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Anesth Analg 2005;101:1750-1756
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184136.08194.9B

PAIN MEDICINE

A Single Dose of Intrathecal Morphine in Rats Induces Long-Lasting Hyperalgesia: The Protective Effect of Prior Administration of Ketamine

Alain C. Van Elstraete, MD, Philippe Sitbon, MD, Fabien Trabold, MD, Jean-Xavier Mazoit, MD, PhD, and Dan Benhamou, MD

Department of Anesthesiology, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris and the Anesthesia Laboratory UPRES-EA 3540, Faculté de Médecine du Kremlin-Bicêtre Université Paris-Sud, Le Kremlin-Bicêtre, France

Address correspondence to Philippe Sitbon, MD, Service d’Anesthésie-Réanimation, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France. Address e-mail to philippe.sitbon{at}bct.ap-hop-paris.fr.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
An active pronociceptive process involving N-methyl-d-aspartate (NMDA) receptor activation is initiated by opioid administration, leading to opioid-induced pain sensitivity. Experimental observations in rats have reported reduction of baseline nociceptive threshold after prolonged spinal opioid administration. In this study we sought to determine whether a single dose of intrathecal morphine can induce hyperalgesia in uninjured rats and to assess the effects of pretreatment with the NMDA-antagonist ketamine on nociceptive thresholds. Sensitivity to nociceptive stimuli (paw pressure test) was assessed for several days after an acute intrathecal injection of morphine (5 µg and 10 µg) in male Sprague-Dawley rats. The effects of subcutaneously administered NMDA-receptor antagonist ketamine (10 mg/kg) before intrathecally administered morphine were also evaluated. A single intrathecal injection of morphine led to a biphasic effect on nociception; early analgesia associated with an increase in the nociceptive threshold lasting 3-5 h was followed by delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting 1-2 days. Subcutaneous ketamine did not significantly modify the early analgesic component but almost completely prevented the delayed decrease in nociceptive threshold after intrathecal administration of morphine. A single intrathecal injection of morphine in rats produces a delayed and sustained hyperalgesia linked to the development of opioid-induced pain sensitivity.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Systemic delivery of µ-opioid agonists produces potent analgesia through modulation of nociceptive transmission. However, a growing body of evidence suggests that an active pronociceptive process is initiated by opioid administration (1). Preclinical studies have shown that systemic opioid administration in rats can lead to a long-lasting reduction of baseline nociceptive threshold, a sign indicating central sensitization, hence an opioid-induced abnormal pain sensitivity (2–6). Furthermore, it has been shown that tolerance to opioids, defined as a reduction of their analgesic effect, is linked to the development of opioid-induced pain sensitivity and can develop rapidly after an acute systemic opioid exposure in humans (7–9). Decreased analgesia and abnormal pain (thermal hyperalgesia and tactile allodynia) after administration of µ-opioids suggest that neuropathic pain and spinal µ-opioid tolerance share common pathophysiologic mechanisms (10–12). Among these neural mechanisms, the central glutaminergic system plays a pivotal role and N-methyl-d-aspartate (NMDA) receptor has been shown to be critical in the cellular mechanisms of opioid-induced pain sensitivity (11,13,14). On the other hand, experimental observations have reported reduction of baseline pain threshold after prolonged spinal opioid administration using escalating doses or continuous infusion in rats (15–17), and that NMDA antagonists prevented tolerance and hyperalgesia produced by repeated spinal injections or infusions of morphine (10,18). No study has assessed whether a single spinal injection of morphine can induce a delayed hyperalgesia. Consequently, we decided to test the hypothesis that a single dose of intrathecally administered (IT) morphine induces the NMDA-dependent central sensitization process and subsequent hyperalgesia. To determine whether pain sensitization is induced by morphine on its own, nociceptive thresholds after morphine administration were studied in uninjured rats. The effects of pretreatment by subcutaneous (SC) injection of the clinically available NMDA antagonist ketamine on nociception were also studied.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were performed on adult male Sprague-Dawley rats (CD1 Charles River; IFFA-CREDO, L’Arbresle, France) (weight, 250-275 g at the beginning of the experiment) housed in individual standard cages under a 12-h light:12-h dark cycle (lights on at 8.00 am) at a constant room temperature of 22°C ± 2°C 1 wk before experiments. Animals had access to food and water ad libitum. Experiments were approved by the Institution’s Animal Care and Use Committee and were performed in accordance with guidelines from the International Association for the Study of Pain Committee for Research and Ethical Issues (19).

