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The Journal of Neurophysiology Vol. 78 No. 6 December 1997, pp. 3351-3358
Copyright ©1997 by the American Physiological Society
1 Division of Neurosurgery, 2 Department of Physiology and Pharmacology, and 3 Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Heinricher, M. M., S. McGaraughty, and D. K. Grandy. Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla. J. Neurophysiol. 78: 3351-3358, 1997. Several laboratories recently identified a 17 amino-acid peptide, termed "nociceptin" or "orphanin FQ (OFQ)", as the endogenous ligand for the LC132 (or "opioid receptor-like1") receptor. Taken together with the fact that the cellular effects of OFQ are to a large extent opioid-like, the close relationship between the LC132 receptor and known opioid receptors raised expectations that the behavioral effects of this peptide would resemble those of opioids. However studies of the role of OFQ in nociception have not provided a unified view. The aim of the present study was to use a combination of electrophysiological and pharmacological techniques to characterize the actions of OFQ in a brain region in which the circuitry mediating the analgesic actions of opioids has been relatively well characterized, the rostral ventromedial medulla (RVM). Single-cell recording was combined with opioid administration and local infusion of OFQ in the RVM of rats lightlyanesthetized with barbiturates. The tail flick reflex was used as a behavioral index of nociceptive responsiveness. Two classes of physiologically identifiable RVM neurons with distinct responses to opioids have been characterized. OFF-cells are activated, although indirectly, by opioids, and there is strong evidence that this activation is crucial to opioid antinociception. ON-cells, thought to enable nociception, are directly inhibited by opioids. Cells of a third class, NEUTRAL cells, do not respond to opioids and whether or not they have any role in nociceptive modulation remains an open question. OFQ infused within the RVM profoundly suppressed the firing of all classes of RVM neurons, blocking opioid-induced activation of OFF-cells. The antinociceptive effects of a µ-opioid agonist infused at the same site were significantly attenuated in these animals. Those of systemically administered morphine, which can produce its antinociceptive effects by acting at a number of CNS sites, were not blocked by RVM OFQ. Inasmuch as activation of OFF-cells can account for the antinociceptive action of opioids within the RVM, these results demonstrate that, at least within the medulla, OFQ can exert a functional "antiopioid" effect by suppressing firing of this cell class. However to the extent that antinociceptive and pronociceptive outflows from various brain regions involved in both transmission and modulation of nociception are active under different conditions, focal application of OFQ in different regions could potentially produce either hypalgesia or hyperalgesia.
Several laboratories recently identified a 17 amino-acid peptide, termed "nociceptin" or "orphanin FQ (OFQ)", as the endogenous ligand for the LC132 (or "opioid receptor-like1") receptor, a G-protein coupled receptor structurally related to the previously characterized µ-, Animals and surgical preparation
Male Sprague-Dawley rats (250-300g; Bantin and Kingman, Hayward, CA) were anesthetized with pentobarbital sodium (60 mg/kg, ip) and catheters were inserted into external jugular veins for administration of anesthetic and, in some experiments, morphine. The rat was placed in a stereotaxic apparatus, a hole drilled in the skull over the cerebellum, and the dura removed to allow placement of an electrode assembly in the medulla. Body temperature was maintained at ~37°C by a circulating water pad.
Nociceptive testing
TF latency was used as a measure of nociceptive responsiveness. The heat was applied to spots 2, 3, or 4 cm from the tip of the tail in succession. Each trial consisted of a linear increase in temperature at ~1.8°C/s from a holding temperature of 34°C until the TF occurred or to a maximum of 53°C at 10.6 s. TF inhibition was defined as no response before the cutoff latency of 10.6 s.
Recording and drug administration
A gold- and platinum-plated stainless steel recording microelectrode (Frederick Haer, Brunswick, ME) was glued parallel to a single-barrel glass infusion pipette with a 75-80 µm tip (OD) in such a way that the tips were separated by 100-300 µm. This separation allowed us to reliably maintain well-isolated recordings of single neurons during and after infusions of 200 nl of saline vehicle or drug solution in the RVM. The assembly was oriented in the electrode carrier so that the assembly straddled the midline, with both electrode and infusion pipette within the RVM. The infusion pipette was attached to a 1-µl Hamilton syringe with a length of PE-50 tubing for drug infusion.
