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Neurones Ofguinea-Pig Caecum by Activating 3-Receptors Satoshi Mihara & R

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Neurones Ofguinea-Pig Caecum by Activating 3-Receptors Satoshi Mihara & R Br. J. Pharmac. (1986), 88, 315-322 Opioids increase potassium conductance in submucous neurones ofguinea-pig caecum by activating 3-receptors Satoshi Mihara & R. Alan North Neuropharmacology Laboratory, 56-245 Massachusetts Institute ofTechnology, Cambridge MA 02139, U.S.A. 1 Intracellular records were made from neurones in the submucous plexus ofthe guinea-pig caecum. 2 [Met5Jenkephalin, [Leu5]enkephalin, [D-Ala2,D-Leu5]enkephalin (DADLE) and [D-Ser9,Leu5Jenke- phalin-Thr (DSLET) hyperpolarized the membrane when applied in concentrations of 30 nM- 10 gM. Normorphine, [D-Ala2, MePhe4,Gly5]enkephalin-ol (DAGO), [D-Ala2,MePhe4,Met(0)5]enkephalin-ol (FK33824), dynorphin A and tifluadom had no effect at concentrations up to M. 3 The hyperpolarization resulted from an increase in the membrane potassium conductance. 4 Hyperpolarizations induced by [Met5]enkephalin were antagonized competitively by naloxone and by N-bisallyl[aminoisobutyrate2 3, Leu5]enkephalin (ICI 174864). The Schild plots for these antagon- isms had slopes not different from one, and the dissociation equilibrium constants among individual neurones were 5-50 nM for naloxone and 5-60 nM for ICI 174864. 5 The results indicate that the opioid receptors on guinea-pig submucous neurones which are coupled to potassium channels are of the 6-type. Introduction Opioid receptors of the 6-type were discovered as a ors to conclude that the 6-receptor was on the nerves result of their relative insensitivity to blockade by the rather than the mucosal cells themselves. In keeping antagonist naloxone (Lord et al., 1977). They have a with this is the failure to detect any binding of [3HJ- characteristic distribution throughout the nervous [Met5]enkephalin on enterocytes of the rabbit ileum system which is distinct from that of the p- or ic-type (Binder et al., 1984). The nerves have their cell bodies (see Akil et al., 1984). Electrophysiological ex- in the submucous plexus, and are thus accessible for periments have shown that opioids increase mem- intracellular recording. The purpose of the present brane potassium conductance in a variety of tissues experiments was to investigate the effects of opioid (see Duggan & North, 1983). The results of ex- peptides on the ion conductances of neurones of the periments with selective agonists in cultured mouse guinea-pig submucous plexus and to determine the dorsal root ganglia (Werz & Macdonald, 1983a, b) type of opioid receptor involved. and measurements of naloxone dissociation A preliminary account of the findings has been equilibrium constants in neurones of rat locus published (Mihara & North, 1985). coeruleus (Williams & North, 1984) indicate that the receptor involved is the "-type. Activation ofopioid ic- receptors, on the other hand, appears to reduce Methods membrane calcium conductance by an action that is independent ofpotassium conductance (Werz & Mac- Adult male guinea-pigs were stunned and bled. A donald, 1984a, b; Cherubini & North, 1985). segment of caecum was removed and individual One tissue in which the opioid receptor has been ganglia of the submucous plexus were dissected and characterized as the 6-type is the guinea-pig intestinal pinned in a shallow tissue bath (see Surprenant, 1984; mucosa (Kachur et al., 1980); in this case opioids act to Mihara et al., 1985). The ganglia were superfused with reduce the mucosal short-circuit current, reflecting an a solution of the following composition (mM): inhibition of electrogenic chloride secretion. This net NaCl 117, KCl 4.7, NaH2PO4 1.2, MgCI2 1.2, absorption of chloride by opioids is blocked by CaCl2 2.5, NaHCO3 25 and glucose 11. This solution tetrodotoxin (Binder et al., 1984), leading those auth- was gassed with 95% 02 and 5% CO2 and heated © The Macmillan Press Ltd 1986 316 S. MIHARA & R.A. NORTH before entering the tissue bath; the flow rate was ileum (Surprenant, 1984) and caecum (Mihara et al., adjusted (about 1.5 ml min-') so that the temperature 1985). Recordings from 8 AH cells were omitted. in the tissue bath was 37TC. Intracellular recordings Resting membrane potentials ranged from - 50 to were made from microelectrodes filled with a solution - 68 mV (- 54.1 ± 0.67; mean ± s.e.mean, n = 47), of potassium chloride (or acetate), and having resis- input resistances ranged from 52 to 144 MO tances of 70-1I00 M. Membrane currents were (72.9 ± 21.6; n = 33), and time constants ranged from measured in some experiments with a single electrode 8 to 22ms (12.4 ± 0.73; n = 23. voltage-clamp amplifier (Dagan 8100). Drugs were applied to the preparation by two Some opioids hyperpolarize submucous neurones methods. In those experiments in which precise knowledge of the drug concentration was not neces- Submucous plexus neurones were hyperpolarized sary (for example, determination of reversal