The following drugs were used: the clinically available injectable form of morphine hydrochloride (Cooper, Rhône Poulenc Rohrer, Melun, France), lidocaine (Astra-Zeneca, Rueil-Malmaison, France), and ketamine hydrochloride (Sigma-Aldrich, Saint Quentin Fallavier, France). Morphine and ketamine were diluted with saline (0.9%). The doses of IT morphine were chosen according to previous studies in which doses of 5 µg (20,21) and 10 µg (10) were found to provide effective pain control in rats. On the basis of previous studies, 10 µL of diluted morphine was injected intrathecally (20,22). The dose of ketamine was chosen according to the study of Célèrier et al. (4), in which 10 mg/kg of SC ketamine prevented the delayed hyperalgesia induced by systemic fentanyl in rats. Ketamine was administered SC (100 µL/100 g body weight) (4) as was the studied dose of diluted morphine for systemic administration. Twenty µL of lidocaine 2% (400 µg) was injected IT to ascertain actual IT injection. Control animals received an equal volume of saline.

For those animals given IT drugs, a single IT injection was accomplished by acute lumbar puncture between L4 and L5 as previously described (23). The skin of the back was shaved in the lumbar region and prepared with 10% povidone-iodine. Rats were briefly anesthetized with halothane. To flex the lower thoracic and lumbar vertebral column, foam was placed under the animal’s abdomen. The dead-space of the 25-gauge hypodermic needle hub used for puncture was 25 µL. Before IT injection, the needle hub was flushed with 25 µL of the mixture to be injected. To ascertain correct IT injection, 20 µL of 2% lidocaine (400 µg) was injected with either morphine or saline. Only animals that developed transient (10-20 min) bilateral hindlimb motor weakness or paralysis within 30 s of the injection were included in the study. Animals with persistent motor deficit lasting more than 30 min after injection were rejected from further study. SC injections were performed on the rat’s back with a 25-gauge needle. Injections were performed in unanesthetized rats.

Nociceptive thresholds were determined by a modification of the Randall-Selitto method (24). A constantly increasing pressure was applied to the right hindpaw of the rat at the metacarpal level between the third and the fourth finger to determine the minimum stimulus necessary to evoke an obvious nociceptive response (a sharp paw withdrawal). The Basile analgesimeter (Ugo Basile, Biosed, Camerio, Italy) with a stylus tip (diameter 1 mm) was used. A 600-g cutoff value was used to prevent tissue damage (4,25). The experiments were performed in a quiet room by the same investigator blinded as to the treatment used.

After arrival in the laboratory, animals were allowed 5 days to become accustomed to the colony room, gently handled daily for 5 min, and left in the test room for 2 h (from 11:00 am to 1:00 pm). All experiments began at 11:00 am and were performed on groups of 8 animals during the light part of the cycle. To ensure nociceptive threshold stability, the basal nociceptive threshold was measured twice (with 30 min between the measurements) on the 2 days preceding the planned experimental day (D-2 and D-1). On the experimental day (D0), the basal nociceptive threshold was also determined twice before drug injections (30 min between measurements). As previously described, experiments with morphine (or saline) were initiated only if no statistical changes were observed in basal nociceptive thresholds when estimated on days D-2, D-1, and D0 (4).

There were 10 groups with 8 animals per group. In a first set of experiments, the early and long-lasting effects of 5 µg (Group 1) and 10 µg (Group 2) of IT morphine were studied. On D0, the nociceptive threshold was estimated every 30 min for a period of 240-360 min after morphine injection. Subsequent to D0, the nociceptive threshold was measured twice daily (30 min between measurements) for 5 days (D + 1-D + 5) (4). To avoid a delayed decrease in nociceptive threshold caused by an excess of peripheral afferent nociceptive inputs resulting from the evaluation of the analgesic effect at D0, an additional experiment with IT morphine 10 µg (Group 3) was conducted without performing a nociceptive response measurement on the day of treatment (4). To determine whether a systemically administered single dose of morphine 10 µg is able to induce delayed hyperalgesia, an additional experiment was conducted with SC morphine 10 µg (Group 4). To assess the potential effect of IT lidocaine on the nociceptive threshold, an additional experiment was conducted with IT lidocaine alone (Group 5). To assess a potential delayed decrease in nociceptive threshold caused by an excess of peripheral afferent nociceptive inputs resulting from injections, an additional experiment was conducted with SC saline and IT saline (Group 6). To assess potential early and long-term effects on nociceptive thresholds of SC saline or SC ketamine, experiments were conducted with SC saline alone (Group 7) and SC ketamine alone (Group 8). In a second set of experiments, we investigated the effects of pretreatment with the noncompetitive NMDA-receptor antagonist ketamine (10 mg/kg SC 30 min before IT morphine) on early and long-lasting effects induced by IT morphine 10 µg (Group 9). A control group was pretreated with SC saline 30 min before IT morphine (Group 10).

To calculate the basal nociceptive threshold value, 2 measurements were performed daily on days D-2, D-1, and D0. The paired Student’s t-test was used daily to assess comparisons between these 2 measurements. Another comparison was performed between the first daily measurements on days D-2, D-1, and D0 (one-way analysis of variance). The basal reference value of the nociceptive threshold was chosen as the first measurement of the nociceptive threshold performed on day D0 when no statistically significant difference was found between the 2 measurements performed daily on days D-2, D-1, and D0 and between the first daily measurements on days D-2, D-1, and D0 (P > 0.05). The comparison between the first and the second daily measurements was performed to ascertain the reliability of the first measurement.

As described previously (4), an algesic index representing the area under the curve was calculated for each experimental group using the trapezoidal method. The index was represented by the mean of the surface areas of trapezia evaluated for each rat.

To evaluate the time-course effects of treatments on the nociceptive threshold in each group, two-way analysis of variance followed by post hoc analysis using the Neuman-Keuls test was performed on D0 and on days D + 1 to D + 5. Between-group comparisons of algesic index were performed using analysis of variance followed by post hoc analysis using the Neuman-Keuls test. The unpaired Student’s t-test was used to compare the algesic index when two groups only were compared. Statistical analysis have been made using data expressed in grams and presented in the figures as the mean nociceptive threshold ± sem. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
None of the animals was excluded from the study for persistent motor deficit after IT injection. Animals appeared calm after IT injection, with no alterations in spontaneous behavior. No statistically significant difference was found among the basal nociceptive thresholds of each experimental group (one-way analysis of variance, P > 0.05). The mean baseline nociceptive threshold value was 337 ± 4 g (n = 80).

IT morphine 5 µg and 10 µg first caused a statistically significant short-lasting increase in nociceptive thresholds (analgesia) for hours (one-way analysis of variance, P < 0.05; Fig. 1A). Analgesia induced by 10 µg morphine was not significantly different from that obtained with 5 µg (two-way analysis of variance, P > 0.05; Fig. 1A). SC morphine 10 µg did not produce any change in nociceptive threshold (not significant compared with basal value or to saline control group) whereas 10 µg IT morphine produced significant antinociception for 3 h (one-way analysis of variance, P < 0.05; Fig. 1A). IT saline did not alter the nociceptive threshold (one-way analysis of variance, P > 0.05; Fig. 2A). On the contrary, IT lidocaine with saline induced a short-lasting significant increase in the nociceptive threshold for the first 90 min after injections (one-way analysis of variance, P < 0.05; Fig. 2A).



