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-Adrenergic and Cholinergic Mechanism
Department of Anesthesia, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1009
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Xu, Zemin, Chuanyao Tong, Hui-Lin Pan, Sergio E. Cerda, and James C. Eisenach. Intravenous morphine increases release of nitric oxide from spinal cord by an 
-adrenergic and cholinergic mechanism. J. Neurophysiol. 78: 2072-2078, 1997. Systemic opioids produce analgesia in part by activating bulbospinal noradrenergic pathways. Spinally released norepinephrine (NE) has been suggested to produce analgesia in part by stimulating 2-adrenoceptors on cholinergic spinal interneurons to release acetylcholine (ACh). We hypothesized that this spinally released ACh would stimulate synthesis of nitric oxide (NO), and that spinally released NO after intravenous (IV) opioid injection thus would depend on a cascade of noradrenergic and cholinergic receptor stimulation. To test these hypotheses, IV morphine was administered to anesthetized sheep, and neurotransmitters in dorsal horn interstitial fluid were measured by microdialysis. IV morphine increased NE and ACh in dorsal horn microdialysates, and these increases were inhibited by IV naloxone or cervical spinal cord transection. IV morphine also increased dorsal horn microdialysate concentrations of nitrite, a stable metabolite of NO. Increases in NE, ACh, and nitrite were antagonized by prior intrathecal injection of the 2-adrenergic antagonist idazoxan, the muscarinic antagonist atropine, or the NO synthase inhibitor N-methyl-L-arginine (NMLA). To examine the concentration-dependent effects of spinal adrenergic stimulation, isolated rat spinal cord tissue was perfused with the 2-adrenergic agonist clonidine. Clonidine increased nitrite in the spinal cord tissue perfusate, an effect blocked by coadministration of idazoxan, atropine, and NMLA. These data support a previously hypothesized cascade of spinally released NE and ACh after systemic opioid administration. These data also suggest that spinally released NO plays a role in the analgesic effects of systemic opioids. In addition, these data imply a positive feedback whereby spinally released nitric oxide increases NE release and that has not previously been described.
Opioids produce analgesia by actions at several sites, but a major mechanism involves activation of bulbospinal inhibitory, primarily serotonergic (Yaksh and Tyce 1979 Animal preparation
Following animal care and use committee approval, microdialysis experiments were performed on a total of 27 ewes of mixed Western breeds (weight range, 40-50 kg). Sheep were chosen because of their larger spinal cord than rodents, allowing precise localization of microdialysis catheters and destruction of relative less spinal cord tissue by the catheters. The animals were fasted for 24 h, then anesthesia was induced with ketamine (5-10 mg/kg im). The trachea was intubated and anesthesia maintained with halothane, 1-2%, in oxygen by controlled ventilation. Polyvinyl catheters were inserted into a femoral artery and vein under direct vision and advanced 15 cm centrally. The animal was positioned prone and a small laminectomy was performed at the lumbosacral junction to expose a 1-cm diameter patch of dura. A 21-gauge polyvinyl catheter was inserted under direct vision through a small nick in the dura and advanced 25 cm cephalad so that its tip was at the midthoracic level. All incisions were closed, the catheters were placed in a canvas pouch sewn to the flank and the ewe was allowed to awaken. At least 3 days passed before the experimental study. During this time the animals received daily penicillin G (900,000 units im).
Surgical procedure
On the day of the experiment, after a 24-h fast, anesthesia was induced with thiopentone sodium (5 mg/kg IV) and maintained with halothane, 1-2%, during the surgical preparation. Subsequently during the microdialysis experiment, anesthesia was maintained with halothane, 0.5%, in oxygen by controlled ventilation and muscle relaxation with pancuronium (0.1 mg/kg IV, every 2 h). Ventilation was adjusted to keep PaCO2 within a normal range by continuous monitoring of end tidal CO2 and intermittent monitoring of arterial blood gas tensions. Blood pressure and heart rate were continuously monitored via the femoral artery catheter and recorded throughout the experiment.