poten- when the superfusion solution was changed to one that tial), [Met5]enkephalin was ejected from a pipette. The contained [Met5]enkephalin or [Leu5]enkephalin tip of this pipette (diameter 5- 151m) was positioned (Figure 1). The hyperpolarization was rapid in onset, about 10-20 m laterally from the impaled neurone; reaching its peak within 10-20 s of the arrival of the the [Met5]enkephalin (100 FM) was ejected by applying changed solution at the tissue, and the membrane a brief pulse of pressure to the pipette (typically potential reversed rapidly to its resting level when 100 kPa, 30 ms). In the majority ofexperiments, drugs superfusion with the control solution was resumed were applied by dissolving them in known concentra- (Figure 1). When membrane current was recorded tions in the superfusing solution, and then changing under voltage clamp, superfusion with [Leu5]enke- the superfusing solution by means of a three-way tap. phalin evoked an outward current having the same There was a delay of 20 s between turning the tap and time course as the hyperpolarization. The peak the arrival at the tissue bath of the changed solution. amplitude of the hyperpolarization was dependent on Complete exchange of the bath solution, indicated by the concentration of agonist applied (300 nM- 10 aM), effects reaching their steady state, was usually com- but never exceeded 35 mV. [Met5]enkephalin caused plete within 10 s. Antagonist dissociation equilibrium hyperpolarizations of9.1 ± 0.94 mV (range 3- 16 mV, constants (KDs) were determined by the method of n = 24) at 300 nM, 13.0 ± 0.67 mV (range 4- 30 mV, Arunlakshana & Schild (1959); in these experiments, n = 86) at 11 M, 22.9 ± 1.15 mV (range 15-32 mV, non-cumulative agonist concentration-response n = 18) at 31M, and 26.0 ± 2.4 mV (range 19- 34 mV, curves were constructed first before and then in the n = 6) at 10g1M. [Leu5Jenkephalin caused hyper- presence of various antagonist concentrations. When- polarizations of 10.5 ± 1.2mV (range 4-19mV, ever possible, the sensitivity to agonist was determined n = 11) at I00 nM, 15.7 ± 0.88 mV (range 4-26 mV, again after washing out the highest concentration of n = 58) at 1 1M, 22.0 ± 1.2mV (range 17-27mV, antagonist used; this was not always possible because n = 8) at 3 gM, and 24.3 ± 1.6mV (range 19-27 mV, it required recording from a single cell for at least 5 h. n = 4) at 1I1AM. The values given are the means with Compounds used were: dynorphin (Peninsula), P- the s.e.mean. The peak currents (holding at - 60 mV) funaltrexamine (the 6p-fumaramate methylester de- were typically 300 pA, implying a maximal opioid rivative ofnaltrexamine, Dr P. Portoghese, University conductance of about 10 nS (calculated for a driving of Minnsota), [D-Ala2,D-Leu5]enkephalin (DADLE), force of 30 mV, see below). [D-Ala2,MePhe4,Met(0)5]enkephalin-ol (FK33824), When the period of superfusion was continued for [D-Ala2,MePhe4,Gly5]enkephalin-ol (DAGO), [Leu5] more than 2 min, the hyperpolarization often progres- enkephalin, [Met5]enkephalin, [D-Ser2,Leu']enke- sively passed off during the presence of the agonist. In phalin-Thr (DSLET) (all from Peninsula), [N-bisallyl- the same cell, the hyperpolarization evoked by Tyr',Aib2'3Leu5lenkephalin (ICI 174864) (Aib = noradrenaline did not decline during superfusions of aminoisobutyrate) (courtesy of ICI), morphine sul- up to 30min (see also Mihara et al., 1985; North & phate (Mallinckrodt), naloxone hydrochloride Surprenant, 1985). In some neurones, repeated (Endo), noradrenaline bitatrate (Sigma), normor- applications of [Met5]enkephalin separated by phine hydrochloride (National Institute on Drug 20-30 min caused hyperpolarizations ofprogressively Abuse), somatostatin (Peninsula) and tifluadom (San- declining amplitudes, even though the responses ofthe doz). same neurone to noradrenaline and somatostatin (see below) did not decline with time. This was observed in 9 out of 86 neurones to which [Met5]enkephalin was Results applied and 7 out of 58 neurones to which [Leu5]enke- phalin was applied. The 225 neurones from which recordings were made in The opioids which were effective in hyperpolarizing the present study had properties similar to those submucous plexus neurones were [Met5]enkephalin, described in previous experiments on the guinea-pig [Leu5]enkephalin, DSLET and DADLE. The equi- OPIOID 6RECEPTORS AND POTASSIUM CHANNELS 317 a b LE LE AI c ME 0. .3 FM 1 M 3 1JM 10 RM 0. 10 mV 200 pA 30 s Figure 1 Hyperpolarization and outward current caused by [Leu5]enkephalin and [Met5]enkephalin. (a) Membrane potential; downward deflections are electrotonic potentials evoked by passing hyperpolarizing current pulses of 100 pA, l00 ms at 0.5 Hz. The superfusion solution contained [Leu5Jenkephalin (LE) (I JM) during the period indicated by the bar (30 s). The apparent delay in the onset ofthe hyperpolarization in this and other records represents the time required for the changed solution to pass through a heat-exchanger before it reached the tissue.
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