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NEUROPHARMACOLOGY
Department of Anesthesiology (Y.-P.C., S.-R.C., H.-L.P.) and Department of Neural and Behavioral Sciences (H.-L.P.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Anesthesiology (Y.-P.C.), The Second Xiang-Ya Hospital of South Central University, Changsha, People's Republic of China
Received June 21, 2005; accepted July 18, 2005.
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Abstract |
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; Magnuson and Dickenson, 1991; Chen et al., 2005). However, the mechanisms of opioid analgesia and various factors that influence the opioid efficacy in the spinal cord are not fully known. The spinal dorsal horn is a heterogenous region containing inhibitory and excitatory interneurons as well as different types of ascending projection neurons. Interestingly, morphine has distinct effects on dorsal horn neurons in the superficial and deep laminae. For example, morphine given locally or intravenously increases the primary afferent-evoked excitability of lamina II (substantia gelatinosa) neurons but inhibits deep (presumably ascending) dorsal horn neurons in rats and cats (Woolf and Fitzgerald, 1981; Sastry and Goh, 1983; Magnuson and Dickenson, 1991). Because µ opioid receptors are predominantly located in the superficial dorsal horn (Arvidsson et al., 1995; Chen and Pan, 2003), it is possible that the effect of morphine on deep dorsal horn projection neurons is secondary to its potentiating effect on lamina II neurons. Many lamina II neurons are inhibitory interneurons (Cervero and Iggo, 1980; Lu and Perl, 2003) and project ventrally onto the deeper dorsal horn (Light and Kavookjian, 1988). Nevertheless, it remains unclear if the inhibitory action of morphine on dorsal horn projection neurons depends upon its effect on lamina II neurons. The nature of the synaptic inputs from lamina II neurons to dorsal horn projection neurons involved in the effect of morphine is also uncertain.
Chronic neuropathic pain is a clinical condition in which the analgesic efficacy of morphine is often decreased (Sindrup and Jensen, 1999; Woolf and Mannion, 1999). In animal models of neuropathic pain, systemically or intrathecally administered morphine produces a reduced inhibitory effect on dorsal horn neurons (Suzuki et al., 1999; Chen and Pan,2002; Rashid et al., 2004). Spinal nociceptive transmission and dorsal horn neurons in different laminae are under tonic inhibitory control mediated largely by 
-aminobutyric acid (GABA) and glycine (Light and Kavookjian, 1988; Yoshimura and Nishi, 1995; Cronin et al., 2004; Pan and Pan, 2004). Intrathecal bicuculline, a GABAA receptor antagonist, or strychnine, a glycine antagonist, results in hypersensitivity of dorsal horn neurons and allodynia (Yaksh, 1989; Sorkin et al., 1998). Furthermore, spinal disinhibition following nerve injury is considered one of the major mechanisms responsible for central sensitization and neuropathic pain symptoms (Castro-Lopes et al., 1993; Moore et al., 2002). In this regard, several studies have shown a selective loss of GABAergic but not glycinergic inputs to dorsal horn neurons following nerve injury (Castro-Lopes et al., 1993; Ibuki et al., 1997; Moore et al., 2002; Drew et al., 2004). However, it is not known if the reduced GABAergic inhibitory tone in the spinal cord is causally related to the diminished effect of morphine on dorsal horn neurons and nociception in neuropathic pain. In the present study, we tested the hypothesis that removal of GABAergic and glycinergic inhibitory tone attenuates the inhibitory effect of morphine on deep dorsal horn projection neurons. We also determined the role of GABAergic and glycinergic inhibitory tone in the effect of morphine on dorsal horn projection neurons in a rat model of neuropathic pain.
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Materials and Methods |
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). The left L5 and L6 spinal nerves were isolated under a surgical microscope, and both nerves were tightly ligated with 4-0 silk suture (Kim and Chung, 1992). The rats were allowed to recover for 2 weeks before evaluating the mechanical sensitivity of the injured hindpaw. Sham control rats were surgically prepared as described above except that the nerve was not ligated.
