Pharmacological evidence that neuropeptides mediate part of the actions of scorpion venom on the guinea pig ileum.
Severe human scorpion envenoming is characterised by instability of several physiological systems and death. These manifestations are explained by the ability of the venom toxins to activate sodium channels in nerve terminals with the subsequent release of neurotransmitters, specially acetylcholine and noradrenaline. However, there is evidence to suggest that other neurotransmitters are also released. We now have sought evidence for a role of the substance P receptor, the tachykinin NK1 receptor, in mediating part of the contractile actions of Tityus serrulatus venom on the isolated guinea pig ileum. Scorpion venom induced a significant elevation of baseline tension with frequent and periodic superimposed contractions on the elevated baseline. Pretreatment with atropine partially blocked the elevation in baseline and in the number of superimposed contractions. These responses were also partially inhibited by the tachykinin NK1 receptor antagonist, CP96,345 (the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-1-az abicycol[2.2.2]octan-3-amine), but not by its inactive enantiomer, CP96,344 (the 2R-3R enantiomer of CP96,345). Pretreatment with the combination of atropine and CP96,345 completely inhibited the effects of the venom. Moreover, pretreatment with the combined drugs abolished the effects of toxin gamma, a toxin purified from the venom. Finally, another tachykinin NK1 receptor antagonist, RP67,580 ((3aR, 7ar)-7,7-diphenyl-2-[1-imino-2-(2-methoxy-phenyl)ethyl]perhydro isoindol-4-one), significantly inhibited the venom-induced contractions. These results demonstrate an important role for NK1 receptors in mediating part of the contractile effects of the venom on guinea pig ileum. The release of neuropeptides may play an important role in the systemic manifestations of severe envenoming.
Matos
I M
IM
Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Teixeira
M M
MM
Leite
R
R
Freire-Maia
L
L
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides / Q000502:physiology*; D012604:Scorpion Venoms / Q000494:pharmacology*; D013237:Stereoisomerism; D013373:Substance P / Q000037:antagonists & inhibitors
D001713:Biphenyl Compounds; D007211:Indoles; D054833:Isoindoles; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D012604:Scorpion Venoms; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D001285:Atropine; C066892:CP 96345