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Anesth Analg 2001;92:1563-1568
© 2001 International Anesthesia Research Society

PAIN MEDICINE

Modulations of Spinal Serotonin Activity Affect the Development of Morphine Tolerance

Jihn-Yih Li, MD, Chung-Hang Wong, MD, Eagle Y.-K. Huang, PhD*, Yen-Chien Lin, Yun-Long Chen, Peter P. C. Tan, MD, and Jin-Chung Chen, PhD

Department of Anesthesiology, Chang-Gung Memorial Hospital, and Department of Pharmacology, Chang-Gung University, Taiwan, ROC, and *Department of Pharmacology, National Defense Medical Center, Taiwan, ROC

Address correspondence and reprint requests to Dr. Jin-Chung Chen, Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan, Kwei-Shan, Taiwan, ROC. Address e-mail to Jinchen{at}mail.cgu.edu.tw

Abstract

To test whether modulations of spinal serotonin (5-HT) levels would affect the development of morphine tolerance, we treated rats with either intrathecal 5-HT or 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT neurotoxin) in addition to systemic infusion with morphine (2 mg · kg-1 · h-1). Continuous infusion of 5-HT (10 µg · 6 µL-1 · h-1) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the curve for the tail-flick latency test was 454.1 ± 35.1 in the Sham Control group vs 327.6 ± 41.0 in the 5-HT-Infused group. µ-opioid receptor binding in the lumbar spinal cord showed a decrease in the Bmax (maximal binding -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. However, intrathecal injection of 5,7-DHT (50 µg), which resulted in a 48% reduction in 5-HT and 51% reduction in 5-hydroxyindoleacetic acid concentrations, led to an attenuation of morphine tolerance (the area under the curve was 613.0 ± 24.7 in the 5,7-DHT-Lesioned group). The binding study indicated that the affinity of lumbar µ-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 µg · 6 µL-1 · h-1) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that activity of spinal 5-HT-containing neurons plays a crucial role during the development of morphine tolerance.

Implications: Spinal cord serotonin (5-HT) levels seem to be critical in the development of morphine tolerance. Reduction of 5-HT levels in the spinal cord prolonged the development of tolerance to morphine. Manipulation of 5-HT levels could be a valuable method for altering the efficacy of opioid analgesia, particularly during patient-controlled analgesia.

Chronic treatment with opioid analgesics, such as morphine, leads to the development of analgesic tolerance (1). The cellular mechanism underlying the development of morphine tolerance remains controversial. It has been postulated that morphine tolerance is a result of 1) up- or down-regulation of opioid receptors (µ, {delta}, or {kappa} subtypes), 2) uncoupling or desensitization of G-proteins, 3) altered intracellular signaling(s) including adenyl cyclase, protein kinase C, or nitric oxide, and 4) involvement of postreceptor neural events, particularly the glutamate/aspartate, {gamma}-aminobutyric acid, and monoamine neurotransmitters (2).

Central serotonin (5-HT)-containing neurons are involved in spinal cord nociception (3). Activation of 5-HT neurons reduces the nociceptive responses via a descending inhibitory pathway in the spinal cord (4). In addition, morphine evokes the release of 5-HT in several 5-HT projection areas, derived mainly from the median or dorsal raphe (5,6). The analgesic effect of morphine when administered into the periaqueductal gray was inhibited by the 5-HT receptor antagonist methysergide (7). Pretreatment with a 5-HT receptor antagonist also attenuates intrathecal morphine-induced analgesia (8). µ-opioid receptor-induced supraspinal analgesia could be blocked by intrathecal administration of the 5-HT1A receptor antagonist spiperone or the 5-HT1C/2 receptor antagonist mianserin (9). Thus, it appears that a specific 5-HT receptor subtype in the spinal cord could be involved in opioid-mediated antinociception.

