Wen‑Lin Sua,b, Yu‑Ya Wengc, Wen‑Hsin Huangd, Hao‑Ai Shuie, Tz‑Chong Chouf*
aDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan, bSchool of Medicine, Tzu Chi University, Hualien, Taiwan, cGraduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan, dSchool of Pharmacy, National Defense Medical Center, Taipei, Taiwan, eSchool of Medicine, National Defense Medical Center, Taipei, Taiwan, fDepartment of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
Open Access funded by Buddhist Compassion Relief Tzu Chi Foundation
Abstract
Objective: In the present study, we investigated the effects of dextromethorphan (DM) and its metabolites, including dextrorphan (LK2), 3‑methoxymorphinan (LK3), and 3‑hydroxymorphinan (LK4), on platelet aggregation in vitro and the inflammatory pain caused by carrageenan in rats, and their underlying mechanisms. Materials and Methods: Rabbit platelets were pretreated with DM or its metabolites to assess their effects on platelet aggregation and related target mediators. In addition, the analgesic activity and the underlying mechanisms of DM and LK3 were investigated in a carrageenan‑evoked thermal hyperalgesia rat model. Results: The inhibitory potency of DM and its metabolites on platelet aggregation induced by arachidonic acid or collagen was LK3> DM > LK4>> LK2 as demonstrated by the half‑maximal inhibitory concentration values. Moreover, the mechanisms of the antiplatelet effect of DM and LK3 may involve the inhibition of intracellular calcium mobilization, expression of platelet surface glycoprotein IIb/IIIa, the formation of thromboxane B2, and elevation of platelet membrane fluidity. DM and LK3 also exhibited analgesic effects on carrageenan‑evoked thermal hyperalgesia by suppressing the production of pro‑inflammatory cytokines, nitric oxide, prostaglandin E2, and neutrophil infiltration in inflammatory sites. Conclusion: DM and its metabolites, especially LK3, exhibit both antiplatelet and analgesic effects, and may, therefore, potentially ameliorate platelet hyperactivity and inflammatory‑related diseases.
Keywords: Carrageenan, Dextromethorphan, Inflammatory pain, Metabolites, Platelet aggregation
