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Anesth Analg 2004;99:1180-1184
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130383.87438.A9

PAIN MEDICINE

The Effects of Intrathecal Gabapentin on Spinal Morphine Tolerance in the Rat Tail-Flick and Paw Pressure Tests

C. Hansen*, I. Gilron*,{dagger}, and M. Hong*,{dagger}

Departments of {dagger}Anesthesiology and *Pharmacology & Toxicology, Kingston General Hospital, Queen’s University, Ontario, Canada

Address correspondence and reprint requests to Ian Gilron, MD, MSc, FRCPC, Department of Anesthesiology, Queen’s University, Victory 2 Pavilion, 76 Stuart St., Kingston, ON K7L 2V7, Canada. Address e-mail to gilroni{at}post.queensu.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Analgesic tolerance to opioids has been described in both experimental and clinical conditions and may limit the clinical utility of these drugs. We have previously shown that systemic gabapentin (GBP), a non-opioid drug, prevents and reverses tolerance to systemic morphine in the rat. In this study, we investigated the effect of intrathecal GBP on spinal morphine tolerance. Studied rats were given 7 days of intrathecal injections with saline (10 µL), GBP (300 µg), morphine (15 µg), or a GBP-morphine combination, and analgesic testing using tail-flick and paw-pressure tests was conducted before and 30 min after the drug injection. On Day 8, an antinociceptive dose-response curve was constructed and the 50% effective dose (ED50) values for morphine (given alone) were calculated for each study group. Coinjection of GBP with morphine blocked the development of tolerance, as shown by the preservation of morphine analgesia over 7 days as well as by a concomitant decrease in ED50 values on Day 8, as compared with the morphine-alone group. Although additive analgesia over Days 1–7 cannot be ruled out, ED50 reductions in the GBP-morphine combination group indeed suggest some suppression of tolerance. These data support previous evidence that GBP prevents opioid tolerance and, more specifically, indicate that intrathecal GBP prevents the development of spinal opioid tolerance. Future studies are required to examine the respective roles of supraspinal and peripheral sites of GBP-morphine interaction and to investigate the mechanisms underlying the action of GBP on opioid tolerance.

IMPLICATIONS: Analgesic opioid tolerance may limit the efficacy of opioids, such as morphine, and has underlying mechanisms that are also important in the development of neuropathic pain. This study supports previous evidence that gabapentin prevents opioid tolerance and more specifically indicates that intrathecal gabapentin prevents the development of spinal opioid tolerance.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The analgesic efficacy of opioids has been well recognized for several centuries. Exogenous opioids mimic the actions of the endogenous peptides at opioid receptors to produce a variety of actions including the reduction of pain (1). However, the utility of opioids may be limited by analgesic tolerance, which is defined as the phenomenon whereby exposure to opioids results in the attenuation of effect or the requirement of a larger dose to produce the same effect (1). Whereas the conditions required for the development of human opioid tolerance are unclear (2,3), this phenomenon is particularly robust in experimental models of acute nociception (4). Further understanding of this phenomenon will lead to greater insight into pain mechanisms and may be important in developing novel analgesic treatments.

Several contributory mechanisms implicated in the genesis of opioid tolerance include the modulation of dynorphin (5), N-methyl-D-aspartate (NMDA) (6), 2-amino-3-hydroxy-5-methyl-4-isoxazole-propioinic acid (AMPA)/kainate (7), calcitonin gene-related peptide (8), and cyclooxygenase (9) at the level of spinal cord. Modulation of these factors can also produce antinociceptive effects (10–12). Furthermore, the phenomenon of opioid tolerance involves spinal changes that similarly occur in nerve or tissue injury and involve activation and translocation of protein kinase C (PKC) and the modulation of nitric oxide and cholecystokinin (6).

Gabapentin (GBP) is a novel anticonvulsant and analgesic drug that has demonstrated antinociception in several animal models of nerve and tissue injury through several possible mechanisms. Singh et al. (13) found that GBP dose-dependently inhibited the late phase of the formalin test, which is thought to represent a sensitized state of nociception. Hunter et al. (14) found that GBP reversed cold allodynia in the chronic constriction injury model and reversed tactile allodynia in the spinal nerve ligation model. Field et al. (15) reported that GBP prevented the development of allodynia and hyperalgesia in an animal model of postoperative pain. Takasaki et al. (16) showed that systemic or intrathecal GBP dose-dependently inhibited both allodynia and hyperalgesia in mice with acute herpetic pain.

