GABAergic synaptic response and its opioidergic modulation in periaqueductal gray neurons of rats with neuropathic pain
© Hahm et al; licensee BioMed Central Ltd. 2011
Received: 1 March 2011
Accepted: 12 May 2011
Published: 12 May 2011
Neuropathic pain is a chronic and intractable symptom associated with nerve injury. The periaqueductal gray (PAG) is important in the endogenous pain control system and is the main site of the opioidergic analgesia. To investigate whether neuropathic pain affects the endogenous pain control system, we examined the effect of neuropathic pain induced by sacral nerve transection on presynaptic GABA release, the kinetics of postsynaptic GABA-activated Cl- currents, and the modulatory effect of μ-opioid receptor (MOR) activation in mechanically isolated PAG neurons with functioning synaptic boutons.
In normal rats, MOR activation inhibited the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) to 81.3% of the control without any alteration in their amplitude. In neuropathic rats, the inhibition of mIPSC frequency by MOR activation was 82.4%. The frequency of GABAergic mIPSCs in neuropathic rats was 151.8% of normal rats without any difference in the mIPSC amplitude. Analysis of mIPSC kinetics showed that the fast decay time constant and synaptic charge transfer of mIPSCs in neuropathic rats were 76.0% and 73.2% of normal rats, respectively.
These results indicate that although the inhibitory effect of MOR activation on presynaptic GABA release is similar in both neuropathic and normal rats, neuropathic pain may inhibit endogenous analgesia in the PAG through an increase in presynaptic GABA release.
Chronic pain can be classified into three categories: nociceptive pain caused by tissue damage, neuropathic pain caused by nerve injury, and mixed pain . Patients with neuropathic pain usually experience abnormal sensations, including allodynia, which is defined as pain in response to non-nociceptive stimuli and hyperalgesia, which is defined as increased pain sensitivity to nociceptive stimuli . Although opioid receptor agonists are the most widely used therapeutic agents for neuropathic pain, the effectiveness of opioid analgesia is controversial. Several studies have shown that neuropathic pain can be effectively attenuated by morphine and other μ-opioid receptor (MOR) agonists [3–10] as well as delta-opioid agonists [11–14]. By contrast, some studies have indicated that opioid peptides and morphine do not possess potent analgesic efficacy against neuropathic pain in humans  and that this ineffectiveness of morphine can be attributed to a down-regulation of central μ-opioid transmission  and a reduced number of presynaptic opioid receptors due to the degeneration of primary afferent neurons [17, 18].
The midbrain periaqueductal gray (PAG) is believed to be an important component in the endogenous pain control system . Several studies have shown that administration of morphine or opioid peptides, either systemically or directly into the PAG, produces antinociception, which is thought to be associated with inhibition of neuronal activity in the PAG [20, 21]. The inhibitory interneurons in the PAG are thought to contain GABA as an inhibitory neurotransmitter and inhibit tonically the output neurons [19, 22–25]. Opioid agonists have been shown to inhibit GABAergic inhibitory synaptic input to PAG neurons in rat slice preparations [24, 25]. In previous studies, we have shown that MOR activation inhibits presynaptic GABA release in acutely isolated PAG neurons from normal young rats .
Although many studies have investigated the analgesic effects of opioid agonists on neuropathic pain, it is not clear whether opioidergic modulation of the endogenous pain control system in the PAG is altered by neuropathic pain. Therefore, in the present study, we isolated PAG neurons with intact synaptic terminals from rats with neuropathic pain to examine the effects of neuropathic pain on presynaptic GABA release, the kinetics of postsynaptic GABA-activated Cl- currents, and the opioid-induced inhibition of GABAergic synaptic action.
GABAergic mIPSCs in PAG neurons isolated from neuropathic rats
There were no differences in morphological characteristics between normal and neuropathic rats. Mechanically dissociated PAG neurons retained short portions of their proximal dendrites and usually presented an ovoid soma (approximately 10-20 μm in diameter), although some neurons presented a triangular soma.
Effect of MOR activation on GABAergic mIPSCs in neuropathic rats
Effect of neuropathic pain on presynaptic GABA release
Effect of neuropathic pain on the kinetics of postsynaptic GABA-activated Cl- channels
The kinetics of mIPSC in normal adult and neuropathic rats
(Mean ± S.E.)
(Mean ± S.E.)
