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Adenosine Triphosphate–Sensitive Potassium Channel Blockers Attenuate the Antiallodynic Effect of R-PIA in Neuropathic Rats

Song, Jun-Gol, MD, PhD*; Hahm, Kyung Don, MD, PhD*; Kim, Young Ki, MD, PhD; Leem, Jeong Gil, MD, PhD*; Lee, Chung, MD, PhD; Jeong, Sung Moon, MD, PhD*; Park, Pyung Hwan, MD, PhD*; Shin, Jin Woo, MD, PhD*

doi: 10.1213/ANE.0b013e318212b833
Analgesia: Research Reports
Free
SDC

BACKGROUND: Nerve injury can generate neuropathic pain. The accompanying mechanical allodynia may be reduced by the intrathecal administration of adenosine. The neuroprotective effects of adenosine are mediated by the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. We assessed the relationship between the adenosine A1 receptor agonist, N6-(R)-phenylisopropyl adenosine (R-PIA), and KATP channels to determine whether the antiallodynic effects of R-PIA are also mediated through KATP channels in a rat nerve ligation injury model of neuropathic pain.

METHODS: Mechanical allodynia was induced by tight ligation of the left lumbar fifth and sixth spinal nerves. Mechanical allodynia in the left hindpaw was evaluated using von Frey filaments to measure withdrawal thresholds. R-PIA (0.5, 1, or 2 μg) was administered intrathecally to induce antiallodynia. We assessed whether pretreatment with the KATP channel blockers glibenclamide or 5-hydroxydecanoate reversed the antiallodynic effect of R-PIA. Also, we evaluated whether diazoxide, a KATP channel opener, had an antiallodynic effect and promoted the antiallodynic effect of R-PIA. Lastly, we investigated whether the voltage-activated K channel blocker 4-aminopyridine attenuated the effect of R-PIA.

RESULTS: Intrathecal R-PIA produced maximal antiallodynia at 2 μg (P < 0.05). Intrathecal pretreatment with glibenclamide and intraperitoneal pretreatment 5-hydroxydecanoate significantly reduced the antiallodynic effect of R-PIA. Diazoxide produced an antiallodynic effect and also enhanced the antiallodynic action of R-PIA. 4-Aminopyridine had no effect on the antiallodynic action of R-PIA.

CONCLUSIONS: The antiallodynic effects of adenosine A1 receptor stimulation may be related to KATP channel activity in a rat model of nerve ligation injury.

Published ahead of print May 4, 2011

From the *Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul; Department of Anesthesiology and Pain Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung; and Department of Anesthesiology and Pain Medicine, Eulji University College of Medicine, Daejeon, Korea.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Jin Woo Shin, MD, Department of Anesthesiology and Pain Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-2dong, Songpa-gu, Seoul, 138-736, Korea. Address e-mail to sjinwoo@hotmail.com.

Accepted September 14, 2010

Published ahead of print May 4, 2011

Neuropathic pain can arise as the result of peripheral nerve injury, inflammation, compression, ischemia, diabetes, and infections such as postherpetic neuralgia.1 Neuropathic pain may result in mechanical allodynia.1 Animal models are useful in understanding the mechanism of neuropathic pain.2,3 Mechanical allodynia after rat spinal nerve ligation is a well-established model for investigating human neuropathic pain.4

Adenosine A1 receptor activation reduces allodynia in neuropathic pain models.59 After spinal nerve ligation, intrathecal administration of adenosine receptor agonists, including the R(−) isomer of N6-(2-phenylisopropyl)-adenosine (R-PIA), has an antiallodynic effect mediated by the spinal adenosine A1 receptor system in the rat.6,9 Preconditioning with R-PIA has been shown to protect the brain and neuronal tissue against ischemic damage.1013 This protective mechanism, which is mediated via adenosine A1 receptor activation, activates a cascade of intracellular pathways, including adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opening.14

KATP channels are widely distributed on sarcolemmal (sKATP) and mitochondrial (mKATP) membranes in many tissues, including those of the central and peripheral nervous systems.15 Previous reports have shown that activation of the KATP channel using selective agonists has antiallodynic effects in models of neuropathic pain16,17 and in the tail-flick test.18,19 Ocana and Baeyens20 demonstrated involvement of KATP channels in R-PIA–induced antinociception in the tail-flick test. However, the role of the KATP channel in the antiallodynic effects of adenosine A1 receptor activation in neuropathic pain models has not been studied. We investigated the role of KATP channels in mediating the antiallodynic effect of intrathecal administration of R-PIA in a rat spinal nerve ligation model of neuropathic pain.

