Objective Melittin is the main peptide in bee venom and causes both persistent spontaneous nociception and pain hypersensitivity. Our recent studies indicated that both transient receptor potential (TRP) vanilloid receptor 1 (TRPV1) and canonical TRPs (TRPCs) are involved in mediating the melittin-induced activation of different subpopulations of primary nociceptive cells. Here, we further determined whether TRPC channels are involved in melittin-induced inflammatory nociceptive responses in behavioral assays. Methods The anti-nociceptive and anti-hyperalgesic effects of localized peripheral administration of three doses of the non-selective TRPC antagonist, SKF-96365 (1-{beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenyl}-1H-imidazole hydrochloride), were evaluated in melittin tests. Pain-related behaviors were rated by counting the number of paw flinches, and measuring paw withdrawal thermal latency (s) and paw withdrawl mechanical threshold (g), over a 1-h time-course. Results Localized peripheral SKF-96365 given before melittin prevented, and given after melittin significantly suppressed, the melittin-evoked persistent spontaneous nociception. Pre-blockade and post-suppression of activation of primary nociceptive activity resulted in decreased hypersensitivity to both thermal and mechanical stimuli applied to the primary injury site of the ipsilateral hindpaw, despite dose-effect differences between thermal and mechanical hyperalgesia. However, local administration of SKF-96365 into the contralateral hindpaw had no significant effect on any pain-associated behaviors. In addition, SKF-96365 had no effect on baseline threshold for either thermal or mechanical sensitivity under normal conditions. Conclusion Besides TRPV1, SKF-96365-sensitive TRPC channels might also be involved in the pathophysiological processing of melittin-induced inflammatory pain and hypersensitivity. Therapeutically, SKF-96365 is equally effective in preventing primary thermal and mechanical hyperalgesia as well as persistent spontaneous nociception. However, this drug is likely to be more effective in the relief of thermal hyperalgesia than mechanical hyperalgesia when applied 5 min after establishment of primary afferent activation.