Rise 10-90% (ms)
1.07 ± 0.1
0.91 ± 0.1
1.10 ± 0.1
0.94 ± 0.0
Decay 90-37% (ms)
11.74 ± 0.8
8.92 ± 0.4†
13.32 ± 1.3
9.69 ± 0.6†
39.89 ± 2.2
36.64 ± 2.0
46.50 ± 3.9
36.99 ± 2.5
Weighted mean decay time (ms)
21.03 ± 1.2
17.44 ± 0.9†
23.55 ± 1.8
18.65 ± 1.0†
13.29 ± 0.8
10.29 ± 0.5†
14.66 ± 1.1
11.52 ± 0.6†
Area under currents (pAms)
753.6 ± 42.5
551.4 ± 35.4†
897.0 ± 81.4
567.0 ± 39.1†
The present study was performed to examine whether neuropathic pain alters presynaptic GABA release and postsynaptic GABA-activated Cl- currents and whether opioidergic modulation of the GABAergic inhibitory synaptic response might be affected by neuropathic pain. Our results show that neuropathic pain increases the frequency of presynaptic GABA release and decreases both the fast decay time constant and the synaptic charge transfer of postsynaptic GABA-activated Cl- currents, regardless of whether MOR agonists are present. In addition, neuropathic pain did not alter the inhibitory effect of MOR activation on GABAergic mIPSCs.
Neuropathic pain associated with peripheral neuropathy can manifest as severe and intractable pain. However, the mechanism of this severe and intractable pain remains unclear. The PAG is an important component of the endogenous pain control system and is the main site of the powerful analgesic effects by morphine or opioid peptides . In a previous report, we suggested that MOR-induced inhibition of GABAergic inhibitory synaptic influence in the PAG is the main mechanism of the opioidergic endogenous pain control system . If GABAergic synaptic inhibition of PAG neurons is potentiated by neuropathic pain, this may represent a potential mechanism of neuropathic pain. Although the exact mechanisms are not clear, there have been reports supporting this hypothesis. Activation of the descending pain control system was shown to be important in the maintenance of neuropathic pain . The PAG-mediated inhibition of nociception may be activated by persistent nociceptive input, possibly reflecting the long-term changes in the nociceptive circuitry that occur in neuropathic pain states . In this study, neuropathic rats showed an increase in the frequency of presynaptic GABA release in PAG neurons (Figure 4). This finding indicates that endogenous pain control mechanisms in the PAG may be inhibited in animals suffering from neuropathic pain. Thus, this study suggests that neuropathic pain inhibits the efficiency of the endogenous pain control system in the PAG, thereby inducing severe and intractable pain.
Although neuropathic pain does not alter the amplitude of postsynaptic GABAergic response, the kinetics of mIPSC was slightly inhibited in neuropathic rats (Figure 5, Table 1). Neuropathic rats showed a reduction in the fast decay time with a reduced half-width time and synaptic charge transfer of mIPSCs. These findings might indicate that GABAergic inhibitory input to the PAG neurons can be decreased in neuropathic rats, which means that endogenous pain control mechanisms in the PAG may be activated in neuropathic rats. However, the decrease in the fast decay time and synaptic charge transfer of mIPSCs (76.0% and 73.2% of the normal rats, respectively) was significantly less than the increase in presynaptic release of GABA (151.8% of the normal rats, Figure 4). Thus, the changes in mIPSC kinetics in neuropathic rats may not show a significant influence to the inhibitory effect of the decreased presynaptic GABA release in neuropathic rats on endogenous pain control mechanisms in the PAG.
Morphine and opioid peptides exert their powerful analgesic effects through the endogenous pain control system, especially in the PAG . The efficiency of opioid receptor agonists, especially the MOR agonist morphine, has been reported in recent studies of central and peripheral neuropathic pain disorders [31–34]. However, the development of long-term side effects, such as immunological problems, physical dependency, and misuse or abuse, is a limitation to the use of opioid analgesics in patients with neuropathic pain . Furthermore, and the effectiveness of opioid agonists on neuropathic allodynia and hyperalgesia remains controversial. Several studies have supported the effectiveness of opioid receptor agonists on neuropathic pain [3–14]. However, some studies have raised questions about the efficiency of opioid analgesics on neuropathic pain in humans  and animals [16–18, 35]. Other studies have indicated that the PAG is important in opioidergic analgesia of neuropathic pain. Neuropathic pain that is induced by peripheral nerve injury has been effectively alleviated by electrical stimulation of the PAG , microinjection of opioid agonists into the PAG , and supraspinal administration of morphine into the PAG . Although the analgesic mechanisms have not been clearly elucidated, these studies suggest that the endogenous pain control system, including the PAG, is very important in the control of neuropathic pain syndrome and that opioid receptors are involved in this system. In the present study, MOR agonists inhibited GABAergic inhibitory synaptic activity in the PAG of neuropathic rats, and this inhibitory effect of MOR activation was not significantly different between neuropathic and normal rats (Figure 2, 3, and 4). Thus, the results of this study suggest that MOR agonists can effectively exert an analgesic effect on neuropathic pain through the modulation of the endogenous pain control system in the PAG and that the analgesic effectiveness of opioid peptides in neuropathic animals is similar to that in normal animals. However, because neuropathic pain may inhibit the endogenous pain control mechanism in the PAG in the resting state (as described above), it is possible that the analgesic action of exogenous opioid agonists is less effectively in a neuropathic pain state.