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METHODS

Animal Preparation

Male Sprague-Dawley rats (180–200 g; Asan LSI, Seoul, South Korea) were housed individually in a temperature-controlled (21°C ± 1°C) vivarium and allowed to acclimatize for 7 days under a 12-hour/12-hour light/dark cycle before being used in experiments. The study protocol was approved by the Animal Care Committee of the Asan Medical Center.

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Surgical Preparation

Neuropathic pain was surgically produced in rats as previously described.2 Briefly, a dorsal midline incision was made from L3 to S2 under sevoflurane anesthesia. The left L6/S1 posterior interarticular process was exposed and resected. The L6 transverse process was partially excised and the left L5 and L6 spinal nerves were gently isolated and ligated tightly with a 6-0 black silk distal to the dorsal root ganglion and proximal to the formation of the sciatic nerve.

An intrathecal catheter was implanted in rats demonstrating tactile allodynia, defined as a withdrawal threshold of ≤4.0 g by postoperative day 7, as previously described.21 Under sevoflurane anesthesia, each rat was placed in a stereotaxic head frame. The occipital muscles were separated from their attachment points and retracted caudally to expose the cisternal membrane at the base of the skull. Intrathecal PE-10 tubing was passed caudally from the cisterna magna to the spinal cord level of the lumbar enlargement, and the catheter was externalized through the skin. Proper location was confirmed by induction of a temporary motor block of both hindlimbs by injection of a 2% lidocaine solution (7 μL), followed by saline injection. Only animals with no evidence of motor deficit after the operation were studied further. Motor deficit was evaluated by observing righting and placing/stepping reflexes, weight bearing, and ambulation. Motor deficit was identified in approximately 30% of rats after intrathecal cannulation. All experiments were conducted 2 weeks after spinal nerve ligation.

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Behavioral Assessment

Behavioral testing was performed at the same time of day to reduce errors associated with diurnal rhythm. Twenty minutes after placing each rat in an individual plastic cage with a wire mesh bottom, tactile threshold was measured by applying a von Frey hair to the midplantar surface of the hindpaw ipsilateral to the nerve injury. A series of 8 calibrated fine von Frey filaments (0.40, 0.70, 1.20, 2.00, 3.63, 5.50, 8.50, and 15.1 g; Stoelting Co.; Wood Dale, IL) was applied to the lesioned hindpaw in ascending order of strength, using sufficient force to cause a slight bending against the paw, and holding for 6 seconds. A brisk withdrawal or paw flinching was considered a positive response, in which case the next filament tested was the next lower force. In the absence of brisk withdrawal or paw flinching, the next filament tested was the next greater force. In the absence of a response at 15 g pressure, the animal was assigned this cutoff value. The tactile stimulus producing a 50% likelihood of withdrawal was determined using the up-down method.22

Behavioral measurements were taken at baseline and 10, 20, 30, 40, 50, 60, 90, and 120 minutes after administration of the drug. The von Frey withdrawal threshold was reported as the actual threshold in grams and converted to maximal possible effect (%MPE) using the following formula: %MPE for antiallodynia = ([postdrug threshold − baseline threshold]/[15 g baseline threshold]) × 100, where the postdrug threshold was the largest threshold value obtained after intrathecal injection. The cutoff value was defined as a stimulus intensity of 15 g for the tactile threshold (i.e., %MPE = 100).

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Intrathecal Drug Administration

Drugs (10 μL) were administered intrathecally over 60 seconds using a microinjection syringe followed by a 10-μL solvent flush. The experimenter was blinded to the drug administered.

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Experimental Protocols

Experiment 1: Antiallodynic Effects of R-PIA

R-PIA (RBI, Natick, MA) dissolved in 10 μL normal saline was injected intrathecally in doses of 0.5, 1, or 2 μg (n = 10 rats/group). The vehicle control group received 10 μL normal saline. %MPE was determined as described above.

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Experiment 2: Effects of Glibenclamide on R-PIA Antiallodynia

To investigate the relationship between KATP channel and antiallodynic effects of R-PIA, we tested the effects of pretreatment with the nonselective KATP channel blocker glibenclamide (GliB) compared with vehicle (20% dimethyl sulfoxide [DMSO]; Sigma Co., St. Louis, MO). Ten animals were used per group. GliB, dissolved in 20% DMSO, was administered intrathecally at doses of 2, 5, 10, and 20 nM. Five minutes later, 2 μg R-PIA was injected intrathecally and the %MPE determined as described above. To assess possible effects of GliB on allodynia in a rat model of neuropathic pain, we also measured %MPE after intrathecal injection of 20 nM GliB alone.

