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View Full Page The Journal of Neuroscience, October 1992, 72(10): 4023-4036 A Confocal Laser Microscopic Study of Enkephalin-lmmunoreactive Appositions onto Physiologically Identified Neurons in the Rostra1 Ventromedial Medulla P. Mason,i,a S. A. Back,’ and H. L. Fields’-* Departments of ‘Neurology and 2Physiology, and the William B. Keck Center for Integrative Neuroscience, University of California at San Francisco, San Francisco, California 94143 Neurons in the rostra1 ventromedial medulla (RVM) are im- sible on-cell inhibition of off-cells, which are thought to inhibit portant in the opioid modulation of dorsal horn nociceptive nociceptive transmission. transmission. Systemically administered morphine inhibits one class of RVM cells, the on-cells; excites a second class Opioids, the most powerful pain-relieving agentsknown (Fields, of RVM cells, the off-cells; and has no effect on a third class, 1987; Jaffe and Martin, 1990) produce their analgesiceffect neutral cells. In contrast, iontophoretic application of mor- through actions at CNS sites that include the midbrain peria- phine inhibits on-cells but does not alter the activity of either queductal gray (PAG) and the rostra1 ventromedial medulla off- or neutral cells. The present study addresses whether (RVM). The RVM, a region that includes nucleusraphe magnus the differential sensitivity to exogenous opioids is correlated and the adjacent ventromedial reticular formation (Basbaum with a differential termination pattern onto the three classes and Fields, 1984; Mason et al., 1990) is of particular interest of RVM neurons by afferents containing endogenous opioids. becauseit contains neurons that project to spinal and trigeminal Intracellular recordings were made from RVM neurons in dorsal horn laminae that are implicated in pain transmission. rats under light halothane anesthesia. Physiologically char- Endogenousopioid peptides were originally purified using a acterized neurons were injected with Neurobiotin and then bioassayfor opioid receptor activity and were subsequentlyde- subsequently visualized with a Texas red fluorophore. Thick fined as peptidescontaining the sequenceTyr-Gly-Gly-Phe-[Leu (50 Am) sections containing labeled RVM cells were pro- or Met] (Hughes, 1975; Akil et al., 1984; Simon, 1991). The cessed for enkephalin immunoreactivity (ENK-IR) using an three families of endogenousopioid peptides include peptides FITC fluorophore and then optically sectioned at 1.5 pm in- derived from proopiomelanocortin, prodynorphin, and proen- tervals using a dual-channel confocal laser scanning micro- kephalin. The contribution of endogenousopioid peptides to scope. ENK-IR appositions were found on the somata and the modulation of nociceptive transmissionis best understood dendrites of all on-cells. Although ENK-IR varicosities were for those peptides that are derived from proenkephalin. also apparently apposed to off- and neutral cells, the density The enkephalins, leu-enkephalin, met-enkephalin, and sev- of such appositions was significantly less than the density eral C-terminal extended forms of enkephalin, have a wide- of ENK-IR appositions onto on-cells. The greater overall den- spreaddistribution in the CNS (Murakami et al., 1987; Mansour sity of ENK-IR appositions onto on-cells was apparently due et al., 1988) and are concentrated in pain modulatory regions to a concentration of appositions on the soma and proximal of the brainstem including the RVM (Khachaturian et al., 1983; dendrites of these neurons. Williams and Dockray, 1983; Guthrie and Basbaum, 1984). These results support a model of RVM function in which Despite extensive literature on the enkephalinergic modulation endogenous opioid peptides produce an antinociceptive ac- of pain transmission (Azami et al., 1982; Akil et al., 1984; tion by a direct inhibitory action on on-cells that facilitate Dickenson and Le Bars, 1987; Randich et al., 1987; Basbaum nociceptive transmission. This on-cell inhibition may pro- and Besson, 199 1; Vaught, 1991), the mechanismsby which duce an additional antinociceptive effect by removing a pos- endogenousopioids produce antinociception in vivo remain ob- scure. Microinjections of metabolically stable synthetic enkephalin analogsinto the RVM produce antinociceptive effects both on Received Feb. 6, 1992; revised May 2 1, 1992; accepted May 26, 1992. nociceptive reflexes and on nociceptive dorsal horn cells (Geb- This research was supported by U.S. Public Health Service Grant NS-21445 (H-L-F.1 and bv the Bristol-Mvers Sauibb Foundation. P.M. was suonorted bv hart, 1982; Jensen and Yaksh, 1986). Furthermore, microin- \------ .I I U.S. Public Health Service Grant NS-07265 and by a presidential fellowship from jection of SCH326 15, a specificinhibitor of endopeptidase24.11, the