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U and K Opioids Inhibit Transmitter Release by Different Mechanisms (Synaptic Potentials/Potassium Conductance/Calcium Action Potentials/Dynorphin/Morphine) E

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U and K Opioids Inhibit Transmitter Release by Different Mechanisms (Synaptic Potentials/Potassium Conductance/Calcium Action Potentials/Dynorphin/Morphine) E Proc. Nati. Acad. Sci. USA Vol. 82, pp. 1860-1863, March 1985 Neurobiology ,u and K opioids inhibit transmitter release by different mechanisms (synaptic potentials/potassium conductance/calcium action potentials/dynorphin/morphine) E. CHERUBINI AND R. A. NORTH Neuropharmacology Laboratory, Massachusetts Institute of Technology, 56-245, Cambridge, MA 02139 Communicated by Hamish N. Munro, November 13, 1984 ABSTRACT The actions ofvarious opioids were examined myenteric plexus neurones when they are excited by a brief on calcium action potentials in the cell somata of guinea pig electrical field stimulus (6, 19). In such assays, all agonists myenteric neurones and on the release of acetylcholine at inhibit the release of AcCho, but the ,u and K receptors synapses onto these cells. The opioids morphine, normor- responsible for this action can be differentiated by their phine, and [D-Ala2, MePhe4, Mete(O)]enkephalin-ol caused sensitivity to blockade by naloxone (6, 19) and 3-funal- membrane hyperpolarizations resulting from an increase in trexamine (/3-FNA) (26-29). The purpose of the present potassium conductance; opioids that are more selective agon- experiments was to investigate the ionic mechanisms ists for the Kc receptor subtype (dynorphin, tifluadom, through which ,- and K-receptor agonists might inhibit the U50488H) did not. Conversely, calcium action potentials were release ofAcCho. The amount ofAcCho released from a few depressed or abolished by the K opioids but were not affected by morphine and [D-Ala2, MePhe4, Met(O)5]enkephalin-ol. presynaptic nerves was assayed by recording the amplitude Both groups of opioids caused presynaptic inhibition of acetyl- of the excitatory postsynaptic potential (EPSP). The cell choline release in the myenteric plexus, depressing the ampli- bodies of these presynaptic nerves are contained also within tude of the fast excitatory postsynaptic potential. The the myenteric plexus; the actions of ;u and K agonists on the presynaptic inhibition caused by [D-Ala2, MePhe , Met(O)s]- properties of the soma membrane were therefore compared. enkephalin-ol, morphine, and normorphine, but not that caused by the K opioids, was prevented by pretreatment with MATERIALS AND METHODS the selective ,u site-directed irreversible antagonist ,B- Intracellular recordings were made with microelectrodes funaltrexamine. Furthermore, the presynaptic inhibitory ac- containing potassium chloride (3 M) from 98 neurones in tion of morphine and [D-Ala2, MePhe4, Met(O)s]enkephalin- myenteric ganglia dissected from the ileal wall of adult ol, but not that of the K-receptor agonists, was reversibly guinea pigs. A piece of tissue comprising several ganglia blocked by barium. The results suggest that presynaptic adherent to the longitudinal muscle layer was superfused inhibition caused by IA receptor activation probably results with the following physiological salt solution at 37°C: 117 from an increase in potassium conductance, whereas mM NaCl/4.7 mM KCl/1.2 mM NaH2PO4/1.2 mM K-receptor agonists may depress the release of acetylcholine by MgCl2/2.5 mM CaCl2/25 mM NaHCO3/11 mM glucose, directly reducing calcium entry into the nerve terminals. gassed with 95% 02/5% C02 (pH 7.4). Drugs were applied by changing this solution to one that differed only in its There are three major classes ofopioid peptides, represented content of the drug. The superfusing solution was pumped at by the enkephalins, ,B-endorphin, and dynorphin. They are 1-2 ml-min-'; the ratio of flow rate to bath volume ensured synthesized independently and have distinct distributions in complete exchange of the solution in 1 min. The period of the mammalian nervous system (1-4). Several types of drug application was 2-5 min, during which time any effect opioid receptor have also been distinguished, the best doc- reached steady state; 15-30 min was allowed for washing umented of which are now termed ,u, 8, and K (5-9). It is between drug applications. EPSPs were evoked by applying generally thought that these receptors are cell-surface mol- a single pulse (typically 1-ms duration) of electric current to ecules that recognize one or more of the opioid peptides and that the peptide binding leads to a change in function of the the presynaptic nerves entering the ganglion, by means of a cell. One important functional change is a reduction in the saline-filled micropipette. In some experiments, tbe EPSPs amount of transmitter released by the neurone when it is were mimicked by applying AcCho iontophoretically from a excited, but the ionic mechanisms that underlie this may be third micropipette positioned within 5 ,m of the membrane different for the different receptors. For example, occupa- of the