Behavioral Assessment of Tactile Allodynia
Sham and nerve-injured rats were placed in individual plastic boxes on a mesh floor and allowed to acclimate for 30 min. A series of calibrated von Frey filaments (Stoelting Co., Wood Dale, IL) were applied perpendicularly to the plantar surface of the left hindpaw with sufficient forces to bend the filaments for 6 s. Brisk withdrawal or paw flinching was considered a positive response. In the absence of a response, the filament of next greater force was applied. In the presence of a response, the next lower force was applied (Chaplan et al., 1994; Chen and Pan, 2002). The tactile stimulus producing a 50% likelihood of withdrawal response was calculated by using the up-down method (Chaplan et al., 1994; Chen and Pan, 2002). Each trial was repeated two or three times at approximately 2-min intervals, and the mean value was used as the force to produce withdrawal responses.
Single-Unit Recording of Dorsal Horn Projection Neurons
Allodynic conditions were verified first in all nerve-ligated rats before the electrophysiological experiments. Anesthesia was initially induced with 2% halothane in 100% oxygen. The left jugular vein and carotid artery were cannulated for intravenous drug administration and blood pressure monitoring, respectively. Following cannulation, sodium pentobarbital (50 mg/kg) was given intravenously and supplemented when necessary. A sufficient anesthesia level was judged by the absence of corneal reflexes, withdrawal reflexes to a noxious stimulus, and spontaneous blood pressure fluctuations. The trachea was cannulated, and the rat was ventilated mechanically. The respirator was adjusted to keep the end-tidal CO2 concentration at 4%, monitored by a Capstar-100 CO2 Analyzer (IITC Life Science Instruments, Woodland Hills, CA). A limited laminectomy was performed to expose the spinal cord at the C1-3 and L2-5 levels. Around the exposed lumbar spinal cord, a small pool (approximately 0.2 ml) was formed by the surrounding tissues to serve as a reservoir for topical application of drugs. After the dura was removed at both sites, the spinal cord was covered with artificial cerebrospinal fluid solution. A bipolar, concentric metal stimulating electrode was inserted into the ventrolateral quadrant of the spinal cord at the C1-3 segment. Dorsal horn neurons in the contralateral (left) side of the lumbar enlargement were recorded with a glass electrode filled with 5% KCl solution (resistance, 4-6 M
). A motorized manipulator (David Kopf Instruments, Tujunga, CA) was used to descend the recording electrode gradually until the single-unit activity of a dorsal horn projecting neuron was recorded. The electrode was descended up to 1 mm in depth from the dorsal surface of the spinal cord. Individual ascending dorsal horn neurons in the lumbar enlargement were antidromically identified and characterized, as we described in detail previously (Chen and Pan, 2002). The stimulus was 0.5 to 1.0 mA, 0.2 ms, and 0.8 to 1 Hz (S48 Stimulator; Grass Instruments, Quincy, MA). The dorsal horn neurons were considered to be antidromically activated if the following criteria were met: 1) the antidromically evoked spikes occurred at a constant latency, 2) the antidromically evoked spikes followed a high frequency (400 Hz) stimulation, and 3) the antidromic action potential collided with the orthodromic spike within the critical interval. Single-unit activity of the dorsal horn neuron was isolated using a software window discriminator (Data-Wave Technology, Longmont, CO). The action potential of the neuron was amplified, filtered with a band-pass filter (DAM 80; World Precision Instruments Inc., Sarasota, FL) and processed through an audioamplifier (model AM9; Grass Instruments, West Warwick, RI) and monitored on a storage oscilloscope (Tektronix Inc., Beaverton, OR). The neuronal activity also was recorded into a computer through an A/D interface board for subsequent off-line quantitative analysis. Discharge frequency was quantified using data acquisition and analysis software (Experimental Workbench; DataWave Technology).
