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PAIN MEDICINE

The Antiallodynic Action Target of Intrathecal Gabapentin: Ca²⁺ Channels, K_ATP Channels or N-Methyl-d-Aspartic Acid Receptors?

Jen-Kun Cheng, MD^*, Chien-Chuan Chen, MD^*, Jia-Rung Yang, BS^*, and Lih-Chu Chiou, PhD

*Department of Anesthesiology, Mackay Memorial Hospital; Institute and Department of Pharmacology, College of Medicine, National Taiwan University; Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan

Address correspondence and reprint requests to Professor Lih-Chu Chiou, Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei 100, Taiwan. Address e-mail to lcchiou{at}ha.mc.ntu.edu.tw.

	Abstract

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Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca²⁺ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 µg) was not affected by intrathecal pretreatment with antagonists of K_ATP channels, NMDA receptors or gamma-aminobutyric acid (GABA)_A receptors. K_ATP channel openers and GABA_A receptor agonist, per se, had little effect on the postincision allodynic response. The Ca²⁺ channel blocker of N-type (-conotoxin GVIA, 0.1–3 µg), but not of P/Q-type (-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and -conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca²⁺ channel activator. These results provide correlative evidence to support the contention that N-type Ca²⁺ channels, but not K_ATP channels or NMDA or GABA_A receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.

	Introduction

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Gabapentin, a -aminobutyric acid (GABA) analog, was developed as a brain-penetrating anticonvulsant (1). It is also an analgesic for postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and migraine prophylaxis (2). The mechanism of action of gabapentin remains unclear, although several targets have been proposed.

Adenosine triphosphate-sensitive K⁺ (K_ATP) channels were found to be involved in gabapentin-induced inhibition of [³H]-noradrenaline release in rat hippocampal slices (3). In the spinal cord, K_ATP channels were implicated in the antinociceptive effects of morphine and norepinephrine in the tail-flick test (4), as were pinacidil, a K_ATP channel opener, and gabapentin in a nerve ligation neuropathic pain model (5). We have demonstrated that intrathecal injection of gabapentin induced an antiallodynic effect in the Brennan postoperative pain model (6). In this study, we examined whether spinal K_ATP channels are involved in this pain model and if intrathecal gabapentin induces an antiallodynic effect through opening these K_ATP channels.

Gabapentin was also found to increase N-methyl-d-aspartic acid (NMDA) current in GABAergic, but not non-GABAergic, spinal dorsal horn neurons in inflamed rats (7). Therefore, it is possible that the analgesic effect of intrathecal gabapentin might be attributed to this enhancement of NMDA current in spinal GABAergic neurons. The present study also validated this possibility by investigating the interactions of NMDA and GABA_A receptor blockers with gabapentin in the postoperative pain model.

A specific binding site of gabapentin in the brain was found to be the ₂ subunit, the auxiliary subunit, of voltage-dependent Ca²⁺ channels (8). In neuropathic pain models, the Ca²⁺ channel ₂ subunit has been implicated in the antinociceptive actions of gabapentin and its analogues (9). In the postoperative pain model, we have shown that the ₂ subunit of Ca²⁺ channels might also be involved in the antiallodynic effect of intrathecal gabapentin (6) because the effect of gabapentin was attenuated by MgCl₂ and ruthenium red, the modulators of gabapentin binding at the Ca²⁺ channel ₂ subunit. In the spinal cord, P/Q-, N-, L-, and T-types Ca²⁺ channels are present and functional (10). The present study further examined which type of Ca²⁺ channel blockers would mimic the antiallodynic effect of gabapentin when administered intrathecally. The interaction of the L-type Ca²⁺ channel activator Bay K 8644 with gabapentin was also investigated.

	Methods

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All experiments conformed to the guidelines of and were approved by the Institutional Laboratory Animal Care Committee of Mackay Memorial Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

The intrathecal catheterization, paw incision surgery and analysis of allodynic responses are similar to our previous report (6). Briefly, under isoflurane anesthesia, male Sprague-Dawley rats (250–300 g) received intrathecal catheterization via a PE-5 catheter advanced to the lumbar enlargement of the spinal cord. Five days after catheterization, a 1-cm longitudinal incision on the plantar surface of the rat right hindpaw was made and the plantaris muscle was elevated and incised longitudinally to induce postoperative allodynia. The allodynic responses were evaluated by the withdrawal thresholds to punctate mechanical stimuli induced by calibrated von Frey filaments with logarithmically incremental stiffness from 0.6 to 60 g (Stoelting CO, Wood Dale, IL). Beginning with the 6.0-g probe, the filament was applied vertically to the area adjacent to the incision wound for 6 s while the filament was bent. Brisk withdrawal or paw flinching was considered as a positive response. If a positive response was observed, the filament with the next lower force was applied; otherwise, the next stiffer filament was used. The stimulus producing a 50% likelihood withdrawal was determined using the Dixon "up-and-down" method. Rats with postincision withdrawal thresholds <5 g were considered to have marked allodynia and were used in the present study. The withdrawal thresholds were measured before and 2 h after paw incision and every 5 to 30 min for 2 h after intrathecal treatment.