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  		Figure 1. Short- (A) and long-lasting (B) effects induced by intrathecal (IT) morphine 5 µg (Group 1), IT morphine 10 µg (Group 2), and subcutaneous (SC) morphine 10 µg (Group 4) as measured by the paw-pressure test (n = 8 for each group). *P < 0.05 compared with the basal nociceptive threshold value. For graphic clarity, values are mean ± sem.

 


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  		Figure 2. Short- (A) and long-lasting (B) effects induced by intrathecal (IT) lidocaine (Group 5), and IT saline (Group 6) as measured by the paw-pressure test (n = 8 for each group). *P < 0.05 compared with the basal nociceptive threshold value. For graphic clarity, values are mean ± sem.

 

IT morphine 5 µg and 10 µg induced a statistically significant long-lasting decrease in nociceptive thresholds on D + 1 and D + 2 (respectively 264 ± 4 g versus 251 ± 7 g on D + 1 and 280 ± 6 g versus 266 ± 7 g on D + 2, one-way analysis of variance, P < 0.05; Fig. 1B). The decrease in nociceptive threshold was significantly less on D + 1 and D + 2 after a single SC injection of morphine 10 µg than that caused by IT morphine 10 µg (respectively 344 ± 23 g versus 251 ± 7 g on D + 1 and 298 ± 11 g versus 266 ± 7 g on D + 2, two-way analysis of variance, P < 0.05; Fig. 1B). There was a significant delayed pronociceptive effects of 10 µg SC morphine on D + 2 and D + 3 when compared with SC saline (respectively 296 ± 10 g versus 352 ± 18 g on D + 2 and 295 ± 8 g versus 358 ± 21 g on D + 3, two-way analysis of variance, P < 0.05; Fig. 1B).

IT saline and IT lidocaine did not alter the nociceptive threshold from D + 1 to D + 5 (one-way analysis of variance, P > 0.05; Fig. 2B).

IT morphine 10 µg also induced a statistically significant long-lasting decrease in nociceptive thresholds on D + 1 and D + 2 in rats that had not received nociceptive inputs associated with the measurement procedure on D0 (one-way analysis of variance, P < 0.05; Fig. 3). This long-lasting decrease in nociceptive thresholds on D + 1 and D + 2 was not statistically different from that observed after IT morphine 10 µg in rats that had received nociceptive inputs associated with the measurement procedure on D 0 (respectively 258 ± 15 g versus 251 ± 7 g on D + 1 and 268 ± 15 g versus 266 ± 7 g on D + 2, two-way analysis of variance, P > 0.05; Fig. 3).



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  		Figure 3. Long-lasting effect induced by intrathecal (IT) morphine 10 µg compared with that of IT morphine 10 µg in an experimental group that had not received nociceptive inputs associated with the measurement procedure on D0 (Group 3) (n = 8 for each group).*P < 0.05 compared with the basal nociceptive threshold value. For graphic clarity, values are mean ± sem.

 

SC ketamine 10 mg/kg did not modify the short-lasting effect of IT morphine 10 µg (one-way analysis of variance, P > 0.05; Fig. 4A).



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  		Figure 4. Short- (A) and long-lasting (B) effects induced by intrathecal (IT) morphine 10 µg after ketamine pretreatment (Group 9) versus saline pretreatment (Group 10) as measured by the paw-pressure test (n = 8 for each group). *P < 0.05 compared with the basal nociceptive threshold value. # P < 0.05: long-lasting hyperalgesia induced by IT morphine 10 µg after ketamine pretreatment versus after saline pretreatment. For graphic clarity, values are mean ± sem.

 

In ketamine-pretreated rats IT morphine 10 µg produced no long-term changes in nociceptive thresholds from D + 2 to D + 5 (one-way analysis of variance, P > 0.05; Fig. 4B) but a significant decrease in nociceptive thresholds on D + 1 (325 ± 10 g versus 351 ± 8 g, respectively, one-way analysis of variance, P < 0.05; Fig. 4B). The decrease in nociceptive thresholds on D + 1 was significantly smaller than that observed in the saline pretreated rats (325 ± 10 g versus 251 ± 7 g, respectively, two-way analysis of variance, P < 0.05; Fig. 4B). SC ketamine 10 mg/kg alone did not induce a significant decrease in nociceptive thresholds on D + 1 when compared with the decrease in nociceptive thresholds in the SC ketamine/IT morphine group (352 ± 18 g versus 325 ± 10 g respectively, two-way analysis of variance, P < 0.05).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding of our study was that a single dose of IT administered morphine induced a long-lasting delayed hyperalgesic effect in rats.