Involvement of 5-HT in the development of morphine tolerance has also been examined, but without consistent results. For example, evoked 5-HT activity by systemic administration of 1-tryptophan or 5-hydroxytryptophan was found to accelerate and attenuate morphine tolerance, respectively (10,11). Administration of 5-HT3 receptor antagonist ondansetron or a tryptophan hydroxylase inhibitor suppressed the development of morphine tolerance (12,13). However, coadministration of 5-HT uptake inhibitor fenfluramine with morphine resulted in an inhibition of morphine tolerance (14). Although the effect could not be explained by the synaptic 5-HT concentration, those studies explored the functional significance of central 5-HT on the development of morphine tolerance.

Previously, we reported that the concentrations of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were increased in the spinal cord of morphine-tolerant rats (15). To further characterize the functional role of spinal 5-HT in the development of morphine tolerance, we designed experiments to up- and down-regulate 5-HT levels in the spinal cord and examine the rate of development of morphine tolerance. This was accomplished by intrathecal infusion of a 5-HT solution or single injection with 5,7-dihydroxytryptamine (5,7-DHT), a selective toxin for 5-HT-containing neurons, to rats before IV morphine infusion. The results reveal that an increase in spinal 5-HT levels accelerates the development of morphine tolerance, whereas 5-HT depletion significantly attenuates the rate of morphine tolerance.

Methods

Male Sprague-Dawley rats (Academia Sinica, Taiwan) weighing 200–250 gm were used. They were kept five per cage for at least 5 days after their arrival and housed in a room with a 12:12 h dark-light cycle, and a room temperature of 22°C ± 0.5°C, with food (Lab Diet 5010; PMI Nutrition, Brentwood, MO) and water available ad libitum. The ethical guidelines provided by Chang-Gung Animal Core were followed throughout the study.

Rats were randomly divided into three groups (n = 20/group). Group I received both intrathecal 5-HT and IV morphine infusion. Group II received intrathecal 5,7-DHT injection two weeks before IV morphine infusion. Group III control received a sham operation and a lumbar cannulation followed by IV morphine infusion. Half of the animals in each group received jugular vein cannulation one week before the experiment to evaluate the development of morphine tolerance (defined as the animal losing the analgesic response to constant morphine infusion) during IV infusion of morphine (1 mg/kg loading dose followed by 2 mg · kg-1 · h-1) with hourly tail-flick tests. The rest of the rats in each group, which were not infused with morphine, were analyzed for the binding characteristics of µ-opioid receptors. To determine the effect of 5,7-DHT on the lumbar spinal cord, a separate set of rats was analyzed 2 wk after treatment with 5,7-DHT for the amount of 5-HT and 5-HIAA in the lumbar spinal cord and the analgesic response induced by 5 mg/kg intraperitoneal morphine injection. To test if 5-HT infusion would alter the threshold of spinal nociception, a set of rats were intrathecally infused with 5-HT followed by a tail-flick test.

Group I and III rats were anesthetized with a mixture of 10 mg/kg ketamine and 3 mg/kg xylazine given IM. A midline incision of approximately 5 cm was made between the T13 and L2 regions and the paravertebral muscles were dissected from the T13 and L1 spinous processes to expose the dura. The dura was perforated with a short bevel needle (20 gauge), followed by the insertion of an intrathecal catheter (PE10; Becton Dickinson, Parsippany, NJ) that was advanced 3 cm caudally. After the insertion, the catheter was cemented to the bone (T13-L1 spinal process) with cyanoacrylate. The free end of the catheter was then tunneled subcutaneously to the shoulder area and sealed by melting. Any animals that showed neurological signs (paralysis, leg dragging), on postoperative days were excluded from the experiment. For Group I rats, one week after operation, a solution of 5-HT (10 µg · 6 µL-1 · h-1) was infused (CMS 102 microsyringe pump; CMA/microdialysis AB, Stockholm, Sweden) alone for 2 h through the implanted catheter followed by 7 h concomitant infusion of IV morphine. Group III rats received intrathecal normal saline at the same flow rate and time interval (9 h). It was noted during the infusion that animals showed no obvious neurological signs.

