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INNOVATIVE METHODOLOGIES
Department of Psychology, University of Texas at Arlington, Arlington, Texas
Submitted 12 January 2005; accepted in final form 11 February 2005
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ABSTRACT |
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INTRODUCTION |
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; Coghill et al. 1994; Hsieh et al. 1996; Kwan et al. 2000; Ploghaus et al. 1999; Svensson et al. 1997). The ACC is consistently activated in chronic conditions such as neuropathic pain (Hsieh et al. 1995). Recordings from nociceptive specific neurons located in the ACC have revealed large, bilateral receptive fields that often include the entire body (Sikes and Vogt 1992), suggesting a nondiscriminative function (Yamamura et al. 1996). The afferent inputs to the ACC originate from the intralaminar thalamic nuclei and submedius nucleus (Craig et al. 1982; Vogt et al. 1992). The ACC projects to the intralaminar thalamic nuclei (Kaitz and Robertson 1981;Royce 1983; Yeterian and Pandya 1988), the ventrolateral, lateral, and dorsolateral columns of the periaqueductal gray (PAG) (An et al. 1998; Floyd et al. 2000), and the posterior hypothalamic nucleus (Cavdar et al. 2001; Ongur et al. 1998). Behavioral studies showed decreased pain related avoidance behavior without change in mechanical threshold following stimulation of the anterior cingulate cortex (LaGraize et al. 2001). In rats, the prefrontal cortex (PFC) is subdivided into medial, lateral, ventral, and orbital parts. The ACC belongs to the medial PFC (Groenewegen 1988; Krettek and Price 1977b; Leonard 1969). Increases of hot plate and tail flick latencies were found following electrical stimulation of the PFC (Hardy 1985). The finding that the rat became docile during the period of PFC stimulation suggests an antinociceptive effect during PFC stimulation (Hardy 1985). There are no previous studies evaluating the responses of spinal cord dorsal horn neurons during ACC stimulation.
We hypothesized that ACC stimulation has two phases: a short-term phase in which stimulation elicits antinociception and a long-term phase that follows stimulation to change the affective response to noxious input. The purpose of this study was to examine the response of spinal cord dorsal horn neurons during stimulation of the anterior cingulate cortex in the short-term phase. Preliminary results have previously been reported (Peng et al. 2004).
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METHODS |
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). Animal preparation
Animals were anesthetized using pentobarbital sodium (50 mg/kg, ip). As described previously (Peng et al. 2003), the spinal cord was exposed by performing a 3- to 4-cm laminectomy over the lumbosacral enlargement. A cannula was inserted in the trachea for artificial respiration. The anesthesia and paralysis of musculature was maintained by intravenous administration of a mixture of 50 mg of pentobarbital sodium and 5 mg of pancuronium bromide in 9 ml of 0.9% saline at a rate of 0.02 ml/min. The pupillary reflex was monitored periodically to ensure proper depth of anesthesia. The spinal cord was immobilized in a stereotaxic frame and covered with mineral oil. The end tidal CO2 was maintained at 
30 mmHg, and body temperature was maintained at 37°C using a feedback-controlled heating pad and rectal thermal sensor probe.
Data acquisition
A 10- to 12-M
tungsten microelectrode (FHS, Brunswick, ME) was used for electrophysiological recordings in the L5 and L6 region of the spinal cord dorsal horn. Spinal dorsal horn neurons were initially searched by applying mechanical stimulation to the plantar region of the hindpaw. Responses to intensity-coded mechanical (brush, pressure, and pinch) stimulation within the receptive field of the dorsal horn neuron were recorded using SPIKE2 computer software program (CED).
MEASUREMENT OF MECHANICAL STIMULATION RESPONSES.
After the identification of a differentiable cell, three mechanical stimuli of increasing intensity (brush, pressure, and pinch) were applied to the receptive field. Each stimulus was applied once for 10 s, with an interstimulus interval of 20 s. The response to each mechanical stimulus was measured as the number of action potentials per second. Wide dynamic range (WDR) spinal dorsal horn neurons were selected for this study (Chung et al. 1986).
ANTERIOR CINGULATE CORTEX STIMULATION.
