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Anesth Analg 1999;88:1125-1130
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Activation of the Rostral Ventrolateral Medulla in an Acute Anesthetized Rodent Strychnine Model of Allodynia

Sean R. Hall, MSc*, Louie Wang, MD*, Brian Milne, MD*, and Christopher Loomis, PhD{dagger}

Departments of *Anaesthesia and Pharmacology & Toxicology, Queens University, Kingston, Ontario; and {dagger}School of Pharmacy, Memorial University, St. John's, Newfoundland, Canada

Address correspondence and reprint requests to Dr. Louie Wang, Department of Anaesthesia, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario, Canada K7L 2V7. Address e-mail to wangl{at}KGH.KARI.NET


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
After the administration of intrathecal strychnine, allodynia is manifested as activation of supraspinal sites involved in pain processing and enhancement of cardiovascular responses evoked by normally innocuous stimuli. The objective of this study was to investigate the effect of strychnine-induced allodynia on adrenergic neuronal activity in the C1 area of the rostral ventrolateral medulla (RVLM), a major site involved in cardiovascular regulation. The effect of intrathecal strychnine (40 µg) or saline followed by repeated hair deflection to caudal lumbar dermatomes in the urethane-anesthetized rat was assessed by measuring voltammetric changes in the RVLM catechol oxidation current (CA · OC), mean arterial pressure (MAP), and heart rate (HR). After the administration of intrathecal strychnine, hair deflection evoked a significant and sustained increase in the RVLM CA · OC and MAP (peak 146.4% ± 5.6% and 159% ± 18.4% of baseline, respectively; P < 0.05). There was a nonsignificant increase in HR (peak 128% ± 8.2%). In the absence of hair deflection, there was no demonstrable change. Intrathecal saline-treated rats failed to demonstrate changes in RVLM CA · OC, MAP, or HR. In the present study, we demonstrated that, after the administration of intrathecal strychnine, innocuous hair deflection evokes temporally related neuronal activation in the rat RVLM and an increase in MAP. This suggests that the RVLM mediates, at least in part, the cardiovascular responses during strychnine allodynia.

Implications: Neural injury-associated pain, as manifested by allodynia, is resistant to conventional treatment. In a rat model of allodynia, we demonstrated activation of the brain region involved in sympathetic control. Innovative therapies that target this region may be successful in managing this debilitating condition.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The rostral ventrolateral medulla (RVLM), an important center involved in the control of sympathetic outflow, participates in vasomotor control (1). Anatomically, the RVLM represents a restricted region within the larger nucleus paragigantocellularis (2). Adrenergic neurons staining for the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase comprise the C1 area and represent a substantial proportion of the neurons in the RVLM (3). These neurons have a direct monosynaptic projection to the intermediolateral cell column of the thoracic spinal cord. C1 neurons provide excitatory input to sympathetic preganglionic neurons (4); electrophysiologically, the activity of this restricted group of vasomotor neurons is coupled to sympathetic nerve discharge. Importantly, the C1 neuronal group serves as the major site mediating the sympatholytic effects of {alpha}2-agonists (5). However, little is known of the role played by these neurons in integrating the cardiovascular responses related to neural pain states.

Neural injury pain can generate lasting pain and an exaggerated sensory phenomenon to light touch, in which innocuous, low-intensity mechanical stimuli evoke a powerful pain-like response termed allodynia. The acute blockade of spinal glycine receptors with the glycine antagonist strychnine produces a reversible allodynia-like state in both conscious and lightly anesthetized rodents (6,7). In the presence of intrathecal strychnine, hair deflection produces enhanced cardiovascular responses comparable to those elicited by other nociceptive stimuli (7). Simultaneously, there is a nociceptive-like activation of supraspinal structures involved in pain processing, such as the locus coeruleus (LC) (8). Because C1 adrenergic neurons in the RVLM have extensive excitatory projections to the LC (9) and because these neurons function in cardiovascular control, we postulated that they play an important role in strychnine-induced allodynia.

The aim of the present study was to examine the effect of strychnine-induced allodynia on C1 adrenergic neuronal activity in the rat RVLM to determine whether changes in RVLM activity correlate with changes in blood pressure.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All surgical procedures and experiments were conducted in accordance with the guidelines set forth by the animal care committee of Queen's University. The general methods of animal preparation and experimental protocol have been described in detail elsewhere and are summarized below.

Adult male Sprague-Dawley rats (300–400 g; Charles River, St. Constant, Quebec) were anesthetized using halothane and oxygen and were intubated for artificial respiration (f = 50 strokes/min, tidal volume 12 mL/kg, induction 4% halothane, maintenance dose 1.0%–1.25% halothane). Body temperature was monitored and maintained at 37 ± 0.5°C with a thermostatically controlled heating pad. Left carotid catheters (PE-50) coupled to a blood pressure transducer were used for blood pressure and heart rate measurements monitored on a physiograph. The administration of IV drugs and a continuous infusion of physiological saline (0.9% NaCl 5 mL · kg-1 · h-1) was accomplished via the insertion of a catheter (PE-50) into the jugular vein. After muscle paralysis with vecuronium (400 µg/kg IV) and adequate anesthesia in response to tail pinch, anesthetized animals were placed prone in a stereotaxic frame with bite bar set at –10 mm to undergo voltammetric experiments in the RVLM.

Under halothane anesthesia (1%–1.25%), intrathecal catheters (PE-10) were inserted through a slit in the atlantooccipital membrane of the cisterna magna and guided through the spinal subarachnoid space (approximately 8.5 cm caudally) with the tip terminating near the L1 spinal segment (8). After stabilization of the intrathecal catheter, prepared carbon fiber electrodes were electrochemically treated in vitro and tested in a standard phosphate-buffered saline (pH 7.4) solution containing ascorbic acid (200 µM; Sigma Chemical Co., St. Louis, MO) and 3,4-dihydroxyphenylacetic acid (DOPAC; 20 µM; Sigma Chemical Co.) (10). After removal of the left occipital bone, the treated electrode was lowered through the brainstem surface toward the C1 group of the RVLM using the coordinates: electrode holder 30° angle with vertical zero, 1.0 mm rostral and 1.8 mm lateral to the calamus scriptorius, depth of 2.5–3.5 mm below the dorsal medullary surface (11). This allowed the electrochemical recording of