Two weeks before the experiment, Group II rats was anesthetized with the ketamine/xylazine mixture. The T13-L1 spinal cord was exposed as described above. A solution of 5,7-DHT (50 µg/20 µL) was given intrathecally using a microsyringe pump with a flow rate of 1 µL/min. All the rats were pretreated with desipramine (25 mg/kg intraperitoneally) 45 min before 5,7-DHT to prevent the uptake of neurotoxin into the noradrenergic neurons. Animals exhibiting any neurological signs after surgery were excluded from the experiment.

All the animals were administered systemic morphine through a jugular vein cannula. A small skin incision was made on the right side of the neck to expose the jugular vein. IV cannulation was performed with a PE-50 tubing inserted into the right internal jugular vein and tightened with surgical suture. The free end of the catheter was tunneled subcutaneously to the shoulder area and sealed by melting. One week later, after a 1 mg/kg bolus, a morphine solution (2 mg · kg-1 · h-1) was driven by a Pain Management Provider (Abbott Laboratories, North Chicago, IL) at a flow rate of 2 mL/h.

The nociceptive response was measured with a tail-flick apparatus (Ugo Basile, Italy). In each group of rats its baseline latency as well as hourly responses after morphine infusion were recorded. It was noticed that repetitive tail-flick tests at hourly intervals did not change the baseline latency in control rats up to 14 h (data not shown). The rats were accommodated to the restrainer with their tail moving freely outside. A beam of infrared light was projected on the tip of tail with the intensity set to achieve an average basal latency of 2–3 s. The cut-off time was set at 7 s to avoid any thermal injury to the tail. The degree of antinociception was expressed either as postdrug latency or as a percentage of the maximal possible effect (%MPE) according to the formula:

equation


The concentrations of 5-HT and 5-HIAA in the lumbar spinal cord were determined using reverse phase (C-18 column, 3 µm; 15 cm) (Beckman Instrument, Fullerton, CA) high-performance liquid chromatography (Beckman System Gold system). The mobile phase consisted of 5 mM NaH2PO4, 30 mM citric acid, 0.1 mM EDTA, 0.02% sodium octylsulfate, and 9% methanol (pH 3.4–3.5) with flow rate of 1 mL/min. The tissues were treated with 0.1 N perchloric acid and separated by centrifugation (34,000g for 30 min). The resulting supernatants were filtrated through a 0.2 µm syringe filter (Millex-GS, Millipore, Bedford, MA) and injected directly into the high-performance liquid chromatography apparatus. The neurochemicals were detected with an electrochemical detector (LC-4C; BSA Inc., Indianapolis, IN) with the oxidation potential setting at +0.65V. External standards were prepared freshly in a similar way and injected every five sample runs.

To determine µ-receptor binding, lumbar spinal cords (L1-6) were dissected and homogenized in 10 volumes (w/v) of binding buffer containing 30 mM Tris-HCl (pH 7.5), 1 mM EDTA, and proteinase inhibitors (aprotinin, leupeptin, and phenylmethylsulfonyl fluoride) as described previously (16). The homogenates were centrifuged at 34,000g for 30 min at 4°C. The resulting pellets were recentrifuged (34,000g for 30 min), and suspended to give a final concentration of 10 mg/mL. A saturation experiment was performed with 80 µg of protein and various concentrations of [3H][D-Ala (2), N-MePhe (4),Gly-ol5]enkephalin (0.1–20 nM; New England Nuclear, Boston, MA) in the presence or absence of 10 µM [3H][D-Ala (2), N-MePhe (4),Gly-ol5]enkephalin to define nonspecific binding. After incubation at 22°C for 60 min, the reaction mixtures were filtered rapidly through a GF/B filter via a 24-well cell harvester (PHD; Cambridge Technology, Watertown, MA). The radioactivity were determined by a liquid scintillation counter (Packard 1600TR) with approximately 50% efficiency. The Bmax (maximum density of binding sites) and Kd (apparent binding affinity) values were determined with the GraphPad Prizm program (GraphPad, San Diego, CA).

