Antinociceptive Activity of Petiveria alliacea L. Extract via GABAergic and Serotonergic Pathways in Diabetic Neuropathy Model

Petiveria alliacea L. (commonly known as “anamu,” “guiné,” “hierba de zorro,” and “tipi”) has been widely used in Mesoamerican traditional medicine to treat pain and inflammation. However, scientific evidence supporting its efficacy in diabetic neuropathy remains limited. This study evaluated the antinociceptive potential of a methanolic leaf extract of P. alliacea in a murine model of alloxan-induced diabetic neuropathy and investigated its possible mechanisms of action. Diabetic CD-1 mice were evaluated for mechanical allodynia and hyperalgesia using the Von Frey test and for tonic pain using the formalin test. Pharmacological antagonists were administered to assess the involvement of opioid, nitric oxide, serotonergic, and GABAergic pathways. Phytochemical profiling was performed by LC-ESI-MS/MS, and potential pharmacological and pharmacokinetic properties of the identified metabolites were predicted using in silico tools (PASS online, SwissTargetPrediction, SwissADME, and pkCSM). The methanolic extract significantly reduced mechanical allodynia and hyperalgesia in diabetic mice and attenuated nociceptive responses in both phases of the formalin test, showing an effect comparable to gabapentin. Antinociceptive activity was not altered by naloxone or L-NAME but was significantly attenuated by methiothepin and bicuculline, suggesting that serotonergic and GABAergic pathways contribute, at least in part, to the observed antinociceptive effects. LC-ESI-MS/MS analysis identified 38 metabolites, including flavonoids, alkaloids, and terpenes, with in silico predictions supporting their potential analgesic and anti-inflammatory activities. The methanolic leaf extract of P. alliacea exhibits significant antinociceptive activity in diabetic neuropathy, partially likely to involve serotonergic and GABAergic mechanisms, supporting its ethnomedicinal use and its potential as a source of novel analgesic agents.