A drug-induced antiallodynic effect was expressed as the percentage of maximal possible effect (%MPE) as follows:

The mean withdrawal thresholds of 229 tested rats before and after incision were 45.6 ± 1.1 g and 1.5 ± 0.1 g, respectively.

All drugs were injected intrathecally in a volume of 5 µL followed by a 10 µL normal saline flush. The receptor or channel ligands were pretreated 10 min before gabapentin was administered. The von Frey filament testing was conducted 15, 30, 45, 60, 90, and 120 min after drug administrations. For the L-type Ca²⁺ channel blockers, the testing was conducted earlier and more frequently (5, 10, 15, 20, 30, 60, 90, and 120 min) because they induced antinociception 5 min after intrathecal injection in tail-flick and colorectal distension tests (11). Rats showing any sign of motor dysfunction, including abnormal ambulation or placing/stepping reflex after drug injections, were excluded from the study.

Drugs were dissolved in normal saline, except for pinacidil, diazoxide, glibenclamide and nimodipine, which were dissolved in 20% dimethylsulfoxide (DMSO). Pinacidil, diazoxide, glibenclamide, 2-amino-5-phosphonovaleric acid (APV), (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), isoguvacine hydrochloride, bicuculline methiodide, nimodipine, mibefradil dihydrochloride, -agatoxin IVA (AGA-IVA), and S(-) Bay K 8644 were purchased from Sigma Chemical (St. Louis, MO, USA). Verapamil hydrochloride, diltiazem hydrochloride, and -conotoxin GVIA (CTX-GVIA) were purchased from Tocris (Bristol, UK). Two batches of CTX-GVIA (batch No: 6/18477 and 16A) were purchased. The former was used in constructing its dose-response curve and the latter was used in its interaction with Bay K 8644. Gabapentin was a generous gift from Pfizer (Groton, CT, USA).

Data are presented as mean ± sem with n indicating the number of rats tested in each group. Two-way repeated-measures analysis of variance was used to compare the time courses of drug effects among drug- and vehicle-treated groups. The ED₅₀ for intrathecal CTX-GVIA-induced antiallodynic effect was estimated from the dose-response curve constructed by logistic fitting. One-way analysis of variance with post hoc Scheffé's test was used to compare the peak antiallodynic effects of Ca²⁺ channel blocker-treated groups with that of the saline-treated group. P < 0.05 was considered to be statistically significant.

	Results

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As reported previously (6), intrathecal gabapentin dose-dependently reduced the incision-induced allodynic response in the rat model of postoperative pain. A median effective dose of gabapentin, 100 µg, was used to examine its interactions with the receptor or channel ligands. The antiallodynic effect of 100 µg gabapentin peaked at approximately 45-60 min after intrathecal injection and lasted for more than 2 h (Figs. 1 and 2). In the same model, Whiteside et al. (12) found that intraperitoneal injection of gabapentin produced only 19% antiallodynic effect at the largest dose, 100 mg/kg. It seems that increased efficacy can be achieved for gabapentin via intrathecal administration.

View larger version (29K): [in this window] [in a new window]   Figure 1. Effects of intrathecal adenosine triphosphate-sensitive K+ (KATP) channel ligands on the allodynic response and the antiallodynic effect induced by intrathecal gabapentin in a rat model of postoperative pain. The ordinate is the antiallodynic effect, expressed as percentage of maximal possible effect as described in Methods, induced by KATP channel openers, pinacidil, and diazoxide, as well as by gabapentin in the absence and presence of glibenclamide, a KATP channel blocker. Glibenclamide (dissolved in 20% dimethylsulfoxide, DMSO) was pretreated 10 min before the administration of gabapentin. Note that KATP channel openers did not induce an antiallodynic effect in this model. Data are expressed as mean ± sem. P = 0.68, glibenclamide-pretreated group versus the gabapentin control group (two-way repeated-measures analysis of variance).

