Exploring the role of alpha-tocopherol in pain and inflammation: interplay with TRPV1, PKA, and PKC pathways

Background: Alpha-tocopherol (vitamin E) is a fat-soluble antioxidant with neuroprotective properties. There is a gap in research regarding the anti-nociceptive and anti-inflammatory effects of alpha-tocopherol in different tests of nociception as well as its signaling pathways. Therefore, this study aimed to assess the anti-nociceptive and anti-inflammatory effects of alpha-tocopherol in vivo and examine the potential involvement of transient receptor potential vanilloid 1 (TRPV1) and downstream kinase pathways, particularly protein kinases protein kinase A (PKA) and protein kinase C (PKC). Methods: Male Swiss albino mice were used in acetic acid-induced writhing, immersion tail-flick, and hot-plate tests for nociception while male Wistar rats were used in carrageenan-induced paw edema assay for inflammation. Alpha-tocopherol (50 mg/kg, i.p.), alone or in combination with TRPV1 antagonist (capsazepine) or PKC/PKA inhibitors (Go 6976, H89, respectively) was administered, followed by conducting the behavioral tests. TRPV1 expression in brain and skin tissues was examined using immunohistochemistry. Results: Alpha-tocopherol significantly reduced writhing responses and extended heat latency in thermal tests. The TRPV1 was involved in the hot-plate and immersion tail-flick assays, while PKC and PKA pathways were implicated in the supraspinal analgesic effect (the hot plate test). Alpha-tocopherol (20 μg) did not exert any significant anti-inflammatory effect in the carrageenan model. Intense TRPV1 immunolabeling was observed in the alpha-tocopherol/ carrageenan condition, particularly in the skin. Conclusions: Alpha-tocopherol possesses a strong anti-nociceptive effect through TRPV1 modulation via PKC/PKA-dependent mechanisms. These findings suggest that alpha-tocopherol can be used as an adjuvant in multimodal pain management protocols.