For humans, treatment of chronic pain associated with nerve injury or disease is one of the leading indications for GBP. Several randomized, controlled trials have reported pain reduction with GBP in conditions such as postherpetic neuralgia (17), painful neuropathy associated with diabetes mellitus (18), and postamputation phantom limb pain (19). GBP is well tolerated in patients (20), and the list of potential unlabeled indications is expanding.

Whereas GBP has been shown to reduce experimental and clinical neuropathic pain, the relative contribution of several pharmacological mechanisms to its antinociceptive effect is uncertain. GBP is an analog of the neurotransmitter {gamma}-aminobutyric acid (GABA); however, there is no evidence for the binding of GBP to GABA receptors, and GBP’s actions are not antagonized by GABA receptor antagonists (21). More recent evidence points to a previously identified GBP binding site—the {alpha}2{delta} subunit of the calcium channel (22). The antinociceptive efficacy of GBP analogs seems to depend upon their binding affinity at the {alpha}2{delta} site (23), and one study has shown that up-regulation of this site in experimental neuropathic pain was associated with GBP efficacy (24).

Field et al. (25) have previously demonstrated that GBP analgesia is naloxone insensitive, chronic GBP administration does not lead to analgesic tolerance, and morphine tolerance does not influence GBP analgesia in the rat formalin test. Previous preclinical studies have shown additive, or possibly synergistic, analgesic interactions between GBP and opioids such as morphine. Shimoyama et al. showed that intrathecal GBP significantly enhanced the effect of an intrathecal subanalgesic dose of morphine in the rat (26). An electrophysiological study in the rat suggests that GBP enhances the antinociceptive effectiveness of morphine after experimental nerve injury (27). Eckhardt et al. (28) showed that GBP increases morphine analgesia in normal volunteers, and Dirks et al. (29) found that a preoperative dose of GBP resulted in a significant reduction in morphine consumption and movement-related pain after mastectomy. We have reported (30) on the prevention and reversal of systemic opioid tolerance by systemically administered GBP in the rat tail-flick and paw-pressure tests. The purpose of the present study is, more specifically, to evaluate the effect of intrathecal GBP on spinal opioid tolerance to test the hypothesis that intrathecal GBP prevents spinal opioid tolerance.


   Methods
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Results
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Experiments were performed on male Sprague-Dawley rats (250–350 g; Charles River, St Constant, QC, Canada). All procedures were in accordance with the Guidelines of the Canadian Council on Animal Care and approved by the Queen’s University Animal Care Committee. Rats were housed in a controlled environment on a 12-h light/dark cycle at 22°C and allowed free access to food and water.

Intrathecal catheters (polyethylene PE10 tubing, 8 cm; Becton Dickinson, Franklin Lakes, NJ) were inserted under 2% halothane anesthesia using the method of Yaksh and Rudy (31). Briefly, rats were placed prone in a stereotaxic frame. A posterior cervical incision was made, and the atlanto-occipital membrane was exposed at the level of the cisterna magna. The catheter was inserted through a puncture in the membrane into the subarachnoid space and advanced caudally so the tip rested on the lumbar enlargement. The rostral end of the catheter was exteriorized at the top of the head, and the wound was closed with sutures. The rats were allowed 5 days to recover from surgery. Rats showing signs of motor dysfunction (e.g., paralysis) were excluded from the study. All drugs were injected through the exteriorized portion of the catheter in a volume of 10 µL followed by 10 µL of saline (0.9%) to flush the catheter.

Nociceptive testing was performed using two spinal reflex tests: the tail-flick test and the paw-pressure test. The tail-flick test was administered first, immediately followed by the paw-pressure test. Each test was performed 3 times, and an average of the 3 results was used. Testing was performed before and 30 min after drug administration to determine baseline and treatment responses, respectively.

The tail-flick test measures the response to a thermal nociceptive stimulus (32). Radiant heat generated from a 150-W bulb is applied to the base of the tail. The tail-flick latency is defined as the time between the onset of the heat stimulus and voluntary tail withdrawal. A photosensor automatically shuts off the bulb and records the time when the rat moves its tail. The intensity is adjusted to yield a baseline response of 2–3 s. A cutoff time of 10 s is used to avoid tissue injury, in which case, 10 s is recorded.

