Topical Calendula officinalis L. inhibits inflammatory pain through antioxidant, anti-inflammatory and peripheral opioid mechanisms

Objective: The present study evaluated the antinociceptive activity of Calendula officinalis L.(Ca) cream on inflammatory hypernociception.Methods: Creams with different Ca concentrations were tested for their ability to ameliorate pain-related behavior and edema in rats using formalin test, carrageenan (Cg)-induced acute inflammation model, bradykinin (BK)-induced acute inflammation model, and complete Freund's adjuvant (CFA)-induced chronic inflammation model. Using the formalin test, we also examined the implication of peripheral opi-oid receptors in the antinociceptive mechanisms of Ca cream, by means of Q-naloxone, a peripherally act-ing nonselective opioid antagonist.Furthermore, the effects of Ca cream compared with diclofenac on BK-induced edema were examined when the kininase II in tissue was preserved or inhibited by captopril. The local production of redox biomarkers in formalin model, tumor necrosis factor-a (TNF-a) in Cg model and histopathological changes in CFA model were also evaluated. Results: A single application of Ca cream at a dose of 10% or 30% (w/w) decreased the formalin-induced licking/biting behavior during both phases of this test in a Q-naloxone-sensitive manner. This effect was associated with the reduction of oxidative stress in the injured paw and the edema associated with the later phase of formalin-induced pain. A single application of Ca cream (10% or 30%) reduced paw edema and thermal hypernociception in Cg-induced acute inflammation, corresponding with a local decrease in TNF-a. Ca cream also inhibited BK-induced spontaneous nociceptive behavior and paw inflammation in both paradigms studied. Repeated applications of Ca cream also decreased CFA-induced chronic inflam-mation, mechanical hypernociception and histopathological changes in the paw.Conclusion: These results reveal the topical antinociceptive and antiedematogenic effects of Ca cream. A modulatory action on peripheral opioid receptors associated with its antioxidant mechanism may be involved, at least in part, in its analgesic effects. These findings may have an impact on the clinical man-agement of painful inflammatory diseases.Please cite this article as: Garrido-Suarez BB, Garrido G, Menendez AB, Merino N, Valdes O, de la Paz N, Romero A, Delgado L, Fernandez MD, Pineros O, Delgado-Hernandez R. Topical Calendula officinalis L. inhi-bits inflammatory pain through antioxidant, anti-inflammatory and peripheral opioid mechanisms. J Integr Med. 2023; 21(1): 34-46.(c) 2022 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. All rights reserved.