Promising effects of astaxanthin on pain-related behaviors and morphine tolerance in a mouse model of neuropathic pain: Possible involvement of Nrf2 and the NMDA receptor subunit NR2B

The search for new analgesics remains an important issue because therapy for neuropathic pain is still ineffective. Astaxanthin is a naturally derived compound with well-established antiinflammatory and antioxidant properties; however, its pain-relieving mechanisms are not fully understood, and its potential to improve morphine efficacy in neuropathic pain remains poorly defined. This study investigated the effect of astaxanthin on pain-related behaviors in male and female mice, as well as its impact on morphine tolerance and to elucidate the molecular mechanism of its action in neuropathy evoked by chronic constriction injury (CCI) of the sciatic nerve. A single intraperitoneal injection of astaxanthin reduced pain-related behaviors similarly in both sexes after CCI. Importantly, repeated, twice-daily intraperitoneal astaxanthin administration delayed morphine tolerance and prevented motor disturbance. Notably, astaxanthin administered alone induced a long-lasting decrease in hypersensitivity, even to a greater extent than morphine. Western blot results indicated that astaxanthin altered Nrf2 and NR2B proteins expression, suggesting that these factors are involved in analgesic effects of this substance. Pharmacological studies in mice supported these findings: first, the intrathecal administration of trigonelline (an Nrf2 inhibitor) prior to astaxanthin injection caused the loss of its analgesic effect in a CCI model; second, the intrathecal administration of astaxanthin followed by quinolinic acid (an NMDA receptor agonist) prevented the development of hypersensitivity in naive animals. In sum, these results indicate a novel mechanism of analgesic action of astaxanthin, involving Nrf2 and NMDA receptor signaling, and highlight its therapeutic potential in the treatment of neuropathic pain.