Microdialysis procedure
Microdialysis probes were prepared within 3 days of surgical implantation using hollow fiber bundles (Spectrum, Los Angeles, CA) with an internal diameter of 150 µm and a molecular weight cutoff rate of 9,000 Da. The window of active membrane for exchange was defined precisely using two pieces of silica tubing (SGE, Ringwood, Australia), which were inserted through each end of the hollow fiber and advanced so that the tips of each silica tube were separated by 4 mm, corresponding to the length necessary to cover the two dorsal horns of the thoracic spinal cord. The junctions between the silica tubing and the hollow dialysis fiber were sealed using acrylic glue (Borden, Columbus, OH). A wire, 0.035 mm OD (Fisher Scientific, Pittsburgh, PA), was inserted and sealed on one end of the probe and the free end sharpened, thereby allowing penetration of the probe through the dura mater and cord with minimal tissue damage. After insertion, the portion of the silica tubing connected to the wire was cut and removed to allow perfusion. The inlet of the probe was perfused continuously via a pump at a rate of 2 µl/min with artificial CSF at the following composition (in mM): 145 NaCl, 2.7 KCl, 1.0 MgCl2, 1.2 CaCl2, and 2.0 Na2HPO4 in filtered deionized water.
Neurochemical assays
After collection, samples were fast frozen to Spinal cord tissue perfusion
To examine the interactions at the spinal level of noradrenergic, cholinergic, and nitrergic activation without the confounding factors of effects of compounds on blood flow or distribution to supraspinal sites, a spinal cord perfusion method was developed. Adult male Sprague-Dawley rats were euthanized with sodium pentobarbital (50 mg/kg ip) and the spinal cord removed. Each spinal cord was divided into two parts, then chopped in 0.5-mm slices. Tissue sections from each hemispinal cord were put into an incubation chamber surrounded by a temperature-controlled water bath maintained at 37°C. Tissue slices were perfused continuously with a multichannel pump at 0.5 ml/min with oxygenated modified Krebs-Henseleit solution [composition (in mM) was 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3, 0.027 ethylenediamine tetraacetic acid (EDTA), 5 N-2-hydroxyethylpiperazine-N Drugs
Drugs for intrathecal injection were dissolved in sterile 0.9% saline. Atropine, clonidine, idazoxan, naloxone, NMDA, NMLA, and yohimbine were purchased from Sigma Chemical (St. Louis, MO). Halothane, ketamine, pancuronium bromide, penicillin G, thiopentone sodium, and methylene blue, were obtained from Barber Veterinary Supply, Richmond, VA.
Data analysis
Data are presented as means ± SE if normally distributed and as median ± 25th and 75th percentiles if not normally distributed. Within groups values of nitrite, ACh or NE were compared with baseline by one-way Kruskal-Wallis analysis of variance (ANOVA) on ranks followed by Dunnett's test. The groups were compared with these variables by two-way nonparamentric ANOVA followed by Newman-Keuls test. P < 0.05 was considered statistically significant.
Microdialysis studies
All animals recovered normally from intrathecal catheter insertion, and none exhibited behavioral deficits on the day of the experiment. Arterial blood gas tensions and pH and arterial blood pressure remained stable and within normal limits for sheep throughout the experiment in all animals.
EFFECT OF IV MORPHINE ALONE.
IV morphine increased NE, ACh, and nitrite in dorsal horn microdialysates (Figs. 1-3). In each case, the time course was similar with a statistically significant increase in neurotransmitter at the first sample (30 min) after IV morphine injection and continued increase for 2 h after morphine injection. Microdialysate concentrations of NE, ACh, and nitrite after cervical cord transection were similar to those in sheep with intact spinal cord (median value in intact vs. spinal cord transected animals 0.26 vs. 0.18 pmol/µl for NE, 4.5 vs. 9.5 fmol/µl for ACh, and 16 vs. 19 nmol/µl for nitrite). However, NE, ACh, and nitrite failed to increase after IV morphine in animals with cervical cord transection (maximum concentrations for NE of 0.17 pmol/µl, for ACh of 9.5 fmol/µl, and for nitrite of 19 nmol/µl). Similarly, pretreatment with IV naloxone did not affect basal concentrations of NE (0.27 pmol/µl) or ACh (11 fmol/µl) but blocked the increase in both NE (maximum concentration 0.37 pmol/µl) and ACh (maximum concentration 15 fmol/µl) after IV morphine.