The paw-pressure test measures the response to a mechanical nociceptive stimulus (33). An inverted air syringe is used to apply mechanical pressure to the dorsal surface of the rat’s hindpaw. The paw-pressure is defined as the pressure at which the rat voluntarily withdraws its hindpaw and is measured from a blood pressure gauge and recorded. A cutoff of 300 mm Hg is used to avoid tissue injury, in which case, 300 mm Hg is recorded.

To induce spinal tolerance, rats were given 15 µg of morphine in 10 µL of saline followed by a 10-µL saline flush daily between 10:00 and 11:00 AM for 7 days (morphine group). The dose of 15 µg of morphine used for daily administration was known to provide maximal antinociception from previous work, and work in other laboratories has shown this dose results in the development of tolerance over a 7-day treatment period (9). Nociceptive testing was performed before drug administration to determine baseline and 30 min after to determine drug effect. On the eighth day, a cumulative dose response curve was generated for morphine alone. This was performed by administering morphine in ascending doses at 30-min intervals and performing nociceptive testing every 30 min. This was continued until a maximal antinociceptive response was obtained in both tail-flick and paw-pressure tests. The 50% effective dose (ED50) values for each dose-response curve were calculated as an indicator of morphine potency. The development of tolerance was recognized by a progressive decline in morphine effect over the 7 days and an increase in the morphine ED50 values caused by a rightward shift in the morphine dose-response curve.

To investigate the effect of GBP on the development of tolerance, GBP (300 µg/5 µL of saline), morphine (15 µg/5 µL of saline), and 10 µL of saline were coinjected for 7 days (combo[1–7] group). The daily dose of 300 µg of GBP was selected based on a literature search of doses that had no effect in acute pain (26). Preliminary studies performed in our laboratory confirmed this. Nociceptive testing was performed before and 30 min after, as described above. On the eighth day, a morphine dose-response curve was performed with ascending doses of morphine alone (i.e., in the absence of GBP), and an ED50 value was calculated.

Additionally, a vehicle control group and a GBP-alone treatment control group were studied. The vehicle control group received 10 µL of saline with a 10-µL saline flush for Days 1–7 (saline group), the GBP-alone treatment control group received GBP (300 µg/10 µL of saline) with a 10-µL saline flush for Days 1–7 (GBP group). ED50 values were determined on Day 8, as described above.

The cumulative doses of morphine used for the ED50 determination (in micrograms) were 0, 2.5, 7.5, 17.5, and 37.5 for the saline, GBP and combo(1–7) groups, and 0, 12.5, 37.5, 87.5, 187.5, and 387.5 for the morphine group. Drug dosing was performed directly after predrug nociceptive testing, and postdrug nociceptive testing was performed 30 min after treatment.

Morphine was obtained from BDH pharmaceuticals (Toronto, ON, Canada), and GBP was obtained from Pharma Science Inc (Montreal, QC, Canada). All drugs were dissolved in 0.9% saline.

Tail-flick and paw-pressure values were converted to a maximum percent effect (MPE): (A) for tail flick latency: MPE = 100 x (postdrug latency – baseline latency)/(cutoff time – baseline latency) (cutoff time = 10 s); (B) for paw pressure: MPE = 100 x (postdrug pressure – baseline pressure)/(cutoff pressure – baseline pressure) (cutoff pressure = 300 mm Hg).

Statistical significance (P < 0.05) was determined using a two-way, repeated-measures, analysis of variance (treatment by time) followed by Bonferroni post hoc tests. ED50 values were determined using nonlinear regression analysis followed by one-way analysis of variance with a Newman-Keuls post hoc test for multiple comparisons among groups.


   Results
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Discussion
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Figures 1 and 2 show the effects of GBP on the induction of spinal morphine tolerance in the tail-flick (Fig. 1) and paw-pressure (Fig. 2) tests, respectively. As shown, the administration of a 15-µg dose of intrathecal morphine alone produced antinociception in both tests, which progressively declined over 7 days of repeated administration. The administration of GBP alone exerted no significant effect on nociception in the tail-flick or paw-pressure tests, and the values obtained after the daily administration of the drug corresponded with those obtained with saline. However, the combination of GBP with morphine on a daily basis (combo(1–7) group) significantly attenuated the decline of morphine effect. The antinociceptive effect of morphine was maintained at maximal value during the entire test period. The potency values of morphine obtained on Day 8 in the four treatment groups are represented in Table 1. As illustrated, administration of chronic morphine produced a significant increase in ED50 value (compared with vehicle controls), reflecting the development of tolerance. Coadministration of GBP with morphine prevented this increase in both the tail-flick and paw-pressure tests, reflecting the inhibition of tolerance. The administration of GBP alone from Days 1–7 did not significantly modify the morphine ED50 value in either test.