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Experiment 3: Effects of 5-Hydroxydecanoate on R-PIA Antiallodynia

We tested the effects of the selective mKATP channel blocker, 5-hydroxydecanoate (5-HD), compared with vehicle. Ten animals were used per group. 5-HD (RBI, Natick, MA), dissolved in 20% DMSO, was administered intraperitoneally at doses of 20, 30, and 40 mg/kg. Five minutes later, 2 μg R-PIA was injected intrathecally and the %MPE determined as described above. To assess possible effects of 5-HD on allodynia in a rat model of neuropathic pain, we also measured %MPE after intrathecal injection of 40 mg/kg 5-HD alone.

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Experiment 4: Effects of Diazoxide Alone on Allodynia

We tested the effect of the KATP channel opener diazoxide compared with vehicle. Eight animals were used per group. Diazoxide, dissolved in 20% DMSO, was administered intrathecally at doses of 10, 30, and 100 μg. Ten microliters 20% DMSO was injected for the vehicle control group. %MPE was determined as described above.

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Experiment 5: Effects of Diazoxide on R-PIA Antiallodynia

To investigate whether diazoxide, a KATP channel opener, can enhance the action of R-PIA, we tested the effect of diazoxide compared with R-PIA. Eight animals were used per group. Diazoxide, dissolved in 20% DMSO, was administered intrathecally at a dose of 100 μg. Five minutes later, 0.5 μg R-PIA was injected intrathecally and the %MPE determined as described above. There were 2 control groups: one received 0.5 μg R-PIA only, and the other received 2 μg R-PIA only.

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Experiment 6: Effects of 4-Aminopyridine on R-PIA Antiallodynia

We examined whether the voltage-gated K channel blocker, 4-aminopyridine (4-AP), can attenuate the effect of R-PIA. Eight animals were used per group. 4-AP, dissolved in 20% DMSO, was administered intraperitoneally at doses of 1 and 2 mg/kg. Five minutes later, 2 μg R-PIA was injected intrathecally and the %MPE determined as described above. To assess possible effects of 4-AP on allodynia in a rat model of neuropathic pain, we also measured %MPE after intrathecal injection of 2 mg/kg 4-AP alone.

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Statistical Analysis

All data are expressed as mean ± SEM. Differences in paw withdrawal thresholds between groups at every time point were analyzed by 2-way repeated-measures analysis of variance, with time and groups as variables, followed by the Dunnett test for multiple comparisons. A P value <0.05 was regarded as statistically significant.

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RESULTS

Experiment 1: Antiallodynic Effects of R-PIA

As shown in Figure 1, R-PIA produced a dose-dependent antiallodynic effect (%MPE) that differed from vehicle at P < 0.05 from 20 minutes onward. The antiallodynic effect of 2.0 μg R-PIA differed from 0.5 and 1 μg R-PIA at P < 0.05 from 30 minutes onward.

Figure 1

Figure 1

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Experiment 2: Effects of GliB on R-PIA Antiallodynia

As shown in Figure 2, pretreatment with GliB induced a significant dose-dependent reversal of the antiallodynic effect of 2 μg R-PIA. The highest concentration of GliB (20 nM) by itself did not affect the withdrawal threshold of allodynia induced by spinal nerve ligation.

Figure 2

Figure 2

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Experiment 3: Effects of 5-HD on R-PIA Antiallodynia

As shown in Figure 3, pretreatment with 5-HD induced a significant dose-dependent reversal of the antiallodynic effect of 2 μg R-PIA. The highest concentration of 5-HD (40 mg/kg) by itself had no effect on the withdrawal threshold of allodynia induced by nerve ligation.

Figure 3

Figure 3

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Experiment 4: Effects of Diazoxide Alone on Allodynia

As shown in Figure 4, diazoxide alone induced a significant dose-dependent antiallodynic effect of similar magnitude to the effect of 2 μg R-PIA.

Figure 4

Figure 4

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Experiment 5: Effects of Diazoxide on R-PIA Antiallodynia

As shown in Figure 5, initially animals receiving 2 μg R-PIA had a more profound antiallodynic response than animals receiving 0.5 μg R-PIA alone or 0.5 μg R-PIA after pretreatment with 100 μg diazoxide. However, as suggested by Figure 4, the onset of a diazoxide effect is relatively slow compared with R-PIA. Over time, the effect of diazoxide increased until the antiallodynic effects of 0.5 μg R-PIA after pretreatment with 100 μg diazoxide were significantly greater than R-PIA given alone.

Figure 5

Figure 5

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Experiment 6: Effects of 4-AP on R-PIA Antiallodynia

As shown in Figure 6, there was no significant intergroup difference between 2.0 μg R-PIA and 4-AP pretreatment groups in the antiallodynic effect. The highest concentration of 4-AP (2 mg/kg) by itself had no effect on the withdrawal threshold of allodynia induced by spinal nerve ligation.