EFFECT OF A2-ADRENERGIC ANTAGONISTS.
Idazoxan, in a dose shown to antagonize the hemodynamic effects of clonidine in unanesthetized sheep (Eisenach and Tong 1991 EFFECT OF CHOLINERGIC ANTAGONISM AND NOS INHIBITION.
Intrathecal pretreatment with the muscarinic antagonist, atropine, blocked morphine-induced increases in nitrite and NE in dorsal horn microdialysates (Figs. 1 and 3). Intrathecal injection of the NOS inhibitor, NMLA, blocked morphine-induced increases in nitrite, NE, and ACh in dorsal horn microdialysates (Figs. 1-3).
Spinal cord tissue perfusion studies
Perfusion of spinal cord slices with clonidine produced a concentration-dependent increase in nitrite in perfusate, with no further increase in nitrite concentration with perfusion of clonidine at concentrations >10
The two major findings of the current study are the increase in spinal cord microdialysate concentrations of nitrite after IV morphine administration and the blockade by idazoxan, atropine, and NMLA of increased NE in these microdialysates. Each of these observations provides novel information on the mechanism of action of systemically administered opioids.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
) and noradrenergic (Tyce and Yaksh 1981) pathways. Thus systemic or intracerebral administration of opioids increases norepinephrine (NE) concentrations in lumbar cerebrospinal fluid (CSF) (Tyce and Yaksh 1981) and microdialysates from spinal cord dorsal, but not ventral horn (Bouaziz et al. 1996). This spinally released NE produces analgesia by stimulation of 2-adrenoceptors, because analgesia from spinally administered NE (Howe et al. 1983) or from centrally administered opioids (Tseng and Tang 1989) is blocked by spinal injection of -adrenergic antagonists. In addition, augmentation of synaptic NE availability by inhibition of NE reuptake in the spinal cord potentiates analgesia from centrally administered morphine (Taiwo et al. 1985).
2-adrenergic agonists increases ACh concentrations in CSF (Detweiler et al. 1993) and microdialysates from spinal cord dorsal but not ventral horn (Klimscha et al. 1995). Acetylcholine produces analgesia when administered spinally, an effect blocked by muscarinic receptor antagonists (Yaksh et al. 1985). Furthermore, centrally administered opioids increase ACh concentrations in CSF and spinal cord dorsal horn microdialysates (Bouaziz et al. 1996), and analgesia from central opioid injection is partially reversed by spinal injection of muscarinic receptor antagonists (Dirksen and Nijhuis 1983).
; Zhuo et al. 1993). In this regard, ACh has been shown to stimulate release of a vasorelaxant from spinal cord tissue in vitro that shares the pharmacology of NO (Xu et al. 1996b), and analgesia from intrathecal injection of muscarinic receptor agonists is blocked partially by NO synthase (NOS) inhibitors (Iwamoto and Marion 1994a). These results suggest that spinally released NO may play a role in analgesia produced by intravenous (IV) morphine, involving a cascade of NE and ACh.
). Systemically administered NOS inhibitors enhance, rather than inhibit, analgesia from systemically administered opioids (Yamaguchi and Naito 1996). Similarly, systemically administered NOS inhibitors prevent the development of tolerance from systemically administered opioids (Kolesnikov et al. 1992). Although these studies support a pronociceptive effect of spinally released NO under pathological conditions and opposing effects of opioids and NO with systemic administration, previous studies have not addressed the interaction between systemic opioids and spinal NOS activity.
