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Muscarine Hyperpolarizes a Subpopulation of Neurons by Activating an M, Muscarinic Receptor in Rat Nucleus Raphe Magnus in Vitro

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Muscarine Hyperpolarizes a Subpopulation of Neurons by Activating an M, Muscarinic Receptor in Rat Nucleus Raphe Magnus in Vitro The Journal of Neuroscience, March 1994, 74(3): 1332-l 338 Muscarine Hyperpolarizes a Subpopulation of Neurons by Activating an M, Muscarinic Receptor in Rat Nucleus Raphe Magnus in vitro 2. Z. Pan and J. T. Williams Vellum Institute, Oregon Health Sciences University, Portland, Oregon 97201 It has been shown previously that the muscarinic cholinergic ical studies (Bowker et al., 1983; Jones et al., 1986; Sherriff et system in the nucleus raphe magnus (NRM) is involved in al., 1991). The NRM receives cholinergic afferents originating the modulation of nociception. In this study, we examined from the cells in the pedunculopontine tegmental nucleus (Rye the direct actions of muscarine on the NRM neurons in a et al., 1988). Behavioral studies have shown that local appli- slice preparation. Muscarine (I-30 PM) produced a dose- cations of both muscarinic receptor agonists and antagonists dependent hyperpolarization in a subpopulation of the NRM into the NRM causeantinociception (Brodie and Proudfit, 1986; cells that contain 5-hydroxytryptamine (5-HT). In voltage Iwamoto, 1991). In previous in vivo studies, iontophoretic ap- clamp, the muscarine-induced outward current reversed po- plication of ACh has been reported to induce an inhibition or larity at the potassium equilibrium potential and was char- excitation in the spontaneousactivity of different groups of the acterized by strong inward rectification. The reversal poten- NRM cells (Behbehani, 1982; Wessendorfand Anderson, 1983; tial was dependent on external potassium concentration, Willcockson et al., 1983; Hentall et al., 1993). Neither the cel- suggesting that the hyperpolarization induced by muscarine lular mechanismunderlying the actionsof thesecholinergic agents was mediated through an increase in an inwardly rectifying on NRM neurons nor the muscarinic receptor subtypes that potassium conductance. 5-HT also hyperpolarized these cells mediate the cholinergic actions is known. by increasing the same inwardly rectifying potassium con- The actions of ACh acting at muscarinic receptors in the CNS ductance. The concentration-response curve for muscarine include a depolarization resulting from a reduction in a potas- (EC,, = 2.7 @I) was shifted in a parallel manner to the right sium conductance (Brown and Adams, 1980; Madison et al., by increasing concentrations of pirenzepine (300 nM to 3 FM) 1987; Uchimura and North, 1990) and a hyperpolarization as and methoctramine (50-200 nM). Schild analysis revealed a result of an increase in a potassium conductance (Egan and that the equilibrium dissociation constant (KJ was 230 nM North, 1986; McCormick and Prince, 1987; McCormick and for pirenzepine and was estimated to be less than 30 nM for Pape, 1988; Gerber et al., 1991). Muscarinic cholinergic recep- methoctramine. These results indicate that the muscarinic tors consist of a heterogeneousfamily of five different subtypes receptor mediating the muscarine activation of the potas- (ml-m5) that have been cloned from rats (Kubo et al., 1986; sium conductance in these cells is of the M, subtype. The Bonner et al., 1987, 1988). The ml-m3 receptors correspond present results suggest an inhibitory cholinergic postsyn- most closely to the pharmacologically defined M,-M, receptors aptic modulation on the activity of a subpopulation of sero- (Kubo et al., 1986; Brann et al., 1988; Maeda et al., 1988; tonergic neurons that are involved in antinociceptive function Buckley et al., 1989). The ml, m3, and m5 receptors are func- in the NRM. tionally coupled primarily to the stimulation of inositol phos- [Key words: muscarine, M, moscarinic receptor, inwardly phate metabolism through a pertussistoxin-insensitive G-pro- rectifying potassium conductance, pirenzepine, methoctra- tein, while the m2 and m4 receptors are associatedmainly with mine, nucleus raphe magnus] an inhibition of CAMP production through a pertussistoxin- sensitive G-protein (Bonner et al., 1988; Fukuda et al., 1988; Neurons in the nucleus raphe magnus (NRM) are involved in Peralta et al., 1988; Wess et al., 1990; Lai et al., 1991). In rat the descendingmodulation of nociceptive processingfrom su- brainstem, the presenceof all five receptor subtypes or their praspinal levels (Basbaumand Fields, 1984).Functionally, there mRNAs has been reported (Buckley et al., 1988; Ehlert and are different groups of putative pain-modulating neurons in the Trait, 1990; Levey et al., 1991; Li et al., 199 1; Zubieta and Frey, NRM and modulation ofthe activity in theseneurons by opioids 1993). and other neurotransmitters results in a significant change in In this study, we examined the direct actions of muscarine pain threshold (Fields et al., 1983, 1991). Among those neu- on the neurons in the NRM in a slice