Voltage-Gated Calcium Channel Antagonists: Potential Analgesics for Jejunal Pains

英语. The significant role of voltage-gated calcium channel (VGCC) L-type antagonists used concomitantly with opioids in attenuation of clinical pain has been confirmed. The aim of this study is to evaluate the comparable effect of intracerebroventricularly (i.c.v.) administered diltiazem, nifedipine and/or verapamil – specific antagonists of VGCCs – in the dose of 1.0 and 2.0 mg in toto on behavioral signs, clinical symptoms, rumen motor activity and biochemical (plasma cortisol and catecholamine—CA) parameters in sheep that have undergone experimental duodenal distension (DD) and to determine whether voltage-gated calcium channel inhibitors (VGCCIs) exert any anti-nociceptive effects under these conditions. The study was carried out using 24 mature, behind reproductive season crossbred ewes, each weighing 32–42 kg. DD was managed by inclusion and the distension of stretching balloon (having 40 mL of water 39°C temperature—DD40). After 5 min of DD40, the signs were observed: an important augmentation of behavioral nociceptive signs, particularly looking around, defecation, head movement, stretching, grinding, lying down, tachycardia, hyperventilation, inhibition of ruminal contractions (70% approximately, during 15 min) and an increase in plasma catecholamine concentration (over sevenfold increase of epinephrine (E): from 0.24 ± 0.12 in control to 2.98 ± 0.21 mM L−1 during 2 h following DD, 2-times norepinephrine (NE): from 1.29 ± 0.23 in control to 2.51 ± 0.30 mM L−1 and 124% increase of dopamine (DA): from 0.94 ± 0.02 in control to 2.10 ± 0.35 mM L−1). VGCCI infusion administered 10 min before duodenal distension diminished severity of jejunal nociceptive reactions, for instance, behavioral symptoms, cardiac acceleration, increase in the number of respiration, inhibition of the reticulum and rumen hypomotility, and effortlessly abolished the increasing presence of plasma cortisol and biogenic amines (CA) release. We suggest that the increase and insistence of visceral hyperalgesia stimulate the flow of Ca2+ ion flow, provoking neurohormones/neuromediators liberatione and cytoplasmic membrane responsiveness modulation. This result confirmed analgesic effects of VGCCIs L- and/or R-type (nimodipine, lercanidipine, SNX-482) obtained by other authors and also suggests that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep and may be a therapeutic target for new drugs.

英语. duodenal distension, diltiazem, nifedipine, verapamil, behavioral signs, clinical symptoms, rumen motility, blood plasma cortisol, catecholamine concentration, sheep

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