2-adrenergic antagonist would block the IV morphine-induced spinal release of ACh and NO and that intrathecal injection of a cholinergic receptor antagonist or a NOS inhibitor would block the increase in spinal NO after intravenous morphine. To avoid confounding factors of agents on tissue blood flow and redistribution in vivo, more detailed concentration-response studies also were performed on rat spinal cord tissue in vitro.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
20°C and stored at 70°C until assay. NE concentrations were determined by high pressure liquid chromatography (HPLC) with electrochemical detection. This method has an interassay coefficient of variation of <9% for NE and an absolute detection limit of 12 fmol (Eisenach et al. 1992). ACh concentrations were determined by a different HPLC-electrochemical detection method, using other equipment than that for catecholamines. This method has an interassay coefficient of variation of 8% and a detection limit of 50 fmol (Detweiler et al. 1993). Nitrite, a stable metabolite of NO (Salter et al. 1996), was measured via a variant of the Greiss reaction with the production of a fluorescent adduct (Miles et al. 1996), with an absolute detection limit of 100 pmol.
-2-ethanesulfonic acid, and 11 glucose] gassed with 95% O2-5% CO2 at 37°C. The effluent from the spinal cord tissue chambers was collected on ice in 4-min aliquots. Experiments were started after spinal cord slices had incubated in the chamber for 60 min.
13 and 1010, 1012 and 109, 1011 and 108, 1010 and 107, 109 and 106, and 108 and 105. At the end of the experiment, to confirm the ability of the tissue to synthesize NO, all chambers were perfused with solution containing N-methyl-D-aspartate (NMDA), 105 M, a known stimulator of NOS in spinal cord (Li et al. 1994). For experiments with antagonists or inhibitors (idazoxan, atropine, NMLA), chambers were perfused with 109 M of clonidine and with randomized, escalating concentration pairs of antagonists in the same concentration pairs as described above.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
), data from consecutive pairs of microdialysis samples, representing 30 min of collection, were averaged to reduce variability. Groups did not differ in baseline concentrations of NE and ACh, but did in nitrite (Table 1). As such, data are presented as raw values for NE and ACh but as change from baseline for nitrite.
View this table:
TABLE 1.
Baseline concentrations of norepinephrine, acetylcholine, and nitrite in spinal cord dorsal horn microdialysates
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FIG. 1.
Effect of intravenous (IV) morphine on norepinephrine in spinal cord. Spinal cord dorsal horn microdialysate concentrations of norepinephrine after IV injection at time 0 of morphine (1 mg/kg) in halothane-anesthetized sheep. Data are from experiments in which an intrathecal injection of saline ( 
), idazoxan (1 mg; 
), N-methyl-L-arginine (NMLA; 1 mg; 
), atropine (1 mg; 
), or yohimbine (2 mgl 
) preceded IV morphine injection by 15 min. Each symbol represents the median of 6-10 probes. Seventy-fifth percentiles for the saline group are shown as error bars.*P < 0.05 vs. time 0.
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FIG. 2.
Effect of IV morphine on acetylcholine in spinal cord. Spinal cord dorsal horn microdialysate concentrations of acetylcholine after IV injection at time 0 of morphine (1 mg/kg) in halothane-anesthetized sheep. Data are from experiments in which an intrathecal injection of saline ( ), idazoxan (1 mg; ), or NMLA (1 mg; ) preceded IV morphine injection by 15 min. Each symbol represents the median of 6-10 probes. Seventy-fifth percentiles for the saline group are shown as error bars. *P < 0.05 vs. time 0.
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FIG. 3.
Effect of IV morphine on nitrite in spinal cord. Spinal cord dorsal horn microdialysate concentrations of nitrite after IV injection at time 0 of morphine (1 mg/kg) in halothane-anesthetized sheep. Data are from experiments in which an intrathecal injection of saline ( ), idazoxan (1 mg; ), NMLA (1 mg; ), or atropine (1 mg; ) preceded IV morphine injection by 15 min. Each symbol represents the median of 6-10 probes. Seventy-fifth percentiles for the saline group are shown as error bars.*P < 0.05 vs. time 0.