View larger version (31K): [in this window] [in a new window]   Figure 2. Effects of N-methyl-d-aspartic acid (NMDA) receptor blockers and gamma-aminobutyric acid (GABA)A receptor ligands on postincision allodynia in the presence or absence of gabapentin. The NMDA receptor blocker, APV (A) or MK-801 (B), or the GABAA receptor antagonist bicuculline (C) was intrathecally administered 10 min before gabapentin was injected. Effects of APV (A) or MK-801 (B) alone as well as that of bicuculline or isoguvacine (C), a GABAA receptor agonist, are also shown. Data are expressed as mean ± sem. P = 0.08, APV-pretreated group versus the gabapentin control group; P = 0.84, MK-801-pretreated group versus the gabapentin control group; P = 0.85, bicuculline-pretreated group versus the gabapentin control group (two-way repeated-measures analysis of variance).

To validate the hypothesis raised by the finding of Gu and Huang (7) (that intrathecal gabapentin exerts an antiallodynic effect by enhancing the NMDA current of spinal GABAergic neurons), the effects of antagonists of NMDA or GABA_A receptors on the antiallodynic effect of gabapentin were examined.

Intrathecal injection of 6 µg APV, the binding site blocker of NMDA receptors, slightly reduced the allodynic response for approximately 30 min (Fig. 2A). Similarly, intrathecal injection of 14 µg of MK-801, the NMDA receptor channel blocker, also produced little antiallodynic effect (Fig. 2B). Increasing the dose of APV to 12 µg and that of MK-801 to 28 µg induced motor weakness in the rats. Pretreatment with 6 µg APV (Fig. 2A) or 14 µg MK-801 (Fig. 2B) did not attenuate the antiallodynic effect of gabapentin. On the contrary, a slight additive antiallodynic effect, though statistically insignificant, was observed in the first 30 min after intrathecal injection of gabapentin in the APV- or MK-801-pretreated group (Fig. 2A, B).

Bicuculline, at 0.3 µg, did not affect the postincision allodynic response nor the antiallodynic effect of 100 µg gabapentin (Fig. 2C). When we increased the dose of bicuculline to 3 µg, the agitated rats squeaked and jumped, which hampered further assessment of this drug. Similarly, isoguvacine, a GABA_A receptor agonist, when given intrathecally at 20 µg, had little antiallodynic effect as well (Fig. 2C). Increasing the dose of isoguvacine to 30 µg or larger resulted in motor weakness.

Intrathecal injection of CTX-GVIA, an N-type Ca²⁺ channel blocker, significantly attenuated the incision-induced allodynic response in a dose-dependent manner (Fig. 3). However, toxic signs, such as agitation, squeaking, tremor, ataxia, and segmental allodynia in response to fur brushing at the hind body, also appeared dose-dependently as described in previous studies (14,15). When the dose of CTX-GVIA was larger than 3 µg, the toxic signs were too severe to evaluate its antiallodynic effect. The ED₅₀ of CTX-GVIA estimated from the dose-response curve is 0.24 ± 0.14 µg (Fig. 3B).

View larger version (18K): [in this window] [in a new window]   Figure 3. Antiallodynic effect of intrathecal -conotoxin GVIA (CTX-GVIA), an N-type Ca2+ channel blocker, in the rat postoperative pain model. A, time courses of various doses of CTX-GVIA. B, the dose-response curve of CTX-GVIA. The ordinate is the peak antiallodynic effect produced by each dose of CTX-GVIA. The curve was fitted based on the logistic equation E = E max/[1+(ED50/D) n], where E is the antiallodynic effect of CTX-GVIA, E max the maximal effect produced by CTX-GVIA within the tested doses, D the dose of CTX-GVIA, and n the Hill coefficient. The estimated ED50 is 0.24 ± 0.14 µg, and the Hill coefficient 1.17 ± 0.68. Data are expressed as mean ± sem. *P < 0.05 versus the saline group (two-way repeated-measures analysis of variance with post hoc Dunnett test).

On the contrary, the postincision allodynia was not affected by intrathecal injection of L-type Ca²⁺ channel blockers (verapamil 300 µg, diltiazem 500 µg, or nimodipine 500 µg), T-type Ca²⁺ channel blocker (mibefradil 600 µg), or P/Q-type Ca²⁺ channel blocker (AGA-IVA 0.1 or 0.3 µg) (Table 1). Increasing the doses of diltiazem to 1000 µg, nimodipine to 1000 µg and mibefradil to 1200 µg produced motor weakness that confounded the evaluation of their possible antiallodynic responses. Severe agitation was also noted when the dose of AGA-IVA was increased to more than 0.3 µg.

