title: Cholinergic activation affects the acute and chronic antinociceptive effects of morphine.
abstract: Current studies indicate that the cholinergic and opioid systems interact to modulate pain. In the present work, we investigated the influence of the cholinesterase inhibitors, donepezil (0.5; 1 or 3mg/kg, i.p.) and rivastigmine (0.03; 0.5 or 1mg/kg, i.p.), on the acute antinociceptive effects of morphine (5mg/kg, i.p.) in the hot plate test in mice. Herein, both inhibitors were found to enhance and prolong the analgesic effects of morphine without affecting latencies themselves. In an extension of this work, we determined which cholinergic receptors subtype mediates the enhancement of analgesic effects of morphine, following inhibition of cholinesterases. In this part of the study, scopolamine (0.5mg/kg, i.p.), a muscarinic cholinergic receptors antagonist, but not mecamylamine (3mg/kg, i.p.), a nicotinic cholinergic receptors antagonist, reversed the enhancing effects of donepezil (3mg/kg, i.p.) and rivastigmine (1mg/kg, i.p.) on the morphine antinociception. Moreover, both cholinesterase inhibitors attenuated the development of tolerance to the antinociceptive effects of morphine. In contrast, acute administration of donepezil (3mg/kg, i.p.) or rivastigmine (1mg/kg, i.p.) on the day of expression of tolerance, had no effect on the already developed morphine tolerance. What is more, in both set of experiments, rivastigmine was slightly more potent than donepezil due to the broader inhibitory spectrum of this drug on acetylcholine degradation. Thus, our results suggest that the cholinesterase inhibitors, donepezil and rivastigmine, may be administered with morphine in order to enhance the latter's analgesic effects for the treatment of acute and chronic pain.
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4a, 20-093 Lublin, Poland; Department of Experimental and Clinical Pharmacology, Medical University, Jaczewskiego 8b, 20-090 Lublin, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Gawel
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gibula-Bruzda
authors.affiliation: Department of Laboratory Diagnostic, Medical University, Chodzki 1, 20-093 Lublin, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Dziedzic
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jenda-Wojtanowska
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Marszalek-Grabska
authors.affiliation: Department of Biochemistry and Neurobiology, AGH University of Science and Technology, Mickiewicza 30, 30-059 Krakow, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Silberring
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4a, 20-093 Lublin, Poland. Electronic address: jolka.kotlinska@umlub.pl.
authors.forename: Jolanta H
authors.initials: JH
authors.lastname: Kotlinska
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007189:Indans / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009020:Morphine / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010880:Piperidines / Q000627:therapeutic use; D000068836:Rivastigmine / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D009020:Morphine; D000077265:Donepezil; D000109:Acetylcholine; D000068836:Rivastigmine
keywords: Donepezil; Hot plate; Mice; Morphine; Rivastigmine; Tolerance