Analgesic response data were analyzed by analysis of variance followed by the post hoc Dunnett’s multiple comparison test. The area under the curve (AUC) for analgesia was calculated for each rat and the mean AUC ± SEM of the experimental groups was compared with the Control group with an unpaired t-test. The Bmax and Kd values of the µ-opioid receptors in experimental groups were compared with the Control group via a paired t-test. P <0.05 was considered to be significant.

Results

Rats that received 1 mg/kg morphine as a bolus followed by continuous infusion of morphine (2 mg · kg-1 · h-1) reached approximately 90% maximal possible effect (MPE) at 30 min (Fig. 1). The peak analgesic effect was maintained for approximately 2 h and then gradually declined until a full analgesic tolerance was achieved at approximately 7 h. However, rats that received only a 1 mg/kg morphine bolus reached 41.5% MPE at 30 min and quickly decreased to 2.8% MPE at 60 min (data not shown). The results clearly indicate that continuous IV infusion of morphine leads to the development of morphine tolerance. As compared with our previous study (15), morphine tolerance produced by the current preparation was faster than that induced by implantation of a 75-mg morphine pellet (Fig. 1). When rats were also given spinal 5-HT (10 µg · 6 µL-1 · h-1), the time to development of maximum morphine tolerance was not different in Sham Control versus the 5-HT-Treated groups. However, the rate of morphine tolerance was accelerated compared with the saline-infused control (Fig. 2A), with a 25.1% reduction in AUC (327.6 ± 41.0 in the 5-HT-Infused group vs 454.1 ± 35.1 in the Control group; Fig. 2B).



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  		Figure 1. Comparison of the effect of continuous morphine infusion (1 mg/kg bolus + 2 mg · kg-1 · h-1) vs implantation of a subcutaneous morphine pellet (75 mg) on the development of morphine tolerance. Animals with a continuous infusion of morphine developed a complete analgesic tolerance at approximately 7 h; whereas those with a morphine pellet reached a 75% maximal antinociception at 14 h (n = 10, n = 7).

 


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  		Figure 2. The effect of intrathecal serotonin (5-HT) and 5,7-dihydroxytryptamine (5,7-DHT) treatment on the development of morphine tolerance. A, hourly tail flick latency of Control, 5-HT- and 5,7-DHT-Treated groups during a 7 h continuous infusion of morphine; B, the bar graph displays the mean area under the curve for the three groups, which was calculated from the corresponding % maximal antinociception profile. (n = 10/group; *P <0.05, **P <0.01 compared with the Control group)

 
Two weeks after injection of 50 µg of 5,7-DHT into the lumbar spinal cord, there was an approximately 48% reduction in spinal 5-HT and a 51% reduction in 5-HIAA levels compared with the Sham-Operated Control group (Table 1). After treatment with 5,7-DHT, approximately 75% of the animals exhibited normal spontaneous behaviors (others showed leg dragging were excluded). These animals were selected for the subsequent behavioral and neurochemical experiments. In the spinal cord of 5,7-DHT-pretreated animals, the rate of morphine tolerance was apparently slowed (Fig. 2) compared with the Saline-Treated Control group (AUC of 613.0 ± 24.7, a 35.3% increase).


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  		Table 1. Spinal Serotonin (5-HT) and 5-Hydroxyindoleacetic Acid (5-HIAA) Levels in the Spinal Cord of Control and 5,7-Dihydroxytryptamine (5,7-DHT)-Treated Rats
 
To examine if 5,7-DHT-treatment would affect acute morphine-induced analgesia, a set of control and 5,7-DHT-lesioned (two weeks after 5,7-DHT injection) animals were challenged with 5 mg/kg morphine (intraperitoneal). It was noticed that 5,7-DHT treatment did not alter the baseline tail-flick latency (2.1 ± 0.4 s in control vs 2.4 ± 0.3 s in 5,7-DHT-lesioned rats). Furthermore, Figure 3 illustrates the similar analgesic effect of morphine on control and 5-HT-depleted rats (AUC ± SEM of 226.8 ± 34.8 and 227.9 ± 28.6 for the Control and 5,7-DHT-Lesioned groups, respectively). Likewise, to test if 5-HT infusion would reset the baseline of spinal nociception, a set of rats (n = 6) were intrathecally infused with 5-HT at 10 µg · 6 µL-1 · h-1 for 9 h with intermittent tail-flick tests. The results indicated that infusion of 5-HT alone did not modify the baseline latency (predrug, 2.8 ± 0.2 s; post-2 h, 2.8 ± 0.2 s; post-9 h, 3.1 ± 0.1 s).