University of California Board of Regents. We thank Drs. Y. N. Jan and L. into the RVM produces a dose-dependentantinociception that Y. Jan for the use of their confocal microscope and Larry Ackerman for assistance in its use. The authors also thank Sonja Potrebic for her assistance and comments, is reversed by systemic naloxone (Al-Rodhan et al., 1990) ev- Drs. Allan Basbaum and Peter Ralston for the use of equipment, Dr. Roger Nicoll idencethat endogenousenkephalins are releasedwithin the RVM for his comments on the manuscript, and Mechelle Williams for histological where they evoke an antinociceptive effect. Clearly, a further support. Correspondence should be addressed to Dr. Peggy Mason, Department of Neu- understanding of how endogenousopioids produce antinoci- rology, M-794, University ofcalifornia-San Francisco, San Francisco, CA 94143- ception requires knowledge of their actions upon the neurons 0114. “Present address: Department of Pharmacological and Physiological Sciences, of the RVM. University of Chicago, Chicago, IL 60637. The RVM contains at leastthree physiologically defined class- Copyright 0 1992 Society for Neuroscience 0270-6474/92/124023-14$05.00/O es of cells (Fields et al., 1983a, 1991). One classof RVM cells, 4024 Mason et al. l Enkephalin Appositions onto Identified RVM Neurons the off-cells, is excited by morphine administration (Fields et pinch. Feedback-controlled noxious thermal stimuli were applied to the al., 1983b; Cheng et al., 1986; Rosenfeld et al., 1990) and is tails of rats as described previously (Fields et al., 1983a; Mason et al., 1990). hypothesized to have a net inhibitory effect on nociceptive trans- Following electrophysiological characterization as described above, mission at the level of the dorsal horn (Fields et al., 199 1). On- neurons that were stably impaled were injected intracellularly with Neu- cells, in contrast, are inhibited by systemic morphine and are robiotin using a constant depolarizing current of l-5 nA for at least 4 activated during periods of increased responsiveness to noxious min (adapted from Horikawa and Armstrong, 1988). In cases where the injected neuron was still impaled after the original 4 min, depolarizing stimuli, evidence that these neurons have a net excitatory effect current was injected for another 2-10 min. on dorsal horn nociceptive transmission (Heinricher et al., 1989; After the recording session, animals were killed by pentobarbital over- Bederson et al., 1990). A third class of RVM neurons, neutral dose and perfused with saline followed by a fixative containing 4.0% cells, do not respond to noxious peripheral stimulation or mor- paraformaldehyde and 0.2% glutaraldehyde with 7% sucrose in 0.1 M phine; their function, with regard to nociceptive modulation, is phosphate-buffered saline (PBS). The tissue was blocked coronally and then immersed in 30% sucrose in 0.1 M PBS overnight. Serial transverse unclear. About 30% of on-, off-, and neutral cell populations sections, 50 pm thick, were then cut on a freezing microtome. can be antidromically driven by dorsolateral funiculus stimu- All sections were reacted in 0.4% avidin conjugated to Texas red lation, evidence that members of each class project to the spinal (Vector Labs) and 0.5% Triton X-100 in 0.1 M PBS for 4 hr at 4°C. cord (Vanegas et al., 1984). After rinsing the sections in PBS, the sections were examined under a The cellular mechanisms by which RVM neurons respond to fluorescent microscope. Sections containing labeled neurons, including adjacent sections both rostra1 and caudal to the soma, were then further exogenous opioids are of obvious interest and importance in processed for enkephalin immunocytochemistry. understanding the endogenous opioid modulation of nocicep- The primary antibody employed in the present study was raised against tive transmission. Iontophoretically applied morphine inhibits leu-enkephalin (Sera Labs). Since this monoclonal antibody was raised RVM on-cells (Heinricher et al., 1992). In contrast, although against the NH, terminal of the opioid peptide, it also recognizes met- enkephalin and has substantial cross-reactivity to several C-terminal- systemic, midbrain, or RVM microinjection ofmorphine excites extended enkephalin peptides (Cue110 et al., 1984). However, the an- off-cells, iontophoretic morphine has no effect on off-cell dis- tibody has no detectable cross-reactivity with fl-endorphin or charge, evidence that opioid excitation of off-cells is indirect. dynorphin,_,,. Morphine, administered by iontophoresis, microinjection into The protocol used for enkephalin immunocytochemistry involved is the midbrain, or systemically, has no effect on neutral cells. brieflv described below. Sections were incubated in 0.1 M lvsine in PBS containing
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