While the majority of proximal dendrites are still attached to the neurons, the mechanical dissociation can alter the majority of distal dendrites. Although the remaining dendritic as well as somatic synapses are well elucidated to be still functioning , it cannot be ruled out that the dendritic synapses may be modulated in a different manner shown in the present study.
The results of this study suggest that neuropathic pain inhibits the endogenous pain control system through an increase in presynaptic GABA release in the PAG, which then induces severe and intractable pain. Thus, although the effect of MOR activation on presynaptic GABA release in neuropathic rats is similar to that in normal animals, exogenous opioid agonists may exert their analgesic actions less effectively in neuropathic rats.
Animals and surgical procedures
All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Kyung Hee University and all efforts were made to minimize animal suffering and the number of animals utilized. Male Sprague-Dawley rats (8-12 weeks old) were subjected to a neuropathic pain model, as described in detail previously [39, 40]. In brief, the tail response to a mechanical stimulus was first tested in all animals prior to surgery. The rats were restrained in a transparent plastic tube (5 cm in diameter × 20 cm in length), and their tails were laid onto a table prior to a behavioral tail-flicking test. After rats were habituated to the test environment for 1 h, the mechanical sensitivity of the tail was determined based on the tail withdrawal response evoked by the application of a 0.2 g (1.96 mN) von Frey hair filament. The most sensitive spot of the tail was first determined for each animal by systematically rubbing various areas of the tail with the shank of the von Frey hair; these spots were marked with a sharp marking pen. Then, each spot was challenged ten times with the von Frey hair filament at 10- to 20-s intervals. The occurrence of tail withdrawal in response to the stimulation was expressed as a percentage of trials, which served as an index of mechanical sensitivity following peripheral nerve injury. The surgery was performed on rats that were not responsive to the initial mechanical stimulation. Each rat was anesthetized with an intraperitoneal injection of Zoletil 50® (50 mg/kg), after which the left superior caudal trunk was exposed, freed from the surrounding tissues and transected at the level between the S3 and S4 spinal nerves. To prevent possible rejoining of the proximal and distal ends of the severed trunk, an approximately 1-mm-long section of the trunk was removed from the proximal end. This surgery eliminated the S1-S3 spinal nerve innervation of the tail via the superior caudal trunk. Behavioral tests for signs of neuropathic pain (mechanical allodynia) were performed at 1 week after surgery. Only rats showing greater than 80% mechanical allodynia were considered to conform to the animal model for neuropathic pain.
Isolation of single PAG neurons with synaptic boutons
The mechanical dissociation of single PAG neurons with functioning synaptic boutons was performed by using the technique described previously [38, 41–43]. In brief, rats were decapitated under Zoletil 50® anesthesia (50 mg/kg). The brains were removed, and transverse slices (350-μm thickness) were made with a microslicer (DTK-1000, DSK, Kyoto, Japan). Slices were preincubated in an incubation solution that had been well saturated with 95% O2 and 5% CO2 at room temperature (22-25°C) for at least 1 h before mechanical dissociation. For dissociation, slices were transferred to a 35 mm culture dish (Primaria 3801; Becton Dickinson, Rutherford, NJ, USA), and the ventrolateral region of the PAG was identified under a binocular microscope (SZ-ST, Olympus, Tokyo, Japan). Mechanical dissociation was performed using a custom-built vibration device and a fire-polished glass pipette oscillating at approximately 20-50 Hz (1-2 mm). The tip of the fire-polished glass pipette was lightly touching the surface of the ventrolateral PAG region with a micromanipulator and was vibrated horizontally for approximately 2 min. Slices were removed, and the mechanically dissociated neurons were allowed to settle and adhere to the bottom of the dish for 15 min. The isolated neurons retained short portions of their proximal dendrites.