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  		Figure 3. Analgesic effect of acute morphine (5 mg/kg intraperitoneally) treatment on control and 5,7-dihydroxytryptamine (5,7-DHT)-lesioned rats. The graph illustrates the hourly percentage of maximal antinociception profile within 5 h postmorphine injection. The insert represents the mean area under the curve for the Control and 5,7-DHT-Treated groups (n = 5, n = 5)

 
Separate sets of animal experiments were performed for the µ-opioid receptor binding at time points that were equivalent to the behavioral experiment, except the addition of morphine. As shown in Table 2, intrathecal administration of 10 µg · 6 µL-1 · h-1 5-HT for 9 h significantly decreased the apparent binding of µ-opioid receptors (-46.5%, P < 0.05), whereas the binding affinity remained similar. However, 5,7-DHT pretreatment did not alter the Bmax of µ-opioid receptors; however, it significantly decreased the binding affinity (-196%, P < 0.01). In the latter group, a similar degree of 5-HT and 5-HIAA depletion was seen as in the 5,7-DHT-lesioned rats used for the behavioral experiment (data not shown).


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  		Table 2. Binding Characteristics of Lumbar µ-Opioid Receptors
 
Discussion

The current study demonstrated that manipulations of spinal cord 5-HT levels significantly modify the development of morphine tolerance. The results also suggest that the alteration was partly attributable to changes in the spinal µ-opioid receptors. The significant finding of this study was that intrathecal administration of 5,7-DHT could effectively retard the development of morphine tolerance, whereas it decreased the binding affinity of µ-opioid receptors. However, continuous infusion of 5-HT intrathecally accelerated the development of morphine tolerance and, at the same time, decreased the Bmax for lumbar µ-opioid receptors.

Opioids exert their analgesic effect in part through activation on central 5-HT neurons (17,18). Acute systemic morphine administration evokes the release of 5-HT in several forebrain regions and the spinal cord (5,19). Although the mechanism of morphine evoked 5-HT release remains ambiguous, the involvement of {gamma} -aminobutyric acid and excitatory amino acids has been suggested (18,20). Further, 5-HT1A and 5-HT1B receptor subtypes are involved in modulating spinal nociception (21), and morphine-induced analgesia could be blocked by intrathecal injection of either spiperone, a 5-HT1A antagonist, or mianserin, a 5-HT1C/2 antagonist (9). Those results suggest a complicated interplay between 5-HT receptor subtypes and opioid action in the spinal cord. Central serotonergic neurons may also play a critical role in the development of morphine tolerance and dependence. For instance, coadministration of fenfluramine, a selective 5-HT uptake inhibitor, and morphine inhibits the development of morphine tolerance (14). Pretreatment with either 1-tryptophan, the 5-HT precursor or p-chlorophenylalanine, a tryptophan hydroxylase inhibitor accelerates the development of morphine tolerance (10,11). However, 5-hydroxytryptophan, a direct 5-HT precursor, attenuates the morphine tolerance (13). These apparently contradictory results could possibly be caused by a difference in 5-HT concentration in local synapses. The inconsistent results could also be because of the different projections of 5-HT-containing neurons derived from either the raphe magnus (innervate the spinal cord) or the dorsal/median raphe nucleus (innervate the forebrain regions). If the former determines the rate of tolerance, we would expect it to alter the development of morphine tolerance by controlling the 5-HT levels in the spinal cord.