After the cutaneous receptive field was located and marked, the responses of the dorsal horn neurons to the following mechanical stimuli were initially tested as the control. The brush stimulus was applied to the receptive field by brushing the skin with a camel's hairbrush for three to four back-and-forth cycles. The wooden tip of a cotton-tipped applicator was used to apply the pressure stimulus. The tip was applied perpendicularly to the skin for about 8 s to generate an intense pressure (
200 g/mm2), which was perceived by the investigator as mildly painful. The pinch stimulus was applied for 6 s by means of a small forceps with a strong grip (560 g/mm2) that produces distinct pain when applied to human skin without causing tissue damage (Chen and Pan, 2002, 2004). The dorsal horn neurons were divided into the following three categories according to their differential responses to mechanical stimulation: low-threshold neurons, cells responding maximally to brush (only showing rapid adapting responses to press and pinch at the beginning of the application); high-threshold neurons, neurons responding only to noxious pinch; and wide-dynamic-range neurons, cells responding to brush but responding more intensely to noxious stimuli (pinch > press). At the end of the experiments, rats were killed by an intravenous injection of an overdose of sodium pentobarbital.
Experimental Protocols
Role of Spinal µ Opioid Receptors in the Effect of Topical Morphine on Dorsal Horn Projection Neurons. In normal rats, after recording the baseline activity of the identified dorsal horn projection neurons for 5 min, the neuronal responses to brush, pressure, and pinch applied to the receptive field were examined before and 10 min after the spinal topical application of 10 µM of morphine. This topical application procedure was chosen to simulate the intrathecal administration of drugs used in behavioral studies. To determine whether repeated topical morphine application produced a similar inhibitory effect on dorsal horn neurons, topical application of 10 µM morphine was repeated, separated by 30 min, after washout of its initial effect and when the firing activity and evoked responses of dorsal horn neurons returned to the control. In the pilot study, we observed that the inhibitory effect of topical morphine on dorsal horn neurons lasted less than 20 to 25 min after washout, and the evoked response of dorsal horn neurons fully recovered 30 min after washout of morphine. Previous studies have shown that 10 µM morphine produces a near maximal inhibition of voltage-gated calcium channels in dorsal root ganglion neurons (Wu et al., 2004) and hyperpolarization of lamina II neurons in spinal cord slices (Yoshimura and North, 1983). The similar dose of morphine also inhibits wide-dynamic-range neurons in the lumbar spinal cord in vivo (Reeve et al., 1998). Furthermore, the inhibitory effect on dorsal horn projection neurons by topical 10 µM morphine (see Results) is similar to the inhibition achieved by intravenous 2.5 mg/kg morphine (Chen and Pan, 2002; Chen et al., 2005), which produces analgesia in conscious rats (Chen and Pan, 2001).
To study the role of spinal µ opioid receptors in the effect of morphine on dorsal horn neurons, the inhibitory effect of topically applied morphine (10 µM) on dorsal horn projection neurons was tested before and 10 min after topical application of 1 µM H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), a highly specific µ receptor antagonist (Kohno et al., 1999). CTAP was applied to the exposed lumbar spinal cord at the concentration of 1 µM, which blocks the effect of intravenous morphine on dorsal horn neurons (Chen et al., 2005).
Role of Spinal GABAergic and Glycinergic Inputs in the Inhibitory Effect of Topical Morphine on Dorsal Horn Projection Neurons in Normal and Sham Control Rats. In this protocol, the inhibitory effect of topical morphine (10 µM) on evoked responses of dorsal horn projection neurons to graded mechanical stimuli was tested before and during spinal application of the GABAA receptor antagonist bicuculline and glycine receptor antagonist strychnine. After testing the initial effect of morphine on evoked responses of dorsal horn neurons and washout of morphine for 30 min, 20 µM bicuculline and 4 µM strychnine (Narikawa et al., 2000; Pan and Pan, 2004) was topically applied either separately or in combination for 10 min in both unoperated normal rats and sham control rats. This concentration of bicuculline and strychnine blocks inhibitory synaptic inputs to dorsal horn neurons in vitro and in vivo (Narikawa et al., 2000; Pan and Pan, 2004). Then, the effect of topical morphine on neuronal responses to mechanical stimuli was examined again 10 min after topical application of bicuculline, strychnine, or bicuculline plus strychnine.