Protocol and data analysis
Cell activity was monitored and stored for off-line analysis (Datawave Systems, Thornton, CO) before and after infusions into the RVM. Except for two experiments in which two easily distinguished neurons were simultaneously recorded on a single electrode, only one cell was studied in each experiment. TF trials were initiated at 5-min intervals. In one set of experiments, we determined the effect of OFQ (Phoenix, Mountain View, CA) infused into the RVM on TF latencies, on cell activity, and on the ability of systemically administered morphine to inhibit the TF and alter RVM neuronal activity. Pilot studies indicated that inhibitory effects of OFQ on RVM neuron activity were 40-60 min in duration. Therefore after three baseline trials, OFQ (20 or 40 pmol in 200 nl physiological saline) was infused into the RVM over a period of ~4 min, and TF latencies and cell activity monitored for the next 15 min. Morphine sulfate (0.75 or 1.5 mg/kg, iv) was then given and TF latency and cell activity monitored for an additional 30 min. The effects of OFQ on systemic morphine analgesia were compared with those of the Analysis of cell activity
Cell activity integrated over the 30 s before each TF trial was used as an overall index of ongoing firing. Ongoing firing rates at postdrug time points were then compared with those during baseline. The TF-related ON-cell burst was quantified by determining mean firing rate in a 3-s interval beginning 0.5 s before the flick or, in cases in which the TF was inhibited by opioid administration, in an interval aligned with mean TF latency during baseline. Data are presented as means ± SE. Nonparametric tests and Student's t-test were used for statistical analysis of results; P < 0.05 was considered significant.
Histology
At the conclusion of the experiment, recording sites were marked with an electrolytic lesion. Animals were killed with an overdose of methohexital and perfused intracardially with physiological saline followed by 10% formalin. Recording and infusion sites were histologically verified and plotted on standardized sections (Paxinos and Watson 1986
OFQ Suppresses the firing of all three physiologically identified classes of neurons in RVM
Six OFF-cells, seven ON-cells, and five NEUTRAL cells were recorded in 16 successful experiments. As shown in the examples in Fig. 1, local nanoinfusion of OFQ consistently resulted in a rapid and nearly complete suppression of firing of all three classes of RVM neurons, with the majority of cells of all three classes showing no active periods (Barbaro et al. 1989 OFQ applied within the RVM interferes with the ability of DAMGO applied at the same site to activate OFF-cells and inhibit the tail flick
Given that activation of OFF-cells is a critical step in the complex mechanism of opioid antinociception within the RVM and knowing that OFQ suppresses the activity of these neurons, one might expect that OFQ could block the antinociceptive actions of opioids applied locally within the RVM. To test this, the effects of the µ-opioid agonist DAMGO alone (128 pmol) on TF latency and cell activity were compared with those of DAMGO (128 pmol) plus OFQ (40 pmol). Nine cells of each class were recorded in 29 experiments. (This includes two experiments in which a cell was not successfully recorded and only TF data were used).
OFQ applied within the RVM does not block systemic morphine analgesia
OFQ given in the cerebral ventricles in mice blocks the antinociceptive effects of systemically administered morphine (Mogil et al. 1996a
OFQ also suppresses neuronal activity in medullary regions outside of the RVM
Finally, to determine whether or not the effects of OFQ within the medulla were selective for the RVM, we recorded the activity of neurons outside of the RVM, in two cases at the border of the facial nucleus and in one case in nucleus reticularis gigantocellularis. All three neurons showed responses comparable with those of RVM neurons (data not shown).
The present studies demonstrate that local infusion of OFQ within the RVM suppresses the firing of each of the three physiologically defined classes of neurons found in this region and in so doing, blocks the antinociceptive effects of a µ-opioid agonist applied at the same site.