Our finding that manipulations of 5-HT levels in the lumbar spinal cord alter the development of morphine tolerance confirms the significance of the interaction between 5-HT and opioids in the spinal cord. Further, the observation that increases in spinal fluid 5-HT concentration accelerate the development of morphine tolerance further substantiates our previous finding that the rate of 5-HT turnover increased in morphine-tolerant rats (15). Thus, it is reasonable to speculate that in the spinal cord, morphine-evoked analgesic tolerance involves activation of serotonergic neurons. Consistent with this hypothesis is the fact that chemical neurolysis of spinal 5-HT terminals by intrathecal treatment with 5,7-DHT attenuates morphine tolerance. Hence, up-or down-regulation of the spinal 5-HT levels would effectively modulate the development of morphine tolerance. Whether this interaction between 5-HT and opioids in the spinal cord could explain the mechanism of morphine tolerance at the supraspinal level requires further studies. In addition, to gain a full understanding of the effect of 5-HT on opioid systems, experiments with selective 5-HT receptor ligands on the development of morphine tolerance would be essential.

To evaluate the effect of spinal cord 5-HT on morphine tolerance, the degree of chemical interference on morphine analgesia should be kept minimal but effective. In this study, intrathecal infusion of 5-HT up to 9 h did not reset the pain threshold. Likewise, treatment with 5,7-DHT to reduce 48% of spinal 5-HT did not modify the antinociceptive effect of morphine. Although the profile of drug pretreatment is different, all the animals received IV cannulation one week before morphine infusion. To facilitate the development of morphine tolerance, we treated the animals with a 1-mg initial dose of morphine followed by continuous infusion of 2 mg · 6 µL-1 · h-1. In a pilot study, we showed that IV injection of 1 mg of morphine produced only a transient and submaximal analgesic effect (30% MPE), thus the decreased analgesia in the presence of continuous morphine infusion is a result of the development of tolerance. Comparing the %MPE-time curves of IV morphine infusion versus pellet implantation, our data clearly indicate a more rapid development of morphine tolerance with IV morphine infusion. The results, if transferable to humans, may stimulate consideration in acute/chronic pain management using IV patient-controlled analgesia.

It is generally believed that alterations in opioid receptors could, in part, account for the development of morphine-evoked tolerance/dependence (22). Manipulation of 5-HT may modify the ligand binding of the opioid receptor and affect the development of tolerance via postreceptor events. In 5-HT-treated rats, it was found that continuous intrathecal infusion of 5-HT decreased the Bmax values of lumbar spinal cord µ-receptor without affecting the binding affinity. The decrease in lumbar spinal cord µ-binding sites could explain the acceleration of tolerance development although the neural mechanisms underlying the 5-HT-induced µ-receptor downregulation are still unclear. However, depletion of spinal cord 5-HT by 5,7-DHT treatment decreased the binding affinity of µ-opioid receptors, without altering the number of binding sites. Although a satisfactory explanation is lacking, the results suggest that chronic depletion of spinal cord 5-HT has a profound effect on neural plasticity in the cord. Several cellular variables, such as cyclic adenosine monophosphate-protein kinase A (23), N-methyl-D-asparate receptors and protein kinase C (24), and/or nitric oxide (25) have been suggested to account for the development of opioid tolerance. It is possible that altered µ-opioid receptors, caused by lesions in spinal cord 5-HT, are associated with one of those events.

In conclusion, the current finding that an increase or decrease in spinal cord 5-HT levels is associated unidirectionally with the rate of development of morphine tolerance agrees with the notion that spinal cord 5-HT is involved in opioid-dependent neural events. The results suggest, hypothetically, that coadministration of opioids with serotonergic drugs (such as antidepressants or antiemetics) could alter the opioid tolerance that develops with long-term use.

Acknowledgments

Supported, in part, by grant NSC88-2314-182-032 from National Science Council in Taiwan and grant CMRP414 from Chang-Gung Memorial Hospital.

We are grateful to Dr. Wen-Hsien Wu for his valuable suggestions and Dr. Jerome L. Maderdrut for his assistance in editing this manuscript. We also thank Dr. Kenneth Davis (NIDA, USA) for his generous supply of morphine and placebo pellets.

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Accepted for publication January 26, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press