Benzodiazepine-induced intestinal motor disturbances in rats: mediation by omega 2 (BZ2) sites on capsaicin-sensitive afferent neurones.
1. The central and peripheral effects of the omega (benzodiazepine) site ligands, clonazepam, alpidem, zolpidem, triazolam, flumazenil, ethyl beta carboline-3-carboxylate (beta-CCE) and N-methyl beta carboline-3-carboxylate (beta-CCM) on intestinal myoelectrical activity were evaluated in conscious rats, chronically fitted with Nichrome electrodes implanted on the duodenum and jejunum. The localization of the omega (benzodiazepine) receptors involved in these effects was evaluated by use of systemic and perivagal capsaicin treatments. 2. When administered intraperitoneally (i.p.) the omega site inverse agonists beta-CCE and beta-CCM, and the omega site antagonist flumazenil, did not affect the duodeno-jejunal motility. Alpidem and zolpidem, two selective omega 1 site agonists induced an inhibition of migrating myoelectric complexes (MMCs) only at a high dose (5 mg kg-1). In contrast, clonazepam (a mixed omega 1/omega 2 agonist) and triazolam (a preferential omega 2 site agonist) disrupted the MMC-pattern at doses as low as 0.05 mg kg-1, the effect of trizolam being of much longer duration than that of clonazepam. None of these drugs altered MMC-pattern when administered centrally (i.c.v.). 3. Administered i.p. or i.c.v. prior to triazolam, alpidem blocked the effect of triazolam on duodenojejunal spike activity. Administered i.p. prior to triazolam, flumazenil suppressed the triazolam-induced MMC-disruption. Previous systemic but not perivagal capsaicin treatment suppressed the effects of clonazepam on MMCs. 4. It is concluded that omega-site agonists but not, antagonist or inverse agonists, administered systemically induced intestinal motor disturbances which may be linked to activation of omega 2 (BZ2) sites located on nonvagal capsaicin-sensitive afferent neurones.
Bonnafous
C
C
Department of Pharmacology I.N.R.A., Touluse, France.
Scatton
B
B
Buéno
L
L
D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D004576:Electromyography / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D016065:Myoelectric Complex, Migrating / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002211:Capsaicin