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Background: The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). Methodology/Principal Findings: Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na+ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. Conclusion/Significance: Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for better treating poisoning by P. nigriventer but also appreciating the diversity of targets triggered by PNV toxins. Author Summary: Spiders of the Phoneutria genus live in Central and South America, where relevant envenomation cases have been reported in humans. The incidence of bite by spiders in Brazil has increased in recent years, with Phoneutria nigriventer being the second most important cause of such accidents (approximately 4,000 cases of envenomation in 2011). Pain is the primary local symptom of inoculation with Phoneutria nigriventer venom (PNV), but the mechanisms involved in pain induced by PNV are poorly understood. It is important to find effective treatments to alleviate this pain. This study examined the mechanisms involved in pain caused by PNV in a mouse model as well as the sensitivity of PNV-induced pain to clinically used analgesics. The results show that both the low- and high-molecular-weight components of PNV produce spontaneous nociception action via kinin B2, TRPV1, 5-HT4 or ASIC receptors and the voltage-gated Na+ channels present in sensory fibres. Moreover, PNV-triggered nociception could be alleviated by arachnid antivenin, local anaesthetics, opioids and atypical, but not typical, non-steroidal anti-inflammatory drugs. The elucidation of the mechanisms responsible for the nociception induced by PNV is of interest to not only better treat envenomation by P. nigriventer but also understand the diversity of targets triggered by PNV toxins. [ABSTRACT FROM AUTHOR]