), blocked morphine-induced increases in ACh, nitrite, and NE (Figs. 1-3). To confirm that this was an action on 2-adrenoceptors, three animals received intrathecal injection of yohimbine, which antagonizes 2-adrenergic but not imidazoline receptors. Yohimbine also blocked the increase in NE after IV morphine (Fig. 1).
9 M (Fig. 4), and subsequent antagonist studies were performed with pretreatment with clonidine at this concentration. Perfusion with NMDA, 105 M, also increased nitrite in perfusate from all chambers, as a positive test of tissue viability.
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FIG. 4.
Effect of clonidine on nitrite in perfusates of chambers containing rat spinal cord slices. Clonidine perfusion solution produced a concentration-dependent increase in nitrite. At the end of each experiment, the capability of the tissue to generate nitrite was confirmed by perfusion with N-methyl-D-aspartate (NMDA). Each symbol represents the median + 75th percentile of 6-30 chambers.
8 M idazoxan, 108 M atropine, and 107 M NMLA (Fig. 5). The increase in nitrite found after clonidine was shown in control experiments to be stable during the course of the experiment.
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FIG. 5.
Effect of antagonists on clonidine-induced increases in nitrite from perfusates of rat spinal cord slices. Clonidine, 10 9 M increased nitrite in perfusate, which was antagonized by NMLA (top), atropine (middle), and idazoxan (bottom). Each symbol represents the median + 75th percentile of 6-18 chambers.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). The current study establishes their relationship. Lack of increase after cervical cord transection confirms the observation that all noradrenergic innervation of the spinal cord originates from neurons with cell bodies rostral to the cord (Dahlstrom and Fuxe 1965). Functionally, spinally released NE and ACh must participate in analgesia after systemic or central administration of opioids, because opioid analgesia is antagonized by spinal injection of noradrenergic (Yaksh 1979) and cholinergic (Dirksen and Nijhuis 1983) antagonists and is potentiated by spinal injection of NE reuptake (Taiwo et al. 1985) and cholinesterase (Eisenach and Gebhart 1995) inhibitors in animals. In humans, NE reuptake inhibitors have not been injected spinally, but spinal injection of neostigmine has been shown to potentiate IV opioid analgesia (Hood et al. 1995).
; Xu et al. 1996a), suggesting actions of NO on sensory transduction and hemodynamic control. We and others have hypothesized that actions of ACh in these areas of the cord are mediated in part by NO synthesis (Iwamoto and Marion 1994a; Xu et al. 1996a; Zhuo et al. 1993a). As regards hemodynamic actions, spinal injection of muscarinic agonists increases preganglionic sympathetic nerve activity, blood pressure, and heart rate (Bhargava et al. 1982; Calaresu et al. 1990), as does intrathecal injection of NO donors (Lee et al. 1996). There is also considerable evidence suggesting the analgesic actions of ACh is mediated in part by NO synthesis (see below).
). Blockade of nitrite increase from IV morphine by spinal injection of atropine is also consistent with a cholinergic link in spinal NO synthesis.
ACh NO cascade, and that NE acts on 2-adrenoceptors. The action of 2-adrenergic agonists on spinal cord nitrite was tested directly in the in vitro spinal cord perfusion experiments. Clonidine increased nitrite in this system, an action antagonized by 2-adrenergic, cholinergic, and NOS antagonists or inhibitors, consistent with this hypothesis.
) or intrathecal (Iwamoto and Marion 1994a) administration of cholinergic agonists in rats is antagonized by NOS inhibitors. Some data suggest a tonically active spinal cholinergic antinociception in rats that is dependent on local NO production in rats (Zhuo et al. 1993). Finally, enhanced antinociception by intrathecally administered neostigmine of clonidine is blocked by NOS inhibitors in sheep (Xu et al. 1996a).