Methodological issues
Because no specific LC132 receptor antagonist is yet available, it is not possible to demonstrate conclusively that the observed effects of OFQ were mediated by an action at this receptor. However the depressive effect of OFQ in the RVM is not likely to have been mediated via a µ-opioid receptor, because neither OFF-cell nor NEUTRAL cell firing is depressed by DAMGO infusion within the RVM (Heinricher et al. 1994 Lack of effect of RVM OFQ on TF latency
In this study direct focal application of OFQ within the RVM, a region well known to be important in pain modulation, had no effect on the latency of the TF response. Our results in rat are thus consistent with those of Mogil and colleagues (Mogil et al. 1996a OFQ interactions with opioids
In general the supraspinal actions of opioids involve activating a nociceptive modulating outflow that exerts an antinociceptive effect (Fields and Heinricher 1985
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
-, and 
-opioid receptors. Because of the close relationship between the LC132 receptor and known opioid receptors, and because OFQ has significant homologies with previously described opioid peptides, initial behavioral studies of OFQ focused on a potential role for this peptide in nociception (Bunzow et al. 1994
; Meunier et al. 1995; Reinscheid et al. 1995). Although early reports suggested that OFQ produced an increase in nociceptive responsiveness when injected intracerebroventricularly (icv) in awake mice (Meunier et al. 1995; Reinscheid et al. 1995; Rossi et al. 1996), subsequent studies indicated that OFQ had no effect on nociceptive responsiveness per se, but rather reversed an opioid-mediated, "stress-induced" hypalgesia presumably related to the icv injection procedure (Mogil et al. 1996). OFQ also interferes with the supraspinal analgesic actions of exogenous opioids (Grisel et al. 1996; Mogil et al. 1996a,b).
-, and -opioid receptors (Connor et al. 1996a,b; Meunier et al. 1995; Reinscheid et al. 1995; Vaughan and Christie 1996). The apparent disparity between behavioral and cellular effects of OFQ suggests that the explanation of the "antiopioid" action of this peptide lies at the level of neuronal circuits. It would thus seem useful to characterize the actions of OFQ in a brain region in which the circuitry mediating the analgesic actions of opioids has been analyzed in some detail.
; Fields et al. 1983, 1991; Fields and Heinricher 1985; Heinricher et al. 1992, 1994). ON-cells are defined by a sudden increase in firing just before the occurrence of nociceptive reflexes. ON-cells are directly inhibited by opioids. However suppression of ON-cell firing is not sufficient to account for the analgesic actions of opioids within the RVM, because complete inactivation of the RVM does not reduce nociceptive responses (Lovick 1985; Proudfit 1980a,b; Randich et al. 1992; Young et al. 1984). OFF-cells characteristically display an abrupt pause in firing just before the occurrence of nociceptive reflexes. These cells are invariably activated, via disinhibition, after local or systemic administration of opioids in doses sufficient to produce inhibition of nociceptive reflexes. Disinhibition of OFF-cells is sufficient to produce a behaviorally measurable antinociception (Heinricher et al. 1994; Heinricher and Tortorici 1994). Cells of a third class, NEUTRAL cells, show no response to noxious stimulation or to opioids. The role of this cell class in nociceptive modulation, if any, is unknown.
; Heinricher and Tortorici 1994), blocking OFF-cell activation should also prevent the behavioral antinociception.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
).
). Spike waveforms were monitored and stored for off-line analysis to ensure that the unit under study was unambiguously discriminated throughout the experiment and to verify that the peptide did not have local anesthetic effects. Spike times were stored with a temporal resolution of 0.1 ms. ON-cells were identified by a sudden burst of activity beginning just before the occurrence of the TF. They were also excited by noxious pinch over wide receptive fields that included the four paws and most of the body, and, in most cases, by firm stroking of the hairy skin of the back and flank. OFF-cells were characterized by an abrupt pause in ongoing activity beginning just before the occurrence of the TF and also responded to noxious pinch and very often to firm stroking on the hairy skin of the back and flanks. NEUTRAL cells showed no change in activity associated with the tail flick or with noxious or innocuous somatic stimulation.
-aminobutyric-A (GABAA) receptor agonist tetrahydroioxazolo[5,4-C]pyridin-3-ol hydrochloride (THIP; RBI, Natick, MA) in seven experiments. In a second set of experiments, the ability of OFQ to block the actions of the µ-selective opioid peptide [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO; RBI) infused directly into the RVM was tested. In these experiments DAMGO (128 pmol) or a mixture of OFQ (40 pmol) and DAMGO (128 pmol in 200 nl saline) was infused over a period of ~4 min. This dose of DAMGO was derived from previous experiments using this paradigm (Heinricher et al. 1994). TF trials were then continued at 5-min intervals. Cell activity and TF latencies were generally monitored for an additional 45 min (i.e., 9 postinfusion TF trials).
). The RVM was defined as comprising the nucleus raphe magnus as well as the laterally adjacent reticular formation at the level of the facial nucleus, including the nucleus reticularis gigantocellularis pars alpha and nucleus paragigantocellularis lateralis. To determine whether or not the observed effects of OFQ were specific for the RVM, the recording and injection assembly was placed laterally, in nucleus reticularis gigantocellularis or at the border of the facial nucleus, in three experiments.
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FIG. 1.
Ratemeter records demonstrate characteristic effect of orphanin FQ (OFQ) infusion on activity of rostral ventromedial medulla (RVM) neurons. Before OFQ infusion (40 pmol), each cell showed substantial ongoing and, in case of ON-cell, TF-related, activity. These discharges were rapidly and profoundly inhibited by infusion of OFQ into RVM. Subsequent systemic morphine administration (MS; 1.5 mg/kg, iv) resulted in TF inhibition. OFF-cell (top) showed substantial recovery beginning 25 min after OFQ infusion. This likely reflected, at least in part, activating effect of systemically administered morphine on this cell class. 
, tail flick (TF) occurred within cutoff time; 
, no TF occurred on that trial after systemic morphine administration. Bins of 1 s.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
) in the 10 min period after infusion of 20 (n = 4) or 40 (n = 12) pmol OFQ. By the end of the observation period (45 min post-OFQ), approximately one-third of the neurons showed substantial return of activity.
2, P < 0.01) and then not until over35 min postinfusion, presumably because the OFQ inhibition was waning at that point. Thus coadministration of OFQ significantly attenuates the antinociceptive effect of DAMGO applied within the RVM.
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FIG. 2.
Ratemeter records comparing typical effects of OFQ/DAMGO infusion (left) with those of DAMGO alone (right) on OFF- and ON-cells and NEUTRAL cells in RVM. Infusion of OFQ/DAMGO mixture produced a decrease in cell activity in all cases, but did not inhibit TF reflex. In contrast, DAMGO alone caused OFF-cell to become continuously active, suppressed ON-cell firing, and had no effect on NEUTRAL cell firing. (Note transient volume effect on NEUTRAL cell activity.) Filled triangles, TF occurred within cutoff time; open triangles, no TF occurred on that trial. Note that this occurred only after infusion of DAMGO alone. Bins of 1 s.
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FIG. 3.
Summary of effects of DAMGO and OFQ/DAMGO mixture on firing of RVM neurons. As previously demonstrated (Heinricher et al. 1994 ), DAMGO infused into RVM activated OFF-cells, suppressed ON-cell firing, and had no effect on NEUTRAL cells. When OFQ was combined with DAMGO, all 3 classes showed a decrease in activity. (*: P < 0.05, Mann-Whitney U test, comparison of DAMGO alone with OFQ/DAMGO mixture. Only OFF-cells and NEUTRAL cells were differentially affected by 2 treatments. There were no significant differences between 2 groups in predrug baseline for any cell class.)
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FIG. 4.
Histologically verified locations of ON-cells ( ), OFF-cells (
), and NEUTRAL cells (
) in experiments in which OFQ/DAMGO mixture or DAMGO was infused into RVM. VII, facial nucleus.
). However in the present experiments, focal application of OFQ restricted to the RVM did not prevent the antinociceptive effects of systemically administered morphine. Morphine (1.5 mg/kg, iv) was given to 13 animals 15 min after infusion of OFQ (40 pmols) into the RVM. The TF was inhibited in all animals, with mean time to first trial at cutoff 5.4 ± 0.4 min.
), also failed to block the ability of systemically administered morphine to inhibit the TF. Recording and infusion sites are shown in Fig. 6.
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FIG. 5.
Summary of OFQ and subsequent systemic administration of morphine effects on activity of ON- and OFF-cells and NEUTRAL cells. Activity of all 3 classes was almost completely suppressed by OFQ and remained depressed after systemic morphine administration. There was thus no difference between post-OFQ and post-MS activity for any cell class. (*: P < 0.05, Friedman's test, compared with baseline.)
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FIG. 6.
Histologically verified locations of ON-cells ( ), OFF-cells (), NEUTRAL cells (), and non-RVM neurons (
) in experiments in which OFQ was infused into RVM or adjacent reticular regions before systemic administration of morphine. VII, facial nucleus; IO, inferior olive.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). Moreover potent inhibition is consistent with the effects of OFQ seen in other brain regions in in vitro studies (Connor et al. 1996a; Vaughan and Christie 1996; Vaughan et al. 1997).
; Fields and Heinricher 1985). On the other hand, the relationship between activity of NEUTRAL cells and that of ON- or OFF-cells is completely unknown and it is not impossible that activity in the NEUTRAL cell population is required to maintain activity of either ON- or OFF-cells. If so, the decrease in activity of either ON- or OFF-cell classes could be secondary to inhibition of NEUTRAL cells. Clearly, further experiments using iontophoresis will be required to address this issue.
,b) who found that the nociceptive responses of mice given OFQ icv were not different from untreated controls in which a stress-induced hypoalgesia was not produced as part of the experimental procedure. However given the neuronal effects of OFQ in RVM, the lack of effect on TF latency was somewhat surprising in that local infusion of GABAA receptor agonists, which should also inhibit all three classes of RVM neurons, can produce a decrease in TF latency under some conditions. However the dose-response curves for both GABAA and -aminobutyric acid-B (GABAB) receptor agonists within the RVM are not monotonic, most likely because of the differential role of GABA in controlling the firing of the different cell classes and because relative activity in the three cell classes is likely to vary in different conditions (Drower and Hammond 1988; Heinricher et al. 1991; Heinricher and Kaplan 1991; Heinricher and Tortorici 1994; McGaraughty et al. 1993; Oliveras et al. 1989, 1991a,b; Thomas et al. 1995). It is thus possible that a hyperalgesic effect of OFQ would be revealed in more complete behavioral studies of the OFQ dose-response relationship in RVM.
; Heinricher et al. 1994; Johnson and North 1993; Nicoll et al. 1990; North 1992). Any compound that suppresses activity in this antinociceptive outflow would thus prevent opioid analgesia. -Aminobutyric acid (GABA) for example, was shown to antagonize the antinociceptive actions of opioids within the PAG (Depaulis et al. 1987; Moreau and Fields 1986). In the RVM, where both direct and indirect actions of opioids relevant to pain modulation have been characterized, the indirect activation of OFF-cells was shown to be the crucial step in opioid action (Heinricher et al. 1994; Heinricher and Tortorici 1994). Thus the OFQ blockade of the antinociceptive actions of DAMGO applied within the RVM is most easily explained by the fact that OFQ suppresses OFF-cell firing, preventing opioid disinhibition from producing an activation of these neurons. Although ON-cell firing is also suppressed by OFQ, these cells are similarly inhibited, directly, by opioids (Heinricher et al. 1992). Inasmuch as OFQ and µ-opioid agonists have the same net effect onON-cells, it seems unlikely that the suppression of ON-cell firing by OFQ mediates the attenuation of opioid antinociception by this peptide. Indeed suppression of ON-cell firing would by itself be expected to have an antinociceptive effect under some conditions (Fields 1992). Finally NEUTRAL cell firing was also suppressed by OFQ. However whether or not NEUTRAL cells have any role in pain modulation has yet to be determined, as these neurons do not respond to noxious stimulation or to opioids (Barbaro et al. 1986; Fields et al. 1983; Heinricher et al. 1992). Nevertheless the possibility that ongoing activity in NEUTRAL cells is required in order for opioid-induced changes in ON- and OFF-cell firing to have an antinociceptive effect cannot be ruled out. If this were the case, the suppression of NEUTRAL cell firing by OFQ would contribute to the block of opioid analgesia by this peptide.
