Pharmacological evidence that neuropeptides mediate part of the actions ofscorpion 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 neurotr ansmitters are also released. We now have sought evidence for a role of the substance P receptor, the tachykinin NK1 receptor, in mediating part of th e 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 baseli ne. Pretreatment with atropine partially blocked the elevation in baseline and in the number of superimposed contractions. These responses were also p artially inhibited by the tachykinin NK1 receptor antagonist, CP96,345 (the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl )methyl)- 1-azabicycol[2.2.2]octan-3-amine). but not by its inactive enanti omer, CP96,344 (the 2R-3R enantiomer of CP96,345). Pretreatment with the co mbination 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 tachykin in NK1 receptor antagonist, RP67,580 ((3aR, 7ar)-7,7-diphenyl-2-[1-imino-2- (2-methoxy-phenyl)ethyl]perhydroisoindol-4-one), significantly inhibited th e venom-induced contractions. These results demonstrate an important role f or NK1 receptors in mediating part of the contractile effects of the venom on guinea pig ileum. The release of neuropeptides may play an important rol e in the systemic manifestations of severe envenoming. (C) 1999 Elsevier Sc ience B.V. All rights reserved.