) and NOS inhibitors (Kolesnikov et al. 1992). It has been hypothesized that activation of protein kinase C by opioids results in increased intracellular calcium availability and increased NO production (Mao et al. 1995). The current study provides the first direct evidence that opioid administration can increase spinal NO production.
2-adrenergic antagonist, idazoxan is consistent with a spinal NE ACh NO cascade, its blockade of NE increase is more difficult to explain. Classically, presynaptic 2-adrenoceptors inhibit the release of NE, such that NE spillover is increased by 2-adrenergic antagonists and diminished by agonists (Langer and Hicks 1984). The current results confirm a previous report in sheep that spinal injection of idazoxan diminishes, rather than enhances, morphine-stimulated NE release (Bouaziz et al. 1996). It is possible that idazoxan could produce this effect by its interaction with nonadrenergic, imidazoline receptors. However, this is unlikely because yohimbine, which does not block imidazoline receptors, also diminished morphine-induced increases in spinal NE.
2-adrenoceptor stimulation and NE spillover in the spinal cord. Noxious electrical stimulation in anesthetized sheep activates descending noradrenergic pathways, as evidenced by increases in lumbar CSF NE concentrations in intact, but not in spinally transected animals (Eisenach et al. 1996). As in the current study with morphine, spinal injection of idazoxan blocked the increase in CSF NE from noxious stimulation.
2-adrenergic antagonists decrease spinal NE release, one would expect that 2-adrenergic agonists might increase NE release. We did not examine the effects of 2-adrenergic agonists in the current study but previously found that spinal injection of clonidine increases NE in dorsal horn microdialysates of sheep (Klimscha et al. 1995). This is likely a direct action within the spinal cord because it occurs after local spinal injection of a small dose and occurs similarly in intact and in spinally transected animals.
2-adrenergic agonist ACh NO cascade to increase spillover of NE into interstitial fluid and CSF (Fig. 6).
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FIG. 6.
Proposed cascade consistent with the current experiments. IV morphine injection stimulates descending noradrenergic pathways that release norepinephrine (NE) in the spinal cord. This NE stimulates spinal cholinergic neurons to release acetylcholine (ACh), which in turn stimulates synthesis of nitric oxide (NO). Because blockade of noradrenergic or cholinergic receptors and of nitric oxide synthase diminished the increase in NE from IV morphine, we propose a positive feedback of NO on NE release.
; Lonart and Johnson 1995) and may inhibit NE reuptake mechanisms (Kaye et al. 1997). Because spinally released NO could produce vascular relaxation, it could increase local blood flow. However, one would expect this increased blood flow to reduce NE in interstitial fluid. In contrast, we observed a reduction in NE when NOS was inhibited. NO can react with a variety of molecules in addition to its major known target of guanylate cyclase. We currently are screening several candidate compounds that may react with NO and alter NE release, reuptake, or metabolism. We speculate that these compounds play a major role in the increase in interstitial concentrations of NE observed under the conditions of microdialysis and that local blockade of their production by antagonism of 2-adrenoceptors or cholinergic receptors or by NOS inhibitors is responsible for the lack of apparent increase in such NE concentrations after IV morphine.
2-adrenoceptor activation, leading to ACh and subsequently NO synthesis and release. These results support functional studies demonstrating spinal noradrenergic and cholinergic mechanisms of analgesia from systemically administered opioids and suggest NO may regulate NE release, reuptake, or metabolism.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of General Medical Sciences Grant GM-35523.
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FOOTNOTES |
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Address reprint requests to J. C. Eisenach.
Received 3 January 1997; accepted in final form 16 June 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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systematic studies in sheep and an observation in a human.
Anesthesiology
84: 143-154, 1996.[Medline]antiociceptive interactions with intravenous morphine and intrathecal clonidine, neostigmine, and carbamylcholine in rats.
Anesthesiology
83: 1036-1045, 1995.[Medline]2-adrenergic agonists.
Anesthesiology
74: 766-771, 1991.[Medline]2-adrenergic and cholinergic antinociception.
Anesthesiology
84: 890-899, 1996a.[Medline]This article has been cited by other articles:
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