Centrally administered verapamil prevents the autonomic reaction to visceral pain in sheep

Abstract

The significant role of voltage gated calcium channels (VGCC) L-type antagonists used concomitantly with opioids in attenuation of clinical pain has been confirmed. The aim of this study was to evaluate the effect of centrally administered verapamil on behavior and biochemical parameters in sheep that have undergone experimental duodenal distension (DD) and to determine whether verapamil exerts any anti-nociceptive effects under these conditions. The study was carried out using 24 mature crossbred ewes, each weighing 38–43 kg. Verapamil, a VGCC blocker, was administered through an intracerebroventricular cannula at the following doses: 0.25, 0.5, 1.0 and 2.0 mg in toto. Ten minutes later experimental DD was conducted by insertion and the distension of rubber balloon (containing 40 ml of warm water) inserted into sheep duodenum. After 5 min of mechanical DD the following reactions were then observed: the significant increase in behavioral pain responses, i.e. tachycardia, hyperventilation, inhibition of reticulo-ruminal contractions (70% approximately, during 15 min), an increase of plasma catecholamine concentration (over 7-fold increase of epinephrine during 2 h following DD, 2-times norepinephrine and ±80% increase of dopamine). Verapamil infusion administered 10 min prior to DD decreased intensity of visceral pain responses, such as: behavioral changes, tachycardia, hyperventilation, inhibition of the reticulo-rumen motility and efficiently prevented the appearance of catecholamine release. These data demonstrated that the development and persistence of duodenal hyperalgesia depends on the activation of Ca 2+ ion flux leading to neurotransmitters release and modulation of membrane excitability. The observed antinociceptive action of VGCCs type-L blockers suggests that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep.