Anesth Analg 2000;91:417-422
© 2000 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MEDICINE
The Effect of Spinal Ibuprofen on Opioid Withdrawal in the Rat
Stuart A. Dunbar, MB,
Ivan G. Karamov, MD, and
Hartmut Buerkle, MD
Department of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, Massachusetts
Address correspondence and reprint requests to Stuart Dunbar, MB, Assistant Professor, Department of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, MA 01199. Address e-mail to sdunbar{at}library.bhs.org
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Abstract
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This study examines the effect of spinal ibuprofen on the behavioral manifestations associated with the opioid abstinence syndrome. Rats (n = 8 per group) were infused for 5 days with morphine and then pretreated with a spinal bolus dose of ibuprofen before systemic naloxone antagonism (300 µg). Groups included ibuprofen S(+) 1.36, 13.6, and 136 nmol, and ibuprofen R(-) 136 nmol. A separate group of saline-infused rats was given ibuprofen S(+) 136 nmol before naloxone antagonism. Ibuprofen S(+), but not R(-),dose-dependently and stereospecifically blocked opioid withdrawal hyperalgesia but did not significantly alter other signs of the opioid abstinence syndrome. We conclude that hyperalgesia associated with opioid withdrawal can be blocked by spinally administered ibuprofen, and suggest that there may be a role for spinal prostaglandins in the enhancement of nociception observed in association with the opioid abstinence syndrome.
Implications: This study shows that spinal ibuprofen blocks opioid withdrawal hyperalgesia in the rat in a stereospecific fashion, implicating the likely release of spinal prostaglandins during withdrawal and their possible role as neuromodulators in the enhancement of nociception that accompanies this phenomenon.
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Introduction
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Opioid withdrawal is associated with behavioral manifestations in the rat which can be blocked by various pharmacological drugs, including 
2 agonists, NMDA receptor antagonists, and nitric oxide synthetase inhibitors. One of these signs is an enhancement of nociception or thermal hyperalgesia (1). The cause of this hyperalgesia is unknown, but may be secondary to the spinal release of neurotransmitters (2), which are known to cause dorsal horn excitation (3). Prostaglandins, in particular PGE2, have been implicated as spinal neuromodulators in nociception (4); however, there are no studies examining a potential role for prostaglandins in the manifestations associated with opioid withdrawal. In vitro studies have shown that prostanoids mediate signs of morphine withdrawal in guinea pig ileum (5). We thus, hypothesized that the nonsteroidal antiinflammatory drug (NSAID) ibuprofen, administered spinally, would block signs of the opioid abstinence syndrome, in particular, that of hyperalgesia.
A chronic infusion of morphine to produce a state of dependence was achieved through an indwelling spinal catheter pump system which provided for the continuous delivery of drug to the central nervous system without the use of daily drug injections. This system eliminates the effects of periodic withdrawal that daily dosing has on thermal withdrawal latencies (6). At the end of the infusion period the indwelling spinal catheter was then used to administer ibuprofen directly to the spinal cord just before naloxone-precipitated withdrawal. Any effect that such pretreatment had on signs of withdrawal was then interpreted as being spinal in effect.
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Methods
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Approval for this study was obtained from the institutional animal care and use committee. Male Sprague-Dawley rats (350–400 g) were each implanted with an intrathecal (IT) catheter attached to a subcutaneous miniosmotic pump filled with morphine as described below, and thereafter, housed in individual standard cages at room temperature on a 12 h light/12 h dark cycle (lights on at 7:00 AM). Testing was performed during the light cycle. Animals had free access to food and water. Preparation of catheter and implantation of pump was as described previously (7). A 16-cm length of PE-10 tubing was connected to a 2-cm length of PE-60 tubing by hot-air jet. A 1-cm piece of silastic tubing presoaked in chloroform to increase its internal diameter was then passed over both ends of the PE-10 tubing to form a loop 3 cm from the end of the PE-10 tubing fused to the PE-60 tubing. The long end of the catheter was cut at 9 cm from the silastic tubing and the catheter was soaked in alcohol for sterilization overnight. An Alzet osmotic minipump delivering 1 µL/h (2001; Alza, Palo Alta, CA) was filled with 20 nmol/µL morphine sulfate or saline and attached to the saline-flushed catheter. This pump delivers a constant infusion of 1 µL/h for 7 days after an initial activation period of 4 h in vivo. We used this method of morphine administration because of the associated convenience of attaching an indwelling morphine pump to this spinal catheter without the need to handle the animals daily and inject them with morphine, which we have shown can lead to hyperalgesia (6). For catheter placement, the rat was anesthetized with halothane and placed in a stereotaxic head holder. A midline incision was made to expose the atlantooccipital membrane. The membrane was pierced, and the PE-10 end of the catheter passed intrathecally to a distance of 8.5 cm caudal to the level of the thoracolumbar junction. The pump was then attached to the PE-60 end of the catheter and implanted subcutaneously in a pouch behind one shoulder. The loop end of the catheter was passed rostrally to exit percutaneously on the top of the skull. This PE-10 loop was cut at the end of a 5-day infusion period and used to administer external doses of drug spinally. The wound was then sutured, including a loose ligature at the base of the loop to prevent it from moving. Animals fully recovered 15 to 30 min after implantation. Rats showing any sign of neurological disorder were immediately killed with an overdose of barbiturate.
Rats were randomly assigned to each of the groups described below. All rats received a continuous 5-day infusion of 20 nmol/µL/h spinal morphine (M) or 1 µL/h saline. On the 5th day the external loop of the catheter was cut and the IT part of the catheter flushed with 20 µL of saline. After 4 h, all animals were tested on a hot box (Paw Thermal Stimulator System; University of California, San Diego, CA) infrared thermal stimulus to right rear paw, cutoff latency 21 s. Five minutes before the administration of intraperitoneal (IP) injection of 300 µg naloxone in 0.2 mL saline, morphine-infused animals (n = 8 per group) received a spinal injection of 10 µL of 5% cyclodextrin, (M, Cyclo), ibuprofen S(+) 136 nmol (M, Ibu S[+] 136 nmol), ibuprofen 13.6 nmol (M, Ibu S[+] 13.6 nmol), ibuprofen 1.36 nmol (M, Ibu S[+] 1.36 nmol), or ibuprofen R(-) 136 nmol (M, Ibu R[-] 136 nmol). Five minutes before the administration of IP injection of 0.2 mL saline, a separate saline-infused group (n = 8) received a spinal injection of ibuprofen S(+) 136 nmol; (Sal, Ibu S[+] 136 nmol). The highest dose of ibuprofen S(+) 136 nmol was the highest that could be maintained in solution. The dose of 136 nmol ibuprofen R(-) was selected because it was the highest dose possible to maintain in solution, and doses smaller than this in pilot studies were found to have no significant effect. The dose of naloxone administered was determined from preliminary studies where, after the same 5-day infusion of 20 nmol/µL/h morphine and 4 h after flushing the IT catheter with 20 µL saline, animals received either 0.2 mL IP saline or three doses of IP naloxone (3, 30, or 300 µg) in 0.2 mL saline. Based on these preliminary studies, the dose of naloxone selected produced a significant hyperalgesia lasting up to 60 min (300 µg naloxone). The results of these studies are also shown. Thermal withdrawal latencies were measured at 15, 30, and 60 min after the administration of naloxone in all studies. Animals were observed during this time for the following withdrawal signs: head shaking, teeth chattering, spontaneous squeaking, jumping, urination, and squeaking in response to application of a Von Frey hair (size 4.65) to the rear flank. Previous studies (7) using a similar model had shown these to be the prevalent signs of withdrawal in this model. Animals were given a score of 1 or 0 for each of these signs during the course of each time interval. The Von Frey test was carried out at the start of each of these time intervals. After testing, all rats were killed by overdose of barbiturate on the last day of testing.
The following drugs were used: morphine (morphine sulfate; molecular weight = 334) (Merck, Sharpe and Dohme, West Point, PA); naloxone hydrochloride (molecular weight = 363.8) (Sigma Chemical, St. Louis, MO); and ibuprofen S(+) and R(-) (molecular weight = 206.27) (Research Biochemical, Natick, MA). Morphine was delivered in physiological saline (0.9% wt/vol). Ibuprofen was prepared in a 5% solution of 2-hydroxypropyl-y-cyclodextrin (molecular weight = 1667) (Research Biochemicals).
Escape latencies, in seconds, were analyzed by analysis of variance (ANOVA) repeated measures, significance at P < 0.05. In cases of stated significance, a post hoc Scheffe’s test was performed (significance, 95% confidence interval [CI]). Data for withdrawal signs were assessed as follows. Withdrawal scores for each animal were added to give a total for each group. Groups were then compared by using Kruskal-Wallis analysis, significance at P < 0.05.
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Results
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The effect of naloxone antagonism on escape latencies is summarized in Figure 1. Baseline latencies were not significantly different across all groups. In the group that received saline in lieu of naloxone, there was no significant effect of saline administration, testing, or handling on withdrawal latencies as compared with baseline values. Naloxone IP was associated with a dose-dependent decrease in latencies maximal at 300 µg. Latencies in this group decreased significantly from baseline; 11.1 ± 0.8 s to 7.0 ± 0.3 s, and 7.2 ± 0.6 s at 15 and 30 min, returning to levels not significantly different from baseline at 60 min. This was significantly less than all other groups at 15 and 30 min. Latencies in the 30 µg naloxone group decreased significantly from a baseline of 11.2 ± 0.3 s to 9.3 ± 0.6 s at 15 min returning to levels not significantly different from baseline or any of the other groups at 60 min. Latencies in the 3 µg group did not change significantly over baseline or saline groups at any time.
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Figure 1. The effect of intraperitoneal naloxone or saline on thermal withdrawal latencies in rats (n = 4–7), infused for 5 days with 20 nmol/µL/h intrathecal morphine. Groups include those that received 300 µg, 30 µg, and 3 µg of naloxone in a total volume of 0.2 mL saline, or 0.2 mL intraperitoneal saline after which thermal withdrawal latencies were measured before, and 15, 30, and 60 min after, such treatment. Hyperalgesia lasting up to 60 min occurred after the administration of 300 µg of naloxone. Data show latencies (x ± SE mean) at 15, 30, and 60 min. *Significance versus saline, 30 µg, and 3 µg naloxone groups, **Significance versus saline, 300 µg, and 3 µg naloxone groups, (P < 0.05, analysis of variance, Scheffe’s test, 95% CI).
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The effect of spinal ibuprofen on withdrawal hyperalgesia is summarized in Figure 2. All groups had baseline latencies that were not significantly different. Latencies in the Sal, Ibu S(+) 136 nmol group were not significantly different from baseline at any time showing no significant effect of testing, handling, or Ibu S(+) ibuprofen at this highest dose in the absence of a withdrawal syndrome. A significant decrease in latencies occurred in the M, Cyclo; M, Ibu R(-) 136 nmol; and M, Ibu S(+) 1.36 nmol groups at 15 and 30 min compared with this saline-infused group; 15 min latencies were 6.9 ± 0.4, 7.2 ± 0.3, and 6.9 ± 0.3, respectively, versus 10.7 ± 0.4 s; 30 min data in saline-infused rats was 7.2 ± 0.4, 7.5 ± 0.6, and 8.1 ± 0.5, respectively, versus 10.7 ± 0.5 s. In saline-infused rats, P < 0.05, ANOVA, Scheffe’s test (95% CI). The M, S(+) 13.6 nmol group showed a significant decrease in latencies at 15 min only (8.8 ± 0.3 s), P < 0.05, ANOVA, Scheffe’s test (95% CI). There was, however, no significant decrease in latencies in the M, Ibu S(+) 136 nmol group as compared with the saline-infused control group at any time.
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Figure 2. Effect of intrathecal ibuprofen (ibu) on morphine withdrawal hyperalgesia. Rats (n = 8 per group), infused for 5 days with 20 nmol/µL/h intrathecal morphine (M), were given a spinal injection of 10 µL of 5% cyclodextrin (M, Cyclo); ibuprofen S(+) 1.36 nmol (M, Ibu S[+] 136 nmol); ibuprofen 13.6 nmol (M, Ibu S[+]13.6 nmol); or ibuprofen 1.36 nmol (M, Ibu S[+] 1.36 nmol); or ibuprofen R(-) 136 nmol in 5% cyclodextrin (M, Ibu R[-] 136 nmol), followed 5 min later by 300 µg intraperitoneal injection of naloxone in 0.2 mL saline. A 1 µL/h saline infused (for 5 days) control group, (n = 8), also received a spinal injection of 10 µL of ibuprofen (S+) 136 nmol (Sal, Ibu S[+] 136 nmol), followed 5 min later by the intraperitoneal injection of saline. Data show thermal withdrawal latencies (x ± SE mean) immediately before, and at 15, 30, and 60 min after naloxone antagonism or saline administration. The active enantiomer of ibuprofen dose-dependently blocked withdrawal hyperalgesia. *Significance of M, Cyclo; M, Ibu S(+) 1.36 nmol; and M, Ibu R(+) 136 nmol versus Sal, Ibu S(+) 136 nmol; M, Ibu S(+) 136 nmol; M, Ibu S(+) 13.6 nmol and **Significance of M, Ibu S(+) 13.6 nmol versus Sal, Ibu S(+) 136 nmol and M, Ibu S(+) 136 nmol groups (P < 0.05, analysis of variance, Scheffe’s test, 95% CI).
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Results of spinal ibuprofen on other signs of withdrawal are summarized in Figure 3. No signs were observed in saline-infused rats. There was no significant difference by Kruskal-Wallis analysis in any specific sign among all morphine-infused groups, (P < 0.05).
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Figure 3. Effect of spinal ibuprofen on other signs of withdrawal assessed. Rats (n = 8 per group) infused for 5 days with 20 nmol/µL/h intrathecal morphine, were given a spinal injection of 10 µL of a = 5% cyclodextrin, b = ibuprofen S(+) 136 nmol in 5% cyclodextrin, c = ibuprofen 13.6 nmol in 5% cyclodextrin, d = ibuprofen 1.36 nmol in 5% cyclodextrin, or e = ibuprofen R(-) 136 nmol in 5% cyclodextrin, all followed 5 min later by 300 µg intraperitoneal injection of naloxone in 0.2 mL saline. Animals were then observed for one of five signs of withdrawal at time intervals over 1 h after naloxone antagonism and assigned a score of 1 or 0 for each sign for each time interval, maximal score 18 per animal and 144 per group. Signs included: jumping (j), squeaking to light touch (lt), urination (u), head shaking (hs), spontaneous squeaking (ss), and teeth chattering (tc). A 1 µL/h intrathecal saline infused (for 5 days) control group, (n = 8), also received a spinal injection of 10 µL of ibuprofen (S+) 136 nmol; (Sal, S[+] 136 nmol), followed 5 min later by the same intraperitoneal injection of naloxone; 300 µg in 0.2 mL saline, but showed none of these signs of withdrawal (group not shown). Data show withdrawal scores, represented as a percentage of maximal possible score, for each sign in each group. No significant difference was found across groups, Kruskal-Wallis analysis, (P < 0.05). These results show that pretreatment with spinal ibuprofen at a dose that effectively blocked withdrawal thermal hyperalgesia had no significant effect on other signs of withdrawal observed.
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Discussion
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Naloxone antagonism in the opioid-dependent state produced a dose-dependent enhancement of nociception or "hyperalgesia" as well as a variety of other signs of the abstinence syndrome i.e., jumping, spontaneous squeaking, squeaking in response to light touch, urination, teeth chattering, and head shakes (wet dog shakes). Although hyperalgesia has not yet been proven to be mediated through spinal sites, there are several studies to support this contention (withdrawal is associated with the release of spinal neurotransmitters and a dorsal horn excitation phenomenon that can be blocked by spinally administered drugs, such as NMDA receptor antagonists) (2,3,6). Also withdrawal hyperalgesia has been described in spinalized rats that have had a cervical transection of the cord, indicating that it does not require a supraspinal mechanism (8). The dose of 300 µg IP naloxone was found to be associated with a significant hyperalgesia lasting for at least 30 min in the first part of the study (Fig. 1). Spinal pretreatment with S(+), but not R(-) ibuprofen, dose-dependently and stereospecifically blocked withdrawal hyperalgesia (maximal effect of S(+) at 136 nmol) (Fig. 2). No antinociceptive effect was seen when this dose of 136 nmol of ibuprofen S(+) was administered to animals previously infused with saline showing no direct antinociceptive effect of ibuprofen on thermal escape latencies in the absence of a withdrawal syndrome. This is consistent with previous studies showing a lack of effect in thermal withdrawal tests (9). The observed stereospecificity of ibuprofen suggests that inhibition of spinal cyclooxygenase (COX) and spinal prostaglandins is the mechanism by which this occurs.
Although phospholipase A2, COX-1, COX-2, and 5-lipoxygenase inhibitors have been shown to block guinea pig ileum contracture during antagonism in the opioid-dependent state (5), there are no studies examining a role for spinal prostaglandins in the opioid abstinence syndrome. There is, however, substantial evidence for their role in pain models where spinal facilitation of nociception occurs. The administration of IT NSAIDs blocks nociception in models, such as the chronic sciatic nerve injury model (10). Spinal release studies have also shown that PGE2 is released in the formalin test (11) and that PGE2 antagonist SC-51234A blocks Phase 2 of this test (12). Spinal release of PGE2 after capsaicin administration can also be prevented by pretreatment with ketorolac and indomethacin (13). Furthermore, there is evidence for the presence of COX enzymes in the spinal cord; COX-1 has been identified in the dorsal root ganglia, and COX-2 in laminas 1, 2, and 10 (4). Studies have shown an increase in COX-RNA and PGE2 in the spinal cord after the administration of intraplantar Freund’s adjuvant which can be blocked by pretreatment with indomethacin (14). Finally, the administration of prostanoids (PGE1) directly to the spinal cord has been associated with an allodynic state persisting for several days after a single IT administration (15). Thus, the observation that opioid withdrawal is associated with enhanced nociception, and that this can be stereospecifically blocked by spinal ibuprofen, suggests that withdrawal involves the mobilization of spinal prostanoids which cause a similar effect on nociception to that found in various chronic pain states. In this study, the dose of ibuprofen found to block hyperalgesia was similar to that observed in studies of the antinociceptive effects of spinal ibuprofen in other pain states (16). A systemic effect of this discrete dose delivered to the spinal cord appears unlikely.
How prostaglandins might enhance nociception during withdrawal is unclear. In various pain models, it has been proposed that excitatory amino acid release is the initial event that subsequently leads to PGE2 mobilization (17,18). Thus NSAIDs might be expected to block hyperalgesia associated with withdrawal by inhibition of prostaglandin mobilization that occurs as a consequence of excitatory amino acid release. Arachidonic acid is released during long-term potentiation in the rat hippocampus (19), and thus, to be involved in this type of synaptic plasticity (20). Furthermore, behavioral studies in the rat have shown that hyperalgesia caused by the spinal administration of the glutamate or substance P can be inhibited by spinal COX inhibition (16). PGE2, however, has also been shown to augment depolarization and subsequent excitatory amino acid and substance P release from sensory neurons (20). Thus, PGE2 may have a positive feedback effect on excitatory amino acid release during withdrawal. On the other hand, ibuprofen may have a direct effect on spinal neurons, also. NSAIDs have been shown to hyperpolarize neurons by increasing outward K+ conductance, the reverse of which has been proposed as a mechanism of how PGE2 might enhance nociception (20). Because excitation of the dorsal horn is a feature of opioid withdrawal, ibuprofen may hyperpolarize second-order neurons during withdrawal, raising their threshold for discharge and thus, blunting the reactivity of these neurons. Substance P stimulates the release of PGE2 from spinal neurons (21), and if substance P were to be released during withdrawal, it might mobilize PGE2. On the other hand, hyperalgesia associated with the administration of spinal substance P is unresponsive to spinal ibuprofen in other studies (22), and there is no direct evidence of spinal substance P release during withdrawal (23).
We have previously shown that NMDA receptor activation occurs in association with opioid withdrawal, and that this has a lasting effect on nociception (6). It would appear that withdrawal is associated with similar neuroplastic changes in the nociceptive processing as that associated with chronic pain. This being that case, one might have expected that the "allodynia" or light-touch sensitivity observed in this study would also have been blocked by ibuprofen. This phenomenon does not appear to be a startle effect, but is associated with signs of distress lasting for 5–10 s after the test is administered. This is surprising, given that PGE2 has been observed to cause light-touch hypersensitivity or allodynia when administered spinally (24). However, studies of A ß-fiber-evoked activity in the spinal cord have shown that salicylic acid, even at large doses which significantly depress C fiber activity, appears to have no effect on allodynia (25).
In summary, these results add further evidence to support the hypothesis that opioid withdrawal hyperalgesia is a spinally mediated phenomenon and show that spinal administration of ibuprofen stereospecifically and dose-dependently blocks this hyperalgesia, suggesting that spinal prostaglandins play a role in the opioid abstinence syndrome. Further investigation of the role of spinal prostaglandins in the neuroplasticity associated with opioid withdrawal would, therefore, appear indicated.
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Acknowledgments
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Supported, in part, by a starter grant from Baystate Health Systems.
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Accepted for publication April 21, 2000.
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Abstract
Introduction
