title: Effect of chronic administration of dihydropyridine Ca2+ channel ligands on sufentanil-induced tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus.
abstract: The present investigation was aimed at elucidating if the entry of Ca2+ plays a role in the development of tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus. For this purpose, the influence of the L-type Ca2+ channel modulators nimodipine (Ca2+ blocker) and Bay K 8644 (Ca2+ activator) on the expression of tolerance to the inhibitory effects of mu- and kappa-opioid agonists in the ileum of guinea pigs rendered tolerant to sufentanil was investigated. Chronic perfusion of guinea pigs with nimodipine (2 micrograms/microliter/h for 7 days) or Bay K 8644 (0.5 microgram/microliter/h for 7 days) did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) strip from naive animals. Tolerance to sufentanil (a selective mu-agonist) was induced by s.c. implantation of osmotic minipumps for 7 days, which deliver at 2 micrograms/microliter/h. Control groups received saline. Tolerance to sufentanil as well as to U-50,488H (selective kappa-agonist) was observed following chronic treatment with sufentanil and was revealed as a rightward shift of the concentration-response curves. Chronic perfusion of guinea pigs with the Ca2+ antagonist nimodipine concurrently with chronic sufentanil, markedly blocked the expression of tolerance to sufentanil, as well as the cross-tolerance between sufentanil and U-50,488H. On the contrary, when guinea pigs were perfused with the Ca2+ agonist Bay K 8644 concurrently with sufentanil, it enhanced the magnitude of tolerance to both sufentanil and U-50,488H. These results suggest that, in guinea pig ileum, chronic exposure to opioids may involve the activation of L-type Ca2+ channel, which would indicate that intracellular Ca2+ may be one of the final pathways through which myenteric neurons adapt to the chronic opioid exposure.
authors.affiliation: Department of Physiology and Pharmacology, University School of Medicine, Murcia, Spain.
authors.forename: J V
authors.initials: JV
authors.lastname: Garaulet
authors.forename: M L
authors.initials: ML
authors.lastname: Laorden
authors.forename: M V
authors.initials: MV
authors.lastname: Milanés
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000601:surgery; D015918:Infusion Pumps, Implantable; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects* / Q000502:physiology; D009553:Nimodipine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017409:Sufentanil / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011759:Pyrrolidines; D009553:Nimodipine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D017409:Sufentanil