Our results provide clear experimental evidence of a biphasic effect on nociception after a single IT injection of morphine in rats: early analgesia associated with an increase in the nociceptive threshold lasting 3-5 hours was followed by a delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting 1-2 days. This suggests that the delayed decrease in nociceptive threshold reflects an enhancement of pain sensitivity. Previous preclinical studies have reported progressive reduction of baseline thresholds in animals receiving an IT opioid once daily for 8 days (15,18), or in escalating doses (16), or by continuous infusion for days (17,26). The present study is the first to show that a single dose of IT morphine can induce a delayed hyperalgesia. Interestingly, delayed hyperalgesia after an equivalent single dose of SC morphine was significantly less during the first 2 days after morphine administration, indicative of an actual action of intrathecal morphine at the spinal level.

A SC dose of the clinically available NMDA-receptor antagonist ketamine almost completely prevented the development of delayed enhancement in pain sensitivity in IT morphine-administered rats, indicative of NMDA receptors involvement in morphine-induced hyperalgesia.

The tail-flick test has been used for years to detect differences in nociceptive thresholds. However, this test often uses a steep stimulation curve with a fast-increasing stimulation intensity that could mask changes in baseline nociceptive thresholds (1). In contrast, tests that use a slow-increasing stimulation curve such as the paw withdrawal test enable the detection of even subtle changes in nociceptive thresholds (1). As a result, we used the Randall-Sellito test in which a constantly increasing pressure is applied to the rat hindpaw (24). This might explain the discrepancies between our results and those of studies not showing an early hyperalgesia after the first injection of spinal morphine in rats (15–18,26). However, opioids have been shown to exert biphasic effects on both motricity and nociceptive flexor reflex in rodents (27) and NMDA antagonists have been shown to produce both psychomimetic and motor effects (28). This might have influenced the results obtained in our study.

The decrease in the nociceptive threshold and the subsequent enhancement of pain sensitivity might be explained, at least in part, by peripheral nociceptive imputs resulting from basal nociceptive threshold measurements. This is unlikely because the decrease in the nociceptive threshold was also observed in morphine-treated rats unexposed to repeated nociceptive stimuli on the day of morphine administration. On the other hand, the unchanged nociceptive thresholds in morphine-untreated rats indicate that delayed enhancement of pain sensitivity actually results from morphine treatment.

A possible explanation might be a systemic action of IT morphine. This is unlikely because hyperalgesia after systemic administration of morphine 10 µg was significantly less than that after IT morphine 10 µg.

In previous preclinical studies, SC pretreatment with the noncompetitive NMDA-receptor antagonist ketamine 10 mg/kg completely prevented the development of long-lasting hyperalgesia after systemic opioid administration (4,6). In our study, the prevention of delayed enhancement of pain sensitivity by the same dose of SC ketamine was almost complete. This is in accordance with the results of another study in which 10 mg/kg mg of IV ketamine in rats significantly, but not totally, prevented delayed hyperalgesia after IV alfentanil (29).

Concern may arise as to the actual effect of systemically administered ketamine at the spinal level. Nadeson et al. (30) have demonstrated that systemic ketamine enhances the spinally mediated antinociception caused by the µ-selective opioid fentanyl by an action at the level of the spinal cord. SC ketamine is, therefore, likely to act at the spinal level.

Contrary to previous studies (31,32), our results show that ketamine did not significantly enhance the analgesic effect of spinal morphine. However, the cutoff value of 600 g used in the experimental protocol, as in previous studies (4,25), might have impaired correct assessment of the enhancement of the analgesic effect of morphine.