Role of Spinal GABAergic and Glycinergic Inputs in the Effect of Topical Morphine on Dorsal Horn Projection Neurons in Nerve-Injured Rats. To determine the effect of spinal topical morphine on the dorsal horn projection neurons in the nerve-injured rats and the role of GABAergic and glycinergic inputs in the effect of morphine on dorsal horn neurons, the effect of 10 µM morphine on the responses of dorsal horn neurons to graded mechanical stimuli was tested before and 10 min after topical application of bicuculline and/or strychnine. After testing the initial effect of morphine on evoked responses of dorsal horn neurons and washout of morphine for 30 min, either 20 µM bicuculline or 4 µM strychnine alone or in combination was applied topically to the lumbar spinal cord. Then, the effect of topical morphine on neuronal responses to mechanical stimuli was examined again 10 min after topical application of bicuculline, strychnine, or bicuculline plus strychnine.
Morphine was obtained from Astra Pharmaceuticals (Westboroug, MA). CTAP, bicuculline, and strychnine were purchased from Sigma-Aldrich (St. Louis, MO).
Data Analysis
Data are presented as means ± S.E.M. The baseline firing rate of the dorsal horn projection neurons was averaged during a 5-min control period. The evoked responses were quantified as the mean discharge rate over the duration of the stimulus after subtracting the background activity of the neuron (Chen and Pan, 2002, 2004). Significant changes in the drug effect on evoked responses of dorsal horn projection neurons to graded mechanical stimuli were determined using analysis of variance followed by Tukey's post test. Differences were considered to be statistically significant if P < 0.05.
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Results |
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Role of µ Opioid Receptors in the Effect of Topical Morphine on Dorsal Horn Projection Neurons. Spinal topical application of 10 µM morphine significantly inhibited the evoked activity of dorsal horn projection neurons in response to press and pinch applied to the receptive field in all seven cells tested in normal rats (Fig. 1). Thirty minutes after washout of the initial morphine, the baseline activity and the evoked responses of the dorsal horn projection neurons completely returned to the control. Repeated application of the same concentration of morphine on the same neuron reproducibly inhibited the evoked response of these seven dorsal horn neurons (Fig. 1). There was no significant difference in the inhibitory effect of 10 µM morphine on dorsal horn neurons between the initial and the subsequent two applications of the same concentration of morphine. Spinal topical application of the specific µ opioid receptor antagonist CTAP (1 µM) was used when the baseline and evoked responses of the dorsal horn projection neurons returned completely to the control after morphine. CTAP alone had no significant effect on the evoked response of dorsal horn neurons. In the presence of 1 µM CTAP, subsequent spinal topical application of 10 µM morphine failed to inhibit the evoked response of dorsal horn neurons (n = 7, Fig. 1).
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Furthermore, 4 µM strychnine was applied topically to the recording site 30 min after the washout of morphine and bicuculline. Strychnine alone also significantly increased the evoked response of these 10 dorsal horn neurons. In the presence of strychnine, the inhibitory effect of topical 10 µM morphine was significantly decreased, compared with the initial effect of morphine (Figs. 2 and 3A). The percentage of inhibition by morphine in the presence of strychnine was 46 ± 4 and 44 ± 4% in response to pressure and pinch, respectively. Subsequently, both 20 µM bicuculline and 4 µM strychnine were coadministrated topically to the recording site 30 min after washout of morphine and strychnine. In the presence of both bicuculline and strychnine, topical application of 10 µM morphine showed no significant inhibitory effect on all 10 dorsal horn neurons tested (Figs. 2 and 3A).
Additionally, the above protocol was repeated in another six dorsal horn projection neurons recorded from six sham control rats. Topical application of 20 µM bicuculline and 4 µM strychnine also largely attenuated the inhibitory effect of 10 µM morphine on dorsal horn neurons, similarly to those described in unoperated normal rats (Fig. 3B).