After the craniotomy, a bipolar stimulating electrode was placed in the ACC (0.2 mm rostral to Bregma, 0.5 mm lateral to the midline) based on the coordinates of Paxinos and Watson (1998). Stimulation was delivered at 300 Hz, 0.1-ms duration, at intensities of 10, 20, and 30 V either ipsilateral or contralateral to the side of spinal cord dorsal horn neuronal recording.
HISTOLOGICAL VERIFICATION OF STIMULATION SITE. At the end of experiment, the animal was killed by overdose using an intracardial injection of pentobarbital sodium. The brain was removed and immersed in 10% formaldehyde solution. Serial coronal sections (80 µm thick) of the brain were stained with thionin for histological verification of the stimulating electrode track. The site of the stimulating electrode was determined using a light microscope (Fig. 2A).
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The stored digital record of unit activity was retrieved and analyzed off-line. For single neuron recordings, responses to mechanical stimuli applied to the receptive field for 10 s with or without ACC stimulation were calculated. Statistical significance was tested using an ANOVA followed by posthoc tests (Tukey HSD) for significant change (Statistica, StatSoft). A change was judged significant if P < 0.05. All values are presented as means ± SE.
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RESULTS |
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Effect of contralateral ACC stimulation
The responses to brush at control, 10, 20, and 30 V, and recovery were 20.7 ± 3.2, 16.4 ± 2.5, 15.0 ± 2.6, 12.9 ± 2.3, and 19.2 ± 3.3 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 40.6 ± 9.1, 23.2 ± 4.7, 25.5 ± 5.1, 20.5 ± 3.8, and 31.7 ± 5.8 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 38.8 ± 5.8, 34.6 ± 5.3, 30.4 ± 4.6, 30.9 ± 6.6, and 39.8 ± 7.6 spikes/s, respectively. A two-way repeated measures ANOVA showed a main effect of mechanical stimuli [F(2,26) = 9.38, P < 0.001] and a main inhibitory effect of electrical stimulation [F(4,52) = 8.32, P < 0.001]. However, no significant interaction (electrical intensity x mechanical intensity) was found [F(8,104) = 1.7, P = 0.106]. Posthoc analysis indicated significant inhibition for pressure when 10-, 20-, and 30-V electrical stimulation was delivered (P < 0.001, P < 0.01, and P < 0.001, respectively). No significant inhibition was found for brush or pinch when 10-, 20-, and 30-V electrical stimulation was delivered (P > 0.05; Fig. 2B).
Effect of ipsilateral ACC stimulation
The responses to brush at control, 10, 20, and 30 V, and recovery were 12.0 ± 1.5, 10.8 ± 1.3, 9.5 ± 1.3, 9.4 ± 1.3, and 12.3 ± 1.5 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 39.6 ± 5.5, 26.5 ± 3.7, 24.8 ± 3.6, 22.0 ± 3.0, and 25.1 ± 4.6 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 41.4 ± 4.7, 29.1 ± 3.7, 26.9 ± 3.5, 26.0 ± 3.6, and 36.5 ± 4.6 spikes/s, respectively. A two-way repeated measures ANOVA showed a main effect of mechanical stimuli [F(2,78) = 27.62, P < 0.001] and a main inhibitory effect of electrical stimulation [F(4,156) = 16.06, P < 0.001]. Additionally, a significant interaction (electrical intensity x mechanical intensity) was also found [F(8,312) = 5.75, P < 0.001]. Posthoc analysis indicated significant inhibition by all three electrical stimulation intensities compared with the control for pressure (P < 0.001) and pinch (P < 0.001), but no significant change for brush (P > 0.05; Fig. 2C).
Effect of overall ACC stimulation
Because the overall ANOVA did not reveal a difference between ipsilateral and contralateral ACC stimulation, the data were merged to evaluate the inhibitory effect of electrical ACC stimulation on responses to three mechanical stimuli. The results indicated a main inhibitory effect of electrical stimulation [F(4,120) = 12.7, P < 0.001] and a main effect of mechanical stimuli [F(2,60) = 10.96, P < 0.001]. A significant electrical intensity x mechanical intensity interaction was also found [F(8,240) = 5.37, P < 0.001]. The responses to brush at control, 10, 20, and 30 V, and recovery were 14.2 ± 1.4, 12.3 ± 1.2, 10.9 ± 1.2, 10.3 ± 1.1, and 14.1 ± 1.4 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 39.8 ± 4.7, 25.6 ± 3.0, 25.0 ± 3.0, 21.6 ± 2.4, and 34.2 ± 3.7 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 40.7 ± 3.8, 30.6 ± 3.1, 27.8 ± 2.8, 27.2 ± 3.2, and 37.4 ± 3.9 spikes/s, respectively. Posthoc analysis indicated significant inhibition by the three electrical stimulation intensities compared with the control for pressure (P < 0.001) and pinch (P < 0.001), but no significant change for brush (P > 0.05; Fig. 2D).