preparation and then rotransmitters is ACh. Cholinergic (AChE- or ChAT-positive) identified the ionic mechanism and the receptor subtype in- cells have been identified within the NRM in previous anatom- volved in the muscarine-inducedhyperpolarization observed in a subpopulation of neurons in the NRM. Preliminary results of this study have been presented as an Received Mar. 31, 1993; revised Aug. 4, 1993; accepted Aug. 19, 1993. abstract (Pan and Williams, 1991). We thank Drs. D. Cameron and M. Kelly for comments on the manuscript. This work was suooorted bv NIH Grants DA04523 and DA00 14 I. Materials and Methods Correspondence should be addressed to J. T. Williams, Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR Intracellularrecordings were made from NRM cellsin brain slicesfrom 97201. adult Wistar rats. The methodsemployed were similar to thosepub- Copyright 0 1994 Society for Neuroscience 0270-6474/94/141332-07$05.00/O lishedpreviously (Pan et al., 1990).Briefly, brain slices(300 pm thick) The Journal of Neuroscience, March 1994, 74(3) 1333 A Muscarine 1 uM Figure 1. Hyperpolarization induced 3NJ by muscarinic receptor agonists in neu- rons in the NRM. A, Membrane poten- tial recordings of an NRM cell that was 10 KM hyperpolarized by increasing concen- trations of muscarine. B, Dose-re- sponse curves for the hyperpolarization induced by muscarine (EC,, = 2.7 PM, n = 8) and by carbachol (EC,, = 3.8 30 pM PM, n = 7). Data points are expressed ----------- as a percentage of the maximum hy- -6 -5 -4 -3 perpolarization by 30 WM muscarine (9.8 - 15 mV Log [muscarine] (M) + 1.1 mV) and by 30 PM carbachol(9.4 + I. 1 mV), respectively. Error bars are 2 min SE of the mean. were cut in a vibratome in cold (4°C) physiological saline. Two or three and a maximum hyperpolarization of 9.8 +- 1.1 mV (n = 8) at coronal slices were taken from the level of the facial nerve in each brain. 30 FM. The EC,, was 2.7 FM (Fig. 1B). Carbachol, a muscarinic A single slice was submerged in a tissue bath through which flowed physiological saline (1.5 ml/min) at 37°C. The content of physiological receptor agonist, also hyperpolarized these cells in a dose-de- saline solution was (in mM) NaCl, 126; KCl, 2.5; NaH,PO,, 1.2; MgCl,, pendent manner over a similar concentration range (l-30 PM; 1.2; CaCl, 2.4; glucose, 11; NaHCO,, 25; gassed with 95% O,, 5% CO, Fig. lB), inducing a maximum hyperpolarization of 9.4 + 1.1 at 37°C. mV (n = 7) at 30 FM and having an EC,, of 3.8 WM. The NRM was recognized in the slice as a triangular area in the In 2 1 of 148 cells (14%), muscarine (10 FM) induced a de- midline just above the pyramidal tracts. Neurons were penetrated with polarization of 4.8 * 0.6 mV (n = 21) which often resulted in glass microelectrodes filled with potassium chloride (2 M) having resis- tances of 40-70 MQ. Membrane currents were recorded with a single- the firing of repetitive action potentials. The muscarine-induced electrode voltage-clamp amplifier (Axoclamp 2A) using switching fre- depolarization was observed almost exclusively in secondary quencies between 3 and 6 kHz. The settling time of the clamp following cells. a 10 mV step was typically 3-5 msec. Steady state current-voltage (I- v) plots were constructed directly on an x,y-plotter using a slow de- polarizing ramp potential. The speed of the ramp (1 mV/sec) was suf- Muscarine activated an inwardly rectifying potassium ficiently slow to give the same current as that measured at the termi- conductance nation of a 2 set voltage step. In voltage clamp, muscarine produced an outward current at Drugs were applied by superfusion. The following drugs and salts were used: muscarine (Sigma), carbachol (Sigma), pirenzepine (PZP; the resting membrane potential associatedwith an increasein Research Biochemical Inc.), methoctramine (Research Biochemicals membrane conductance (n = 24; Fig. 2A). At more negative Inc.), 5-hydroxytryptamine (5-HT; Sigma), 5-carboxamidotryptamine potentials than the resting potential, the muscarine-inducedcur- (5-CT; Glaxo), BaClz (Sigma), tetrodotoxin (TTX; Sigma). Dose-re- rent declined in amplitude and reversed polarity. The averaged sponse data were fitted by logistic equation and the EC,, was then reversal potential of the muscarine-inducedcurrent was - 103 determined. Schild analysis was carried out by determining the dose ratios at the EC,, values in the absence and presence of the antagonist * 2 mV (n = 17) in normal concentration of external potassium (Schild, 1949). Numerical data are presented as means ? SE of the (2.5 mM). When the potassium concentration in the perfusing means and compared using an unpaired, two-tailed Student’s t test. solution was increased to 6.5 mM and 10.5 mM, the reversal potential was shifted to -78 f 2 mV (n = 11) and -66 f 2 Results mV (n = 7) respectively (Fig. 2B), giving a Nernst slope of In a previous study, two groups of cells in the NRM have been -59.5 (Fig. 2C). This suggesteda primary involvement of a described: primary and secondary (Pan et al., 1990). Primary potassium conductance.
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