neurone from which the intracellular recording was tion of the A-receptor subtype leads to an increase in made. Full details of these techniques have been published membrane potassium conductance in several mammalian (29, 30). neurones (10-14), and this may reduce transmitter release by The following drugs (and their sources) were used. Ac- shortening the duration of the presynaptic action potential Cho chloride (Sigma), dynorphin A (Peninsula Laborato- (15). On the other hand, the K-receptor agonist dynorphin ries, San Carlos, CA), morphine sulphate (Mallinckrodt), has been found to reduce calcium action potentials in somata normorphine hydrochloride (National Institute on Drug of cultured dorsal root ganglion cells without affecting potas- Abuse), [D-Ala2, MePhe4, Met(O)5]enkephalin-ol (desig- sium conductance (16, 17). nated FK33824, Sandoz Pharmaceutical), trans-(+)-3,4- The guinea pig myenteric plexus contains all three types of dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzene- opioid receptor (6-9, 18-21) as well as several endogenous acetamide methanesulphonate (designated U50488H, Up- ligands (22-25). Pharmacological assays of the receptors in john), tifluadom (Sandoz Pharmaceutical), 6-(P-fumaram- this tissue generally depend upon the ability ofthe agonist to ate)methyl ester of naltrexamine ([,B-funaltrexamine inhibit the release of acetylcholine (AcCho) from the ,B-FNA), P. S. Portoghese and A. E. Takemori, Univ. of Minnesota], tetrodotoxin (TTX, Sigma). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: /3-FNA, ,B-funaltrexamine; EPSP, excitatory post- in accordance with 18 U.S.C. §1734 solely to indicate this fact. synaptic potential; AcCho, acetylcholine. 1860 Downloaded by guest on September 25, 2021 Neurobiology: Cherubini and North Proc. Natl. Acad. Sci. USA 82 (1985) 1861 A 1/ t \, a m " Control1\~~~~~~~--4FK33824 Wash Dynorphin Wash Control P-FNA Wash FK33824 Wash Dynorphin Wash B Control Tifluadom (1 PM) Naloxone , -, 110 mV (100 nM) (3 PM) 5 ms FIG. 1. Both ,u- and K-receptor agonists depress the cholinergic EPSP; ,-FNA selectively blocks the action of the p-receptor agonist. Each trace is four averaged fast EPSPs evoked by single-pulse stimuli (repeated at 0.05 Hz) to the presynaptic nerve entering the ganglion. (A) Superfusion with FK33824 (30 nM), dynorphin (50 nM), and P-FNA (300 nM) each caused a reversible depression of the EPSP. After washing out the 3-FNA, the effect of the P-receptor agonist FK33824 was lost, though the action of dynorphin remained. (B) The depression of the fast EPSP by another K-receptor agonist (tifluadom) was reversed by naloxone. RESULTS (100 nM), 48.4 ± 5.7% (n = 5). The depression of the EPSP Depression of the EPSP. Morphine (10 nM to 1 AM), by the K agonists was unaffected by barium, even in the same normorphine (100 nM to 5 riM), and FK33824 (10-100 nM) cells in which barium prevented the action of normorphine depressed the EPSP amplitude. An example of the effect of (Fig. 2). Pretreatment with f3-FNA did not block the effect of FK33824 is shown in Fig. 1. Normorphine was applied to 22 K agonists, even when it blocked the depressant action of neurones; the mean depression of the EPSP caused by 1 morphine on the same EPSP. 0-FNA itself reversibly de- AM pressed the EPSP, as would be expected for a K agonist. The was 32.6 ± 1.9% (n = 12; this and other values are means ± SEM for the number of observations shown). The effect of depressant action of the K agonists was also blocked by normorphine and FK33824 was readily blocked by naloxone naloxone (100 nM to 1 MM). Nicotinic depolarizations (1-100 nM) (n = 7); it was also irreversibly blocked by evoked by iontophoretic application of AcCho were not affected K P-FNA (n = 6). The P-FNA (200-300 nM) was applied for by the agonists. 20-30 min and washed out for 30 min prior to testing with Depression of the Calcium Action Potential. The finding normorphine or FK33824. The inhibitory action of morphine that barium was able to discriminate between the effects of was still blocked 6 hr after exposure to p-FNA. The action of dynorphin and FK33824 on the EPSP suggested that the K normorphine was presynaptic because normorphine did not agonists might inhibit AcCho release by an action that did affect depolarizations that mimicked the EPSP produced by not involve an increase in potassium conductance. Another iontophoretic application of AcCho to the cell membrane (n possible mechanism of action is a direct reduction in inward = 5). calcium currents close to the release sites. If it is assumed Morphine and normorphine also hyperpolarize some that calcium entry in the cell soma has the same sensitivity to neurones in the myenteric plexus by increasing the mem- opioids as calcium entry close to the AcCho release site, brane potassium conductance (13); it was possible that such then a study of the calcium action potential in the soma may a potassium conductance increase occurring at or near the provide information about the mechanism of action of AcCho release sites might contribute to the presynaptic opioids on AcCho release.
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