Ethnopharmacological relevancePain remains real and still a major problem in clinical medicine which requires new agents with improved efficacy for more therapeutic benefits. Plant sources can serve as a basis for the search for some novel drugs hence the analgesic effects of the hydroethanolic extract of Calotropis procera (CPE) which is widespread in Ghana and other tropical areas and used in folkloric medicine for painful and inflammatory conditions was evaluated. Materials and methodsThe analgesic properties of orally administered CPE at doses of 30, 100, and 300 mg/kg were evaluated in thermal (tail immersion), chemical (acetic acid-writhing, formalin-induced paw licking, glutamate-induced nociception) and mechanical (Randall-Selitto) tests for analgesia. The involvement of tumour necrosis factor-alpha (TNF-α), interleukin 1β (IL 1β), bradykinin, and prostaglandin E2 (PGE2) on the analgesic effects of CPE were also evaluated in hypernociception assays measuring mechanical pain thresholds. ResultsThe latency of tail withdrawal in the tail immersion test was significantly increased (p = 0.0001) while writhing induced by acetic acid was significantly reduced (p < 0.0001) on treatment with CPE (30–300 mg/kg). The extract also significantly inhibited both phase 1 and phase 2 nociceptive states induced by formalin comparable to morphine (p < 0.0001). Furthermore, the extract significantly attenuated hyper-nociception induced by TNF-α (p < 0.0001), interleukin 1β (p = 0.0102), bradykinin (p < 0.0001), and prostaglandin E2 (p < 0.0001). Additionally, glutamate-induced paw licking was reduced significantly (p < 0.05). The antinociceptive effects exhibited by CPE (100 mg/kg) in the formalin test was reversed by systemic administration of naloxone (2 mg/kg) and theophylline (5 mg/kg) but not glibenclamide (8 mg/kg), granisetron (2 mg/kg), atropine (3 mg/kg), yohimbine (3 mg/kg, p.o.) nor nifedipine (10 mg/kg). ConclusionOverall, the hydroethanolic leaf extract of Calotropis procera possesses analgesic properties that is mediated possibly through the glutaminergic, opioidergic, and adenosinergic pathways.