonist) and SB-699551 µg/rat; selective 5-TH5A receptor antagonist) did not prevent the bLF-induced antinociceptive effect. The above finding suggests that bLF reduces acute nociception induced by formalin, and this antinociceptive effect is mediated, at least in part, by the serotonergic system, acting only at the spinal level and not at the peripheral level, via activation of central 5-HT1A/1D serotonergic receptors.