While these snake venom enzymes are perhaps most feared for their properties as preganglionic neurotoxins (β-neurotoxins) that inflict apneic death [
1,
57,
58,
59], they also cause edema, tissue injury and, critically, pain [
57,
58,
59,
62,
72,
73,
74,
75,
76]. PLA
2 activity catalyzes phospholipids in the bite site and beyond after release into the circulation, resulting in formation of bradykinin, biogenic amines, prostaglandins, and other compounds that inflict pain [
57,
58,
62,
72,
73,
74,
75,
76]. For example, PLA
2 isolated from
Crotalus durissus species venom has been demonstrated to activate C fibers, resulting in the release of substance P, mast cell degranulation, and finally, release of histamine and serotonin [
63]. A similar release of substance P and bradykinin was observed following the use of a secretory PLA
2 isolated from
Naja mocambique mocambique venom in a model of acute pancreatitis [
64]. In the same vein, a PLA
2 isolated from
Micruruus lemniscatus, Lemnitoxin, was found to be a potent agent that degranulated mast cells [
65]. A PLA
2 isolated from
Bothrops atrox venom, BatroxPLA
2, caused release of IL-6 and formation of prostaglandin E
2 (PGE
2), leukotriene B
4 (LTB
4), and cysteinyl leukotrienes (CysLTs) in mice [
66]. Further, snake venom PLA
2 from
Bothrops species also inflict pain via cellular release of adenosine triphosphate and potassium [
75,
76]. Of interest, a heteromeric toxin composed of a PLA
2 with minimal enzymatic activity with Kunitz-like protein (MitTx) purified from the venom of
Micrurus tener tener that activates acid-sensing ion channels (ASICs) independent of enzymatic activity has been identified as a source of pain [
61]. Of equal importance, the role of PLA
2 in the development of pain has been demonstrated by inhibition of these enzymes, which results in a decrease in pain in vivo [
77,
78]. For the interested reader, a more in-depth consideration of PLA
2 is recommended [
62]. Thus, it is likely that PLA
2 significantly contribute to the pain syndromes subsequently presented.