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DISCUSSION |
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). It is unknown what neural circuitry is involved in the ACC descending inhibition of the dorsal horn neuronal responses. We hypothesize that when noxious input reaches the ACC, it not only generates an emotional response (long-term effect), but might also suppress incoming signals (short-term effect) at the spinal level through activating the PAG descending inhibitory system, or other possible targets, including the nucleus raphe magnus and the locus coeruleus. It is known that activation of supraspinal structures will induce inhibition at the spinal level (Basbaum and Fields 1978, 1984; Fields and Basbaum 1978; Fields et al. 1991; Mason 1999, 2001; Millan 2002; Sandkühler 1996; Willis 1988; Willis and Westlund 1997). Using electrophysiological recording in combination with ACC stimulation, we showed that spinal cord dorsal horn neurons are only inhibited during ACC stimulation. The responses of dorsal horn neurons to mechanical stimuli in the receptive field recovered almost immediately (1 min) after termination of stimulation, namely a short-term effect. Therefore these results do not explain the long-term antinociceptive effect of ACC stimulation observed in behavioral tests (Fuchs et al. 1996; Hardy 1985; LaGraize et al. 2001). Hardy (1985) found an increase of response latencies in the tail flick and hot plate tests after PFC stimulation. These effects were explained as analgesic at the spinal and supraspinal levels, respectively. The explanation of these findings is that the PFC projects directly to the PAG (Hardy and Leichnetz 1981). Stimulation of the PFC alters the firing rates of the PAG nociceptive neurons (Hardy and Haigler 1985), which in turn initiates descending inhibition. Stimulus-produced analgesia (SPA) was first shown by Reynolds (1969) in the rat in which PAG stimulation elicited an antinociceptive effect and is supported by a large body of literature (Millan 2002). Because the ACC is a part of the PFC (Groenewegen 1988; Krettek and Price 1977b; Leonard 1969), it is reasonable to speculate that ACC stimulation activates PAG neurons, which in turn, send projections to various midbrain nuclei (e.g., the nucleus raphe magnus and the locus coeruleus) to elicit descending inhibition to the spinal cord dorsal horn neurons (Fig. 3). In another study, both electrical and chemical stimulation (activation of mGluR) of the ACC has been found to induce descending facilitation in the rat in the tail flick test (Calejesan et al. 2000). In this study, they used the tail flick test in a lightly anesthetized (halothane) rat during electrical stimulation or chemical activation (mGluRs) of the ACC. In our experiment, we recorded single neuronal responses in a deeply anesthetized (by pentobarbital sodium) rat. The difference in effects could be the result of different anesthesia in two different experimental setups or the differences in peripheral stimuli (heat in the tail flick test vs. mechanical in our test). It has been shown that ACC lesions selectively reduce the affective component of neuropathic pain (LaGraize et al. 2004). The aim of this lesion study was different from our study, in which they focused on the supraspinal effect and we focused on the effect of ACC activation on the spinal dorsal horn neurons. The lesion study provided evidence that correlates with clinical reports, which support the notion that if the ACC is surgically damaged, the patient will experience pain relief (Ballantine et al. 1967; Hurt and Ballantine 1974).