Central sensitization may result from mechanisms including modulation of NMDA (12), dynorphin (33), {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate (34), calcitonin-gene-related peptide (35), and cyclooxygenase (36) in the spinal cord. Furthermore, opioid tolerance is associated with spinal changes that involve activation and translocation of protein kinase C (12–15), modulation of nitric oxide and cholecystokinin (12), and development of neuronal apoptosis (12). In our study, ketamine almost completely prevented the delayed hyperalgesia induced by a single dose of IT morphine but had no effect on the nociceptive threshold when administered alone. Our results indicate that NMDA receptors play a pivotal role in a process of enhancement in pain sensitivity after a single dose of IT morphine. Although speculative, this suggests that preventive administration of systemic ketamine before a single dose of IT opioid may prevent, at least partially, long-lasting enhancement in pain sensitivity induced by the opiate treatment per se.

In the present study, correct placement of the needle into the spinal canal for single IT injection was confirmed by transient bilateral motor hindlimb weakness or paralysis after 400 µg IT lidocaine. In one study, a transient (10-20 min) weakness or paralysis of both hindlimbs was seen in almost all rats after 300 µg IT lidocaine (37). It is therefore likely that transient bilateral motor hindlimb weakness or paralysis after 300 µg IT lidocaine was indicative of correct placement of the needle into the spinal canal. However, concerns may arise as to lidocaine-induced hyperalgesia. In our study, animals receiving IT lidocaine alone did not develop delayed hyperalgesia. Furthermore, in a previous study, lidocaine in combination with morphine did not reduce tolerance to morphine or develop cross-tolerance (20). It is therefore unlikely that lidocaine interfered with the development of morphine tolerance.

Two main reasons led us to use acute puncture at the L4-5 space rather than using a spinal catheter. A single injection was needed in this study, and multiple acute punctures at the spinal level can be successfully performed if needed (23). A catheter implantation as described by Yaksh and Rudy (38) might have been more appropriate to ensure actual IT injection of the total dose of the mixture. However, it has been reported that in rats the location of the catheter tip affects the effect of IT drugs (39). Furthermore, a few days are necessary before experiments to let the animal recover from catheter implantation. Studies have reported that chronic IT catheterization produces morphological signs of inflammation in the spinal cord (40), and can alter the pharmacology of spinally administered drugs (41). Acute spinal injection is therefore preferable to catheter implantation when no more than one spinal injection is necessary. Interestingly, there was no dose-response to IT morphine, whereas a substantial difference between 5 µg and 10 µg might have been expected. This could have resulted from insufficient population of rats in both groups.

From a clinical point of view, the delayed pronociceptive effect demonstrated after a single dose of IT morphine in rats could explain the delayed impairment of postoperative analgesia shown after a single dose of IT opiate in clinical practice. Cooper et al. (42) have indeed shown, in patients undergoing cesarean delivery under spinal anesthesia, a 63% increase in morphine requirement in the postoperative period in patients who had received a single dose of IT fentanyl added to bupivacaine compared with those receiving IT saline. During spinal anesthesia, the addition of IT opioids allows the use of less local anesthetics, provides analgesia in the postoperative period, and decreases the occurrence of side effects (43,44). Association of a single dose of opioid to IT local anesthetics is therefore used worldwide in anesthesia practice (45). In our study, the delayed pronociceptive effect after a single dose of IT morphine was almost completely prevented by systemic ketamine. These findings could therefore be of interest in clinical practice when a single dose of IT opioid is used for analgesia. Further clinical studies are warranted to confirm these experimental results.

In conclusion, a single IT injection of morphine in rats produces a delayed and sustained hyperalgesia linked to the development of opioid-induced pain sensitivity. The noncompetitive NMDA-receptor antagonist ketamine administered SC significantly reduced, but did not completely prevent, the occurrence of morphine-induced hyperalgesia. Further clinical studies are needed to test whether a combined IT morphine-systemic NMDA-receptor antagonist therapy could have a long-lasting beneficial effect in clinical practice.


   Footnotes
 
Accepted for publication June 21, 2005.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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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 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press