All types of Ca²⁺ channels consist of ₂ subunit, the binding site of gabapentin in the brain (8). However, only the N-type Ca²⁺ channel blocker could mimic the antiallodynic effect of intrathecal gabapentin. Because no selective N-type Ca²⁺ channel activator is available and because the L-type Ca²⁺ channel has been reported to be the possible target of gabapentin (16), we examined whether Bay K 8644, a selective L-type Ca²⁺ channel activator, could affect the antiallodynic effect of intrathecal gabapentin. Unexpectedly, intrathecal pretreatment with 5 µg Bay K 8644 attenuated the antiallodynic effect of gabapentin (Fig. 4A). Bay K 8644 5 µg, per se, has no effect on the incision-induced allodynic response (Fig. 4A). Interestingly, Bay K 8644 (5 µg) also attenuated the antiallodynic effect of N-type Ca²⁺ channel blocker, CTX-GVIA (1 µg) (Fig. 4B). The different potencies of 1 µg CTX-GVIA shown in Figures 3 and 4 might be a result of the different batches of CTX-GVIA we used.

View larger version (20K): [in this window] [in a new window]   Figure 4. Effects of L-type Ca2+ channel activator, Bay K 8644, on gabapentin- and -conotoxin GVIA (CTX-GVIA)-induced antiallodynic effect. Bay K 8644 was intrathecally administered 10 min before gabapentin (A) or CTX-GVIA (B) was injected. Effect of Bay K 8644 alone on the allodynic response was also shown (A). Data are expressed as mean ± sem. *P < 0.05 versus the control group (two-way repeated-measures analysis of variance).

	Discussion

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In the present study we found that intrathecal injection of the blockers of K_ATP channels, NMDA receptors, and GABA_A receptors failed to attenuate the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain. The K_ATP channel openers and GABA_A receptor agonist, per se, did not affect the incision-induced allodynia. On the other hand, intrathecal injection of CTX-GVIA, an N-type Ca²⁺ channel blocker, produced a dose-dependent attenuation of postincision allodynia, as did gabapentin. However, the blockers of P/Q-, L-, and T-type Ca²⁺ channels had no effect on the postincision allodynia. Both the antiallodynic effects of gabapentin and CTX-GVIA were reversed by Bay K 8644, an L-type Ca²⁺ channel activator. We suggest that K_ATP channels, NMDA, and GABA_A receptors might not be the action target of the antiallodynic effect of intrathecal gabapentin in the postoperative pain model. In addition, this study provides correlative evidence to support the contention that N-type Ca²⁺ channels might be involved in the effect of gabapentin.

K_ATP channels have been suggested to be involved in the antinociceptive effects of intrathecal morphine, norepinephrine, and pinacidil in the tail-flick test and nerve ligation pain model (4,5). However, in the current postoperative pain model, neither the opener nor the blocker of K_ATP channels affects the incision-induced allodynic response. We suggest that K_ATP channels are not involved in this postoperative pain model, although they might be involved in the acute thermal and/or neuropathic pain models.

Our finding that glibenclamide failed to reverse the antiallodynic effect of intrathecal gabapentin suggests that gabapentin is unlikely to act as a K_ATP channel opener to exert its antiallodynic effect in the current postoperative pain model, unlike in the nerve ligation model (5). This result is in agreement with the finding that gabapentin did not modulate K_ATP currents in primary afferent neurons (17).

Gu and Huang (7) found that gabapentin enhances NMDA currents selectively in the GABAergic neurons of spinal dorsal horn in inflamed rats. It is therefore possible that intrathecal gabapentin induced an antinociceptive response through selective activation of the inhibitory GABAergic neurons in the spinal cord. However, this possibility is negated by the ineffectiveness of the receptor antagonists of NMDA and GABA_A, at the doses effective in other pain models (18,19), in reversing the antiallodynic effect of gabapentin in the current postoperative pain model. GABA_B receptor antagonists were also found to be ineffective in reversing the antinociceptive effects of gabapentin in neuropathic and postoperative pain models (20).

The ineffectiveness of isoguvacine, a GABA_A receptor agonist, in the current model suggests that spinal GABA_A receptors, unlike GABA_B receptors (20), are not potential therapeutic targets for the treatment of postoperative pain. On the other hand, in the nerve ligation pain model, both GABA_A and GABA_B receptor agonists had antinociceptive effects (18).