Figure 1
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  		Figure 1. Tail-flick responses (mean ± SEM) to repeated daily administration of saline, gabapentin, morphine, and morphine plus gabapentin on Days 1–7 (combo(1–7) group). All doses of morphine and gabapentin are 15 µg and 300 µg, respectively. *P < 0.05 compared with morphine alone. {dagger}P < 0.05 compared with saline.

 

Figure 2
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  		Figure 2. Paw-pressure responses (mean ± SEM) to repeated daily administration of saline, gabapentin, morphine, and morphine plus gabapentin on Days 1–7 (combo(1–7) group). All doses of morphine and gabapentin are 15 µg and 300 µg, respectively. *P < 0.05 compared with morphine alone. {dagger}P < 0.05 compared with saline.

 

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  		Table 1. Effect of Gabapentin on the Development and Reversal of Spinal Morphine Tolerance: Morphine ED50 Results
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study suggests that intrathecal GBP blocks the development of spinal opioid tolerance in models of thermal and mechanical nociception. Although the maintenance of morphine antinociception throughout the seven days of morphine-GBP coadministration could have been, in part, due to an additive interaction between intrathecal morphine and GBP (26), the subsequent reduction in Day 8 morphine (alone) ED50 values in the morphine-GBP group indeed suggest some suppression of tolerance. Previous work from our laboratory has demonstrated that systemically administered GBP prevents the development of systemic morphine tolerance (30). The data presented here support this evidence and, more specifically, indicate that intrathecal GBP prevents the development of spinal opioid tolerance.

As indicated in the study methods, we used wider dosage intervals during Day 8 ED50 studies for the morphine group than for the other treatment groups so as to span over the documented wider-ranging dose-response of morphine in opioid tolerant animals. Therefore, the above study results should be interpreted in light of the chance that ED50 differences between the morphine group and the other groups could be partially affected by the differences in ED50 study dosing regimens.

Because the relative importance of GBP’s various analgesic mechanisms and those underlying opioid tolerance are unclear, understanding the interaction between the two is difficult. In the central nervous system, GBP has been found to bind to the {alpha}2{delta} subunit of the calcium channel (22) with binding properties that mirror its activity profile, thus implicating an antinociceptive role for this calcium channel subunit (34). Furthermore, upregulation of the {alpha}2{delta} subunit in a model of neuropathic pain correlates with the antiallodynic effect of GBP (35). Whereas this subunit has not been linked directly to the development or maintenance of opioid tolerance, it may have a role in this phenomenon because tolerance and hyperalgesia are thought to share common mechanisms (36). One common link between morphine tolerance and GBP analgesia is the modulation of glutamate receptors (NMDA and AMPA/kainate). The roles of NMDA (37) and AMPA/kainate (7) receptors have been demonstrated in previous studies of opioid tolerance. GBP seems to decrease both NMDA and non-NMDA-mediated glutamate currents in the superficial lamina of the rat spinal cord (38) and also inhibits nociceptive responses to intrathecal NMDA and AMPA in vivo (39). Furthermore, the analgesic effects of GBP are antagonized by the NMDA/glycine receptor agonist serine (13,40). GBP has also been shown to block the PKC-evoked release of glutamate in vitro (41), increased levels of PKC are involved in morphine tolerance (6).

In conclusion, these data further support previous evidence that GBP prevents opioid tolerance and more specifically indicate that intrathecal GBP prevents the development of spinal opioid tolerance. Future studies are required to examine the respective roles of supraspinal and peripheral sites of action and to investigate the mechanisms underlying the action of GBP on opioid tolerance.


   Acknowledgments
 
Supported, in part, by Queen’s University Research Initiation Grants (Kingston, Ontario, Canada) to I.G. and M.H. and by Pharma Science Inc (Montreal, Quebec, Canada) in the form of study drug (gabapentin) provision. I.G. is supported by a CIHR New Investigator Award (Canadian Institutes of Health Research, Ottawa, Ontario, CANADA).

The authors wish to thank Dr. Khem Jhamandas for helpful comments made on previous versions of this manuscript.


   References
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Accepted for publication April 6, 2004.




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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 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press