Figure 6

Figure 6

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DISCUSSION

Using a rat spinal nerve ligation injury model of neuropathic pain, we confirmed the findings of Lee and Yaksh6 that intrathecal R-PIA injection produces a dose-dependent increase in withdrawal threshold. This antiallodynic effect is attenuated by pretreatment with KATP channel blockers, suggesting that the antiallodynic effect of R-PIA is mediated, in part, by KATP channels. Further support is provided by the observation that the KATP channel opener diazoxide alone has an antiallodynic effect, and diazoxide enhances the action of R-PIA. The nonselective K channel blocker 4-AP did not attenuate the effect of R-PIA. Thus, the antiallodynic effect of R-PIA may be mediated, in part, by KATP channels.

Neuropathic pain can be evoked by neuroanatomical changes and physiological mechanisms.2224 The role of adenosine receptors in nociception is complex.25,26 Adenosine released by tissue injury or ischemia may provoke pain through direct stimulation of peripheral nociceptors.27 Conversely, adenosine can also relieve pain by activating postsynaptic potassium channels and by decreasing the release of neurotransmitters such as substance P and glutamate from the terminal of primary sensory neurons within the spinal cord.2830

Four types of adenosine receptors (A1, A2a, A2b, and A3) have been identified31; A1, A2a, and A2b are usually located in the substantia gelatinosa of the dorsal horn.32 The adenosine analog, R-PIA, produces its antiallodynic effect primarily by binding to the A1 receptor.6 Intrathecal R-PIA injection has been shown to decrease the mechanical allodynia induced in a spinal nerve ligation injury model of neuropathic pain.6 Our results using R-PIA are in agreement with these earlier findings.

These results suggest that R-PIA binds to adenosine A1 receptors to open KATP channels to suppress allodynia, the same mechanism by which adenosine exerts neuroprotective effects in ischemia models10,13,33,34 and antinociceptive effects in acute pain.19 Moreover, in a chronic constriction injury model of neuropathy, KATP channels were present in primary afferent neurons and had a role in controlling neuronal excitability and neurotransmitter release.35 Therefore, together with those of previous studies,15,16 KATP channels may contribute to neuropathic and acute pain.

The KATP channel blockers GliB and 5-HD had no direct effects on allodynia induced by spinal nerve ligation injury in this study. KATP channel blockers likely do not modulate nociceptive activity in response to thermal stimuli and mechanical hyperalgesia,36,37 consistent with our finding that neither GliB nor 5-HD produced a nociceptive effect.

The selective mKATP channel blocker, 5-HD, was injected intraperitoneally because 5-HD crosses the blood-brain barrier.38 In our study, systemic administration of 5-HD adequately crossed the blood-brain barrier and reversed the antiallodynic effect of R-PIA. Intrathecal administration of much lower doses of 5-HD might more effectively reverse the antiallodynic effect of R-PIA, and with a faster onset time.

Previous reports have shown that intrathecal administration of a KATP channel agonist can promote the antiallodynic effect in the neuropathic pain model15,16 and in the tail-flick test.17,18 In agreement with these studies, diazoxide alone had an antiallodynic effect and in our study, as well as enhanced the antiallodynic effects of R-PIA. Previous studies have reached inconsistent results about the role of the voltage-gated K+ channel blocker 4-AP in antagonizing the antinociception of R-PIA.19,39 However, in the present study, 4-AP did not attenuate the antiallodynic effects of R-PIA.

We did not investigate the ability of a selective sKATP channel inhibitor to reverse the antiallodynic effect of R-PIA. However, the only known sKATP channel inhibitor is cardioselective, and thus not relevant to neuropathic pain. Additional studies using better-characterized inhibitors will be needed to clarify the role of sKATP channels on R-PIA–induced antiallodynia.

In conclusion, we have shown that the antiallodynic effect of intrathecal injection of R-PIA was reversed by the nonselective and selective KATP channel blockers GliB and 5-HD, respectively, in a rat neuropathic pain model. Further studies are needed to clarify the relationship between antiallodynia and sKATP channels.

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DISCLOSURES

Name: Jun-Gol Song, MD, PhD.

Contribution: Study design and manuscript preparation.

Name: Kyung Don Hahm, MD, PhD.

Contribution: Conduct of study.

Name: Young Ki Kim, MD, PhD.

Contribution: Conduct of study.

Name: Jeong Gil Leem, MD, PhD.

Contribution: Conduct of study.

Name: Chung Lee, MD, PhD.

Contribution: Data analysis.

Name: Sung Moon Jeong, MD, PhD.

Contribution: Data analysis.

Name: Pyung Hwan Park, MD, PhD.

Contribution: Data analysis.

Name: Jin Woo Shin, MD, PhD.

Contribution: Study design and manuscript preparation.

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ACKNOWLEDGMENTS

The authors thank Min-Ju Kim, BS, for statistical analysis.

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