Electrical recordings were performed in the conventional whole-cell patch-clamp recording mode  under voltage-clamp conditions at holding potential (VH) of -60 mV. Patch pipettes were made from borosilicate capillary glass (1.5 mm outer diameter; 1 mm inner diameter; G-1.5; Narishige, Tokyo, Japan) in two stages on a vertical pipette puller (PP-83; Narishige, Tokyo, Japan). The resistance of the recording pipettes that were filled with internal solution was 5-6 MΩ. The patch pipette was positioned on the neuron using a water-driven micromanipulator (WR-60; Narishige, Tokyo, Japan). Neurons were visualized under phase contrast on an inverted microscope (IX-70, Olympus, Tokyo, Japan). Electrical stimulation, voltage control, current recording, and filtration of current (at 1 kHz) were obtained with an EPC-9 patch-clamp amplifier (EPC-9, HEKA Electronik, Lambrecht, Germany) linked to a PC controlled by HEKA software. Current and voltage were monitored continuously on a computer monitor for the EPC-9 amplifier and displayed on a paper chart linearcorder (WR3320, Graphtec, Yokohama, Japan). Membrane currents were digitized at 5 kHz with an ITC 16 board (HEKA Electronik, Lambrecht, Germany), and stored on a computer equipped with pCLAMP (version 8.0, Axon Instruments Inc., Burlingame, CA, USA). During recordings, -70 mV hyperpolarizing step pulses (30 ms in duration) were periodically delivered to monitor access resistance. All experiments were performed at room temperature (22-25°C).
Drugs and solutions
Zoletil 50® (tiletamine HCl 125 mg/5 ml + zolazepam HCl 125 mg/5 ml) was purchased from Virbac (Carros, France). Potassium phosphate monobasic, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), dimethyl sulfoxide (DMSO), ethylene glycol-bis (β-aminoethylether)-N,N,N'N'-tetraacetic acid (EGTA), tetraethyl ammonium chloride (TEA), BaCl2, CsCl, magnesium sulfate, magnesium chloride, Na-GTP, Mg-ATP, tetrodotoxin (TTX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), DL-2-amino-5-phosphonovaleric acid (DL-AP-5), [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO), naloxone HCl, (-)-bicuculline methochloride, Cs-methanesulfonate and cadmium chloride were purchased from Sigma Chemical Co. (St. Louis, MO, USA). CNQX was dissolved in DMSO at 10 mM as a stock solution. Drugs were added to the standard external solutions at the final concentrations indicated in the Result section and the vehicle concentrations never exceeded 0.01%. Drugs were superfused using a rapid application system termed the "Y-tube method" that has been described elsewhere [45, 46]. The incubation solution had the following composition (in mM): 124 NaCl, 5 KCl, 1.2 KH2PO4, 1.3 MgSO4, 2.4 CaCl2, 10 glucose, and 24 NaHCO3. The pH was adjusted to 7.4 by continuous bubbling with 95% O2 and 5% CO2. The standard external solution had the following composition (in mM): 150 NaCl, 5 KCl, 1 MgCl2, 2 CaCl2, 10 glucose, and 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). The pH was adjusted to 7.4 with tris-hydroxymethylaminomethane (Tris-base). The internal pipette solution for the recording of miniature inhibitory postsynaptic current (mIPSC) had the following ionic composition (in mM): 110 CsCl, 30 TEA-Cl, 5 EGTA, 5 Mg-ATP, 0.4 Na-GTP, and 10 HEPES. The pH was adjusted to 7.2 with Tris base. To isolate spontaneous mIPSCs, external solutions routinely contained 300 nM TTX, 1 μM CNQX, and 10 μM AP-5 to block voltage-dependent Na+ channels and glutamatergic excitatory synaptic currents.
Spontaneous mIPSCs were analyzed using the MiniAnalysis program (Synaptosoft Inc., Leonia, NJ, USA). Kaleida Graph software (Synergy Software, Reading, PA, USA) was used for curve fitting. Spontaneous events were initially detected automatically using an amplitude threshold of 5 pA (for mIPSC) and then visually accepted or rejected on the basis of their rise and decay times. Events with brief rise times (0.5-1.5 ms) and decay times that were fitted by a single-exponential function were selected for fast current detection. Averaged current frequency and amplitude were normalized to the control conditions and were provided as means ± S.E.M. Differences in current amplitude and frequency between each single neuron were tested with Student's paired two-tailed t- test using absolute values. Fisher's Exact test was performed to see if there was a contingency between the two kinds of classification. Difference in amplitude distributions of miniature currents obtained from a single neuron were examined by constructing all-point cumulative probability distributions and compared using the Kolmogorov-Smirnov (K-S) test. Values of P < 0.05 were considered significant. The mIPSC kinetics were fitted by two exponential functions for further detailed analysis and were described as their decay phases with time constants and area under the current. The weighted mean decay time constant (τm) was calculated as τm = (Afast×τfast + Aslow×τslow)/(Afast+Aslow), where τfast and τslow are the respective time constants, and Afast and Aslow are the current amplitude constants. Each parameter was compared using Student's paired two-tailed t- test. Values of P < 0.05 were considered significant.
This work was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No.20100028330).
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