Orofacial anti-hypernociceptive effect of citral in acute and persistent inflammatory models in rats

Both incidence and prevalence of orofacial pain is considered very high, and patients with acute or chronic pain cope with major physical and emotional stress because of significant challenges in obtaining adequate care is still limited, resulting in considerable social costs (Tecco et al., 2018).

Despite several recent reports on fundamental research on the trigeminal nociceptive system (Hargreaves, 2011, Harriott and Gold, 2008, Martinez-Garcia et al., 2019, Okamoto et al., 2010) we are still far from a precise scenario when it comes to the properties of trigeminal afferents innervating distinct target tissues (Herrero Babiloni et al., 2022). On the other hand, it seems clear that the target tissue is not simply a passive site where the terminations of afferent fibers are. Instead, these tissues seem to effectively interact with neuron terminals in a complex way through multiple and tissue-specific innervation, which may account for the differences in the responsiveness of the trigeminal afferent fibers concerning spinal afferent neurons, under basal conditions and after tissue injury (Okada et al., 2019).

Previous studies documented the medicinal use of citral. Citral has gastro-protective (Nishijima et al., 2014), anti-protozoan (Santin et al., 2009), antibacterial (Tofiño-Rivera et al., 2016), anxiolytic (Costa et al., 2011) and systemic analgesic properties (Nishijima et al., 2014). Specifically focusing the inflammatory response, citral has been shown to have an anti-inflammatory effect (Mota et al., 2020, Song et al., 2016;), to act as an antipyretic molecule (Emílio-Silva et al., 2017) and to suppress COX-2 expression in human macrophage-like U937 cells (Katsukawa et al., 2010). Besides such key anti-inflammatory mechanism, citral has also been shown to inhibit: LPS-induced TNF, IL-6, and IL-1β surges in pulmonary macrophages (Shen et al., 2015); oxidant activity (Barroso et al., 2011) and nitric oxide production (Lee et al., 2008). However, all these just mentioned studies refer to other tissues besides the orofacial region in which trigeminal nociceptive system may differ (Herrero Babiloni et al., 2022). Considering the crucial importance of treating orofacial pain, our goal was to test the hypothesis that citral has analgesic effects on the orofacial region. We also assessed the mechanisms associated with these effects using two well-accepted experimental models: formalin test, which is considered a consistent way to produce and quantify hypernociception in the trigeminal region of the rat (Raboisson and Dallel, 2004) and the model of chronic inflammatory pain induced by CFA injection in the temporomandibular joints (Wu et al., 2010).

Finally, citral may be advantageous comparing to other therapeutic strategies because: (i) when administered orally it is rapidly absorbed from the gastrointestinal tract of rats and mice (Diliberto et al., 1988); (ii) twelve hours after its absorption, radiolabeled citral is evenly distributed throughout the body, being excreted mainly by the kidneys (51 %), feces (12 %) and expired air on CO2 formation (17 %) in 24 h; and yet (iii) it has been observed that risks associated with accumulation of citral in tissues after prolonged exposure is minimal (Phillips et al., 1976).

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