Role of Spinal GABAergic and Glycinergic Tone in the Inhibitory Effect of Topical Morphine on Dorsal Horn Neurons in Nerve-Injured Rats. In 10 dorsal horn projection neurons recorded from nerve-injured rats, both the baseline and evoked neuronal discharges were significantly higher than those in both normal and sham control rats. The baseline activity of dorsal horn projection neurons in six sham control and 10 nerve-ligated rats was 0.17 ± 0.12 and 0.56 ± 0.2 Hz (P < 0.05), respectively. The neuronal responses to press (16.9 ± 1.5 versus 11.5 ± 0.8 Hz, P < 0.05) and pinch (23.1 ± 1.8 versus 16.7 ± 1.6 Hz, P < 0.05) were also significantly greater in nerve-ligated than in sham control rats (Figs. 4 and 5).
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Discussion |
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Activation of µ opioid receptors in the spinal dorsal horn produces analgesia most likely through attenuation of glutamatergic synaptic inputs and inhibition of dorsal horn neurons (Schneider et al., 1998; Kohno et al., 1999; Light and Willcockson, 1999; Chen et al., 2005). In this study, topical application of the µ opioid receptor antagonist CTAP completely blocked the inhibitory effect of spinally administered morphine on dorsal horn projection neurons, suggesting that the inhibitory effect of morphine is mediated by µ opioid receptors. Because the µ opioid receptors are predominantly located in laminae I and II (Arvidsson et al., 1995; Chen and Pan, 2003), it is possible that the inhibitory effect of morphine on deep dorsal horn (presumably projection) neurons is secondary to its effect on superficial dorsal horn neurons. Hence, increased excitability of lamina II (presumably inhibitory) interneurons by morphine may indirectly modulate the excitability of deep dorsal horn projection neurons. Many lamina II neurons are inhibitory interneurons, and lamina II is an important site for regulation of nociception and the analgesic action of spinally administered opioids. It has been shown that morphine increases the activity of lamina II neurons but suppresses the firing of deeper dorsal horn neurons (Woolf and Fitzgerald, 1981; Sastry and Goh, 1983; Magnuson and Dickenson, 1991). Opioids administered into the substantia gelatinosa (lamina II) reduce the responses of deeper dorsal horn neurons to noxious stimuli (Duggan et al., 1976, 1977; Johnson and Duggan, 1981). It is possible that morphine may increase the release of inhibitory neurotransmitters through activation of lamina II neurons, which in turn inhibits the deeper dorsal horn neurons. GABA and glycine, through their effect on GABAA and glycine receptors, respectively, are the two most important inhibitory neurotransmitters in the spinal cord (Yoshimura and Nishi, 1995; Li et al., 2002; Cronin et al., 2004; Pan and Pan, 2004). However, little information is available about the relationship between the inhibitory GABAergic/glycinergic tone and the inhibitory effect of opioids on dorsal horn projection neurons and nociception. In this study, we found that topical application of the specific GABAA and glycine receptor antagonists bicuculline and strychnine caused a large reduction in the inhibitory effect of morphine on dorsal horn projection neurons in normal and sham control rats. These data suggest that morphine most likely inhibits the response of dorsal horn projection neurons by augmentation of the GABAergic and glycinergic inputs. Consistent with our finding, it has been shown that the effects of spinally applied morphine on lumbar wide-dynamic-range neurons are largely attenuated by spinal bicuculline (Reeve et al., 1998). Notably, the inhibitory effect of morphine on dorsal horn projection neurons was attenuated to a greater extent by bicuculline than strychnine. Thus, the GABAergic tone appears to be more important than the glycinergic inputs for the inhibitory effect of morphine on dorsal horn projection neurons.
