Hideyuki Nishiwaki (1,2), Noriko Saitoh (1), Hideaki Nishio (1), Tadayoshi
Takeuchi (1,3) and Fumiaki Hata (1,3,*)
(1) Department of Veterinary Pharmacology, College of Agriculture and (3) Department of Molecular Physiology and Biochemistry, Research Institute for Advanced Science and Technology, Osaka Prefecture University, Sakai 599-8531, Japan
(2) Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kawanishi 666-0131, Japan
(*) To whom correspondence should be addressed (1).
Abstract: The relationship between muscarinic autoinhibition and the inhibitory effect of morphine on acetylcholine (ACh) release was investigated in a longitudinal muscle with myenteric plexus (LMMP) preparation of guinea pig ileum. Morphine (10 microM) inhibited spontaneous and evoked ACh release by electrical field stimulation (EFS) at 1 Hz but not at 10 Hz. Atropine (1 microM) did not affect the resting ACh release, but it significantly increased EFS-evoked release, suggesting activation of muscarinic autoreceptors by ACh released during EFS. Only when the autoinhibition was weakened by atropine, morphine exhibited an inhibitory effect on the EFS-evoked release at 10 Hz. Bethanechol (300 microM) inhibited the EFS-evoked release at 1 Hz but not 10 Hz, suggesting that muscarinic autoreceptors are partially or almost fully activated at 1 or 10 Hz stimulation, respectively. After bethanechol treatment, morphine did not exhibit its inhibitory effect on the EFS-evoked release at 1 Hz. Naloxone (1 microM) increased spontaneous and EFS-evoked ACh release at 1 Hz but not at 10 Hz. Following treatment with atropine, naloxone also increased ACh release at 10-Hz stimulation. These results suggest that morphine and an endogenous opioid inhibit ACh release from LMMP preparations when muscarinic autoinhibition mechanism does not fully work. This inhibitory effect of morphine is discussed in relation to the calcium sensitivity of the preparations in ACh release.
Keywords: Muscarinic autoinhibition, Morphine, Acetylcholine release, Myenteric plexus, Ileum (guinea pig)