The intrathecal concentrations of all types of Ca²⁺ channel blockers used in this study, estimated by assuming the cerebrospinal fluid volume of adult rats is about 400 µL (6), are effective in blocking the Ca²⁺ channels of isolated spinal cord slices (10). However, only N-type Ca²⁺ channel blockers display an antiallodynic effect, suggesting that blockade of spinal N-type, but not P/Q-, L-, or T-type, Ca²⁺ channels could produce antiallodynic action in the current postoperative pain model.

Gabapentin was found to bind specifically to the Ca²⁺ channel ₂ subunit, which is the auxiliary subunit of voltage-dependent Ca²⁺ channels (8). In dorsal root ganglion neurons, gabapentin was found to reduce Ca²⁺ influx predominantly through N-type Ca²⁺ channels (21). Therefore, N-type Ca²⁺ channels might be involved in the antiallodynic effect of intrathecal gabapentin in the current postoperative pain model.

No selective N-type Ca²⁺ channel opener is available for testing the potential ability to reverse the effect of gabapentin. However, Bay K 8644, a selective L-type Ca²⁺ channel opener, unexpectedly reversed the antiallodynic effect of gabapentin. Although gabapentin was reported to reduce the Ca²⁺ current sensitivity to Bay K 8644 in cortical neurons (16), it is unlikely that the antiallodynic effect of intrathecal gabapentin is mediated via L-type Ca²⁺ channels. First, L-type Ca²⁺ channel blockers did not show any antiallodynic effect in the present study. Second, Bay K 8644 also reversed the effect of CTX-GVIA, a Ca²⁺ channel blocker selective to the N-type (22). The reason that Bay K 8644 reversed the antiallodynic effect of gabapentin and CTX-GVIA is unclear. It might be that Bay K 8644 increased Ca²⁺ influx through L-type Ca²⁺ channels to indirectly counteract the inhibition of N-type Ca²⁺ channels induced by gabapentin or CTX-GVIA. Bay K 8644 has been reported to enhance catecholamine release from adrenal chromaffin cells through L-type Ca²⁺ channels (23). However, the nerve-stimulation-evoked catecholamine releases in these preparations is mostly mediated by N-type Ca²⁺ channels (23).

In addition to the present postoperative pain model, N-type Ca²⁺ channel blockers have also been shown to have analgesic effects, as has gabapentin (1), in neuropathic (14) and inflammatory (15) pain models. However, the side effects such as tremor and ataxia induced by CTX-GVIA were not observed with intrathecal gabapentin administration. This discrepancy might be because gabapentin and CTX-GVIA act at different sites of Ca²⁺ channels. Instead of binding to the pore-forming ₁ subunit, as the Ca²⁺ channel blockers do, gabapentin might act at the ₂ auxiliary subunit (8).

Upregulation of spinal dorsal horn ₂-1 subunit of Ca²⁺ channels has been noted in gabapentin-sensitive, but not in insensitive, pain models (24). It remains to be elucidated whether the ₂ subunit is also upregulated in the current postoperative pain model. Our previous study inferred that the ₂ subunit might be involved in the antiallodynic effect of intrathecal gabapentin in this model (6). This inference is further supported by the recent finding of Cox et al. (25) that pregabalin, a gabapentin analog, also with ₂ binding activity, fails to induce antinociception in transgenic mice, in which the critical binding site for gabapentin at the ₂ subunit of Ca²⁺ channels was mutated (Arg²¹⁷ Ala²¹⁷). The present study further provides correlative evidence supporting the notion that the ₂ subunit of N-type Ca²⁺ channels might be the antiallodynic action target of gabapentin in the postoperative pain model. Nevertheless, gabapentin might exert its other central nervous system effects, such as antiepilepsy or anxiolysis (1), by acting at the targets other than N-type Ca²⁺ channels.

In conclusion, our findings suggest that the antiallodynic effect of intrathecal gabapentin in the postoperative pain model is not mediated through K_ATP channels, NMDA, or GABA_A receptors. In addition, this behavioral study provides correlative evidence to support the contention that spinal N-type Ca²⁺ channels might be involved in the antiallodynic effect of gabapentin.

	Footnotes

 
Accepted for publication August 31, 2005.

Supported, in part, by grants NSC 93-2314-B-195-024 (to J.-K. C.) and NSC 93-2320-B002-117 (to L.-C. C.) from National Science Council, grant MMH 9308 and 9416 (to J.-K. C.) from Mackay Memorial Hospital, and grant NHRI-EX94-9005NC (to L.-C. C.) from National Health Research Institutes, Taipei, Taiwan. The authors appreciate the generous supply of gabapentin from Pfizer Incorporation, Groton, CT.

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