Assessing the Antinociceptive Effects and Tolerance Development of Decursinol in Nociceptive, Inflammatory, and Neuropathic Pain.

Chemotherapy-induced neuropathic pain is a prevalent side effect of treatment with anti-neoplastic agents. This debilitating neuropathy is characterized by excessive pain resulting in mechanical and sensory hypersensitivity. There is a critical clinical need to develop non-opioid alternatives to manage chronic pain. A potential alternative for the management of pain is decursinol, a pyranocoumarin compound isolated from the root of the Angelica gigas Nakai (AGN) plant. Pharmacokinetic studies find that clinically, AGN is first metabolized into decursin (D) and decursinol angelate (DA) which are subsequently metabolized into decursinol (DOH). D and DA possess anti-inflammatory, neuroprotective, antinociceptive, and antioxidant modulatory properties. Studies have reported acute analgesic properties of DOH, but tolerance development along with its impact on chronic pain remains unknown. Therefore, the goal of this study was to assess the antinociceptive effects and potential tolerance to once-daily injections of DOH (50 mg/kg) in models of thermal (hot plate and tail-flick), inflammatory (formalin test), and chronic (cisplatin-induced neuropathic; CINP) pain. We hypothesized that DOH has prolonged antinociceptive and anti-inflammatory effects. Antinociception and tolerance were assessed in male mice treated once-daily with either vehicle, DOH (50 mg/kg), or morphine (10 mg/kg; formalin only) intraperitoneally (IP) 30 minutes prior to testing for 14 consecutive days. In the formalin assay, following pretreatment, mice received an intraplanar injection of 2.5% formalin into the right hind paw and nocifensive behaviors were recorded and scored. CINP was induced following four weeks of once-weekly IP injections of cisplatin (5 mg/kg). Following pretreatment, mice with CINP were assessed for mechanical allodynia via an electro-von-Frey anesthesiometer. Daily treatment with 50 mg/kg DOH induced prolonged antinociceptive and anti-inflammatory responses in all nociceptive tests. Evidence of tolerance to DOH in acute thermal nociceptive tests occurred around day 10 for both hot plate and tail-flick. Acute administration of DOH eliminated inflammatory pain to an undetectable level in both the acute and inflammatory phases of the formalin test. Further, there is evidence of tolerance by day 14 in the acute (but not the inflammatory) phase of the formalin test. Likewise, tolerance was slower to develop to the antinociceptive effects of DOH compared to morphine in the formalin assay. In mice with CINP, DOH (50 mg/kg) caused a full reversal of mechanical allodynia with evidence of partial tolerance by day 3 with complete tolerance not occurring until day 14. These data indicate that DOH may serve as a potential non-opioid alternative for the management of pain. Future directions for this study include elucidating the mechanism of action for the antinociceptive effects of DOH.