title: Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide.
abstract: Snakebites constitute a serious public health problem in Central and South America, where species of the lancehead pit vipers (genus Bothrops) cause the majority of accidents. Bothrops envenomations are very painful, and this effect is not neutralized by antivenom treatment. Two variants of secretory phospholipases A2 (sPLA2), corresponding to Asp49 and Lys49 PLA2s, have been isolated from Bothrops asper venom. These sPLA2s induce hyperalgesia in rats following subcutaneous injection. However, venom in natural Bothrops bites is frequently delivered intramuscularly, thereby potentially reaching peripheral nerve bundles. Thus, the present series of experiments tested whether these sPLA2s could exert pain-enhancing effects following administration around healthy sciatic nerve. Both were found to produce mechanical allodynia ipsilateral to the injection site; no thermal hyperalgesia was observed. As no prior study has examined potential spinal mechanisms underlying sPLA2 actions, a series of anatomical and pharmacological studies were performed. These demonstrated that both sPLA2s produce activation of dorsal horn astrocytes and microglia that is more prominent ipsilateral to the site of injection. As proinflammatory cytokines and nitric oxide have each been previously implicated in spinally mediated pain facilitation, the effect of pharmacological blockade of these substances was tested. The results demonstrate that mechanical allodynia induced by both sPLA2s is blocked by interleukin-1 receptor antagonist, anti-rat interleukin-6 neutralizing antibody, the anti-inflammatory cytokine interleukin-10, and a nitric oxide synthesis inhibitor (L-NAME). As a variety of immune cells also produce and release sPLA2s during inflammatory states, the data may have general implications for the understanding of inflammatory pain.
authors.affiliation: Instituto Butantan, Sao Paolo, Brazil.
authors.forename: Marucia
authors.initials: M
authors.lastname: Chacur
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
authors.forename: Evan M
authors.initials: EM
authors.lastname: Sloan
authors.forename: Julie
authors.initials: J
authors.lastname: Wieseler-Frank
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Barrientos
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Brono
authors.initials: B
authors.lastname: Lomonte
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Gutiérrez
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Yara
authors.initials: Y
authors.lastname: Cury
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015415:Biomarkers; D003435:Crotalid Venoms / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology; D008159:Lumbar Vertebrae; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009457:Neuroglia / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D010741:Phospholipases A / Q000494:pharmacology*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012585:Sciatica / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology
chemical_list: D000906:Antibodies; D015415:Biomarkers; D003435:Crotalid Venoms; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D016753:Interleukin-10; D009569:Nitric Oxide; D010741:Phospholipases A; D019331:NG-Nitroarginine Methyl Ester