To further understand the mechanism of analgesic activity and structural requirements of pyrrolidinoindoline alkaloids identified in Psychotria colorata, we here report the analgesic activity of the trimer hodgkinsine on thermal and chemical models of analgesia. Results show that hodgkinsine produces a dose-dependent naloxone reversible analgesic effect in thermal models of nociception, suggesting that activation of opioid receptors participates in hodgkinsine's mode of action. Hodgkinsine shows a potent dose-dependent analgesic activity against capsaicin-induced pain, indicating the participation of NMDA receptors in hodgkinsine-induced analgesia. Such a dual mechanism of action may be of interest for developing innovative analgesics.

The discovery that alkaloids isolated from Psychotria colorata Muell Arg (RUBIACEAE), a medicinal species traditionally used as an analgesic in the Brazilian Amazon,9 have a distinctive analgesic profile generated substantial interest.10-12 The mechanisms of action by which these alkaloids exert antinociceptive action were investigated by in vivo and in vitro techniques, particularly regarding their involvement with opioid and glutamatergic pathways.10,13-15 We reported that the natural alkaloid hodgkinsine (1) acts dose-dependently as a potent analgesic in mice.13 Hodgkinsine's effects in thermal models of nociception were naloxone reversible, suggesting that activation of opioid receptors is involved in its mode of action.13 Indeed, binding data revealed that hodgkinsine binds specifically to opioid receptors.15 Hodgkinsine also showed a potent dose-dependent analgesic effect in capsaicin-induced pain,13 suggesting the participation of NMDA receptors in its mode of action.