The mechanisms of potentiation of GABAergic and glycinergic inputs to dorsal horn projection neurons by opioids are not clear. There is no good evidence showing that µ opioids can directly excite dorsal horn inhibitory neurons. It is possible that the µ opioids increase GABAergic and glycinergic inputs to dorsal horn projection neurons through at least two indirect mechanisms. As illustrated in Fig. 6, activation of presynaptic and postsynaptic µ opioid receptors can inhibit glutamate release and the glutamatergic interneurons in lamina II (Schneider et al., 1998; Kohno et al., 1999; Light and Willcockson, 1999). The reduced glutamatergic inputs to the next inhibitory interneurons could decrease the excitability of the inhibitory interneuron. Consequently, the reduced release of GABA and glycine (disinhibition) to the interneuron that synapses with the projection neuron could lead to increased inhibitory tone to the projection neuron. Furthermore, stimulation of presynaptic and postsynaptic µ opioid receptors can depress the excitability of the inhibitory interneurons in lamina II by decreasing glutamatergic inputs and direct hyperpolarization of the cell (Fig. 6). As a result, it could reduce GABA and glycine release (disinhibition) to the interneuron that synapses directly with the projection neuron, which would increase the inhibitory tone to the dorsal horn projection neuron.
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; Tolle et al., 1996). Importantly, GABAergic terminals also make synapses with the primary afferent terminals in the superficial dorsal horn to regulate glutamate release through GABAB receptors (Barber et al., 1978; Li et al., 2002). Nerve injury-induced loss of GABAergic interneurons in the spinal cord is another important mechanism that probably contributes to hypersensitivity of dorsal horn neurons and neuropathic pain (Castro-Lopes et al., 1993; Ibuki et al., 1997; Moore et al., 2002). In this regard, several studies have shown that selective loss of GABAergic, but not glycinergic, inhibition in the spinal dorsal horn plays a critical role in hyperexcitability of dorsal horn neurons in nerve-injured rats (Castro-Lopes et al., 1993; Ibuki et al., 1997; Moore et al., 2002; Drew et al., 2004). We observed that topical application of bicuculline caused a marked increase in the evoked response of dorsal horn projection neurons in normal and sham controls but not in nerve-ligated rats. On the other hand, topical application of strychnine produced a similar enhancement in the response of dorsal horn projection neurons to graded mechanical stimuli in control and nerve-injured rats. Many inhibitory interneurons in the dorsal horn contain glycine and GABA, although a population of cells contains only GABA without glycine (Todd and Sullivan, 1990). These data provide further evidence that the spinal GABAergic input to dorsal horn projection neurons is selectively reduced following nerve injury, which probably contributes to central sensitization and chronic neuropathic pain.
The most salient finding of this study is that reduced GABAergic/glycinergic tone is directly linked to attenuated morphine effect on dorsal horn projection neurons in neuropathic pain. The mechanisms underlying reduced analgesic effect of opioids in neuropathic pain are not fully understood. It remains controversial whether reduced µ opioid receptors in the spinal cord account for diminished opioid effects in neuropathic pain (Stevens et al., 1991; Porreca et al., 1998; Zhang et al., 1998). We found that topical application of bicuculline had little influence on the inhibitory effect of morphine on dorsal horn projection neurons in nerve-injured rats but almost abolished the effect of morphine in normal and sham control rats. In comparison, spinal application of strychnine significantly attenuated the inhibitory effect of morphine on dorsal horn neurons in both normal and nerve-injured rats. Therefore, it is likely that loss of GABAergic tone following nerve injury not only plays a role in hypersensitivity of dorsal horn neurons but also contributes to the reduced analgesic effect of morphine in the spinal cord. It should be noted that degeneration of central terminals of primary afferents following nerve injury may result in a loss of presynaptic µ opioid receptors in the spinal dorsal horn, which also may reduce the antinociceptive action of morphine at the spinal level in neuropathic pain (Zhang et al., 1998). Nevertheless, data from our study provide an important alternative mechanism that could explain, at least in part, the reduced analgesic effect of opioids in neuropathic pain. It has been shown that µ opioids and GABAA receptors can interact synergistically in the spinal cord to produce analgesia (Yanez et al., 1990). The new information from the present study is also important for the design of new strategies to improve opioid efficacy in neuropathic pain.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CTAP, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2.
Address correspondence to: Dr. Hui-Lin Pan, Department of Anesthesiology, H187, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail: hpan{at}psu.edu
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