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; Jones and Leavitt 1974), the mediodorsal thalamic nucleus (Divac et al. 1978a,b; Groenewegen 1988; Jones and Leavitt 1974; Krettek and Price 1977b; Leonard 1969, 1972; Ray and Price 1992; Van Eden et al. 1992; Vogt and Peters 1981; Vogt et al. 1981), the centrolateral thalamic nucleus (Robertson and Gorenstein 1987), the laterodorsal thalamic nucleus (Robertson and Gorenstein 1987), the submedius nucleus (Craig et al. 1982; Vogt et al. 1992), the basolateral amygdaloid nucleus (Divac et al. 1978b; Krettek and Price 1977a), the dorsal and median raphe nucleus (Divac et al. 1978b), the locus coeruleus (Divac et al. 1978b), the lateral hypothalamic area (Divac et al. 1978b), the periventricular hypothalamic nucleus (Saphier and Feldman 1976), the angular insular cortex (Beckstead 1979), and contralateral cingulate cortex areas (Beckstead 1979; Vogt and Peters 1981; Vogt et al. 1981). The ACC efferents project to the intralaminar thalamic nuclei (Beckstead 1979; Kaitz and Robertson 1981; Royce 1983; Yeterian and Pandya 1988), the mediodorsal thalamic nucleus (Beckstead 1979; Divac et al. 1978a; Groenewegen 1988; Leonard 1969, 1972; Ray and Price 1992; Van Eden et al. 1992), the ventromedial thalamic nucleus (Leonard 1972), the ventrolateral, lateral, and dorsolateral columns of the PAG (An et al. 1998; Floyd et al. 2000), the median raphe nucleus (Behzadi et al. 1990; Wyss and Sripanidkulchai 1984), the pontine nucleus (Beckstead 1979; Leonard 1969), the anterior pretectal nucleus (Beckstead 1979; Cadusseau and Roger 1991; Domesick 1969; Leonard 1969), the periventricular hypothalamic nucleus (Saphier and Feldman 1976), the posterior hypothalamic nucleus (Cavdar et al. 2001; Ongur et al. 1998), and the contralateral cingulate cortex areas (Beckstead 1979). The ACC also has projections to the midbrain and pontine reticular formation, the superior colliculus, and the dorsal parts of the periaqueductal gray (Beckstead 1979; Neafsey et al. 1986; Reep et al. 1987; Sesack et al. 1989). Specifically, it has been shown that projections from the caudodorsal medial PFC (e.g., the ACC) predominantly terminate in the dorsolateral PAG (Floyd et al. 2000). A pattern of ipsilateral projection from the ACC to the PAG is shown by both anterograde and retrograde tracing studies in the rat (Floyd et al. 2000), although a smaller contralateral projection does exist. However, bilateral projections have been shown in the monkey (An et al. 1998) and rabbit (Meller and Dennis 1986). In addition, the ACC has reciprocal connections with somatosensory, motor, and visual cortices (Conde et al. 1990, 1995; Reep et al. 1990; Van Eden et al. 1992). The bilateral projections from the ACC to the PAG most likely account for the finding that stimulation of the ipsilateral ACC induced a significant reduction of spinal dorsal horn responses to high-intensity mechanical stimuli. Stimulation of the contralateral ACC induced a significant decrease of the dorsal horn response to pressure but not to pinch. Comparing the response to pinch between ipsilateral (Fig. 2C) and contralateral (Fig. 2B) ACC stimulation groups, no statistical significance was shown. However, compared with their own baseline control, ipsilateral but not contralateral ACC stimulation showed significant inhibition of the dorsal horn neuronal responses to pinch. This finding may suggest less inhibitory effect of contralateral than ipsilateral ACC stimulation on inhibition of dorsal horn neurons. When nociceptive signals ascend to the thalamus, the information flows through different regions of the thalamus to reach the ACC and other parts of the brain. ACC activation most likely triggers the descending inhibitory system to elicit a short-term inhibition of the dorsal horn neurons. In addition, ACC activation most likely activates other limbic structures such as the hypothalamus, amygdala, and hippocampus to contribute to the long-lasting inhibition of emotional responses that is observed in behavioral tests of nociception.
In summary, we conclude that electrical stimulation of the anterior cingulate cortex induces graded inhibition of the responses of spinal cord dorsal horn neurons to noxious mechanical stimuli. This stimulus-produced inhibition starts recovering immediately after the termination of stimulation. These results suggest a differential short-term and long-term modulatory effect of the anterior cingulate cortex stimulation on the somatosensory pathway involved with nociceptive processing.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. B. Peng, Dept. of Psychology, PO Box 19528, Univ. of Texas at Arlington, 501 S. Nedderman Dr., Arlington, TX 76019-0528 (E-mail: ypeng{at}uta.edu)
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