,b) and with the present observation that focal inactivation of the RVM with the GABAA receptor agonist THIP also did not interfere with the ability of systemic morphine administration to inhibit the TF. Thus the RVM is a sufficient (as indicated by the observation that microinjection of opioids within the RVM produces analgesia), but not necessary substrate for analgesia after systemic opioid administration in this lightly anesthetized preparation. In contrast, when OFQ is administered intracerebroventricularly in awake mice, it produces a potent block of the antinociceptive effects of systemically administered morphine (Grisel et al. 1996; Mogil et al. 1996). Presumably this is because morphine given systemically acts at multiple sites in brain as well as in spinal cord (Yaksh et al. 1988) and the icv route of administration gives the peptide access to more of the opioid-sensitive regions involved in pain modulation than with local application method used here. Species differences may also be important.
). Indeed recent studies suggest roles for OFQ in feeding, reward systems, learning, and motor control (Devine et al. 1996; Florin et al. 1996; Kapusta et al. 1997; Murphy et al. 1996; Pomonis et al. 1996; Sandin et al. 1997; Stratford et al. 1997). Nevertheless we have shown that exogenous OFQ can exert a functional antiopioid action in one discrete pain modulating circuit by inhibiting an outflow crucial to the antinociceptive actions of opioids. Whether or not endogenous OFQ is released by opioids to exert an antiopioid effect however, remains an open question. It should also be noted that the behavioral effects of OFQ within the RVM could be very different under other conditions. For example during naloxone-precipitated withdrawal from opioids, activation of ON-cells is associated with a behavioral hyperalgesia (Bederson et al. 1990; Kaplan and Fields 1991). In this situation, infusion of OFQ into the RVM could, by inhibiting ON-cells and thus removing a pronociceptive influence, produce a net decrease in behaviorally measured nociceptive responsiveness. Moreover other CNS regions in which OFQ modulates nociception or opioid-induced antinociception remain to be determined. Interactions between OFQ and the antinociceptive actions of opioids within the PAG have not been examined. However OFQ was reported to increase a potassium conductance in all PAG neurons tested (Vaughan et al. 1997). Given a potent inhibitory effect of OFQ throughout the PAG, it would not be surprising if OFQ were to interfere with the antinociceptive actions of opioids within this region, as was previously shown with GABA (Depaulis et al. 1987; Moreau and Fields 1986). At the level of the dorsal horn, the predominant reported effect of OFQ in electrophysiological experiments is also inhibition (Faber et al. 1996; Stanfa et al. 1996; Wang et al. 1996). Thus because opioids act in the spinal cord to suppress nociceptive transmission directly (rather than activating an antinociceptive outflow as is the case in the RVM), it should not be surprising that OFQ given intrathecally fails to attenuate systemic or intrathecal morphine analgesia (Grisel et al. 1996). Indeed a number of groups report that intrathecal administration of OFQ produces analgesia (Hao et al. 1997; King et al. 1997; Tian et al. 1997; Xu et al. 1996).
), demonstrating that an antisense oligonucleotide to the LC132 receptor produced a measurable decrease in responsiveness on the hot plate test, would be consistent with the idea that endogenous OFQ interferes with nociceptive modulation under certain physiological conditions. However a more complete understanding of the role of endogenous OFQ will require development of an antagonist that will allow acute block of the actions of the peptide in specific brain regions, with parallel analysis of behavioral effects and underlying neuronal circuits.
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ACKNOWLEDGEMENTS |
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We thank D. A. Farr for technical assistance.
This work was supported by National Institute of Drug Abuse (NIDA) Grants DA-05608 and DA-08562 as well as grants from the National Headache Foundation and the Markey Charitable Trust. S. McGaraughty was supported by a NIDA International Visiting Scientist and Technical Exchange Program fellowship.
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FOOTNOTES |
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Address for reprint requests: M. M. Heinricher, Division of Neurosurgery, L-472, Oregon Health Sciences University, Portland, OR 97201.
Received 13 June 1997; accepted in final form 25 August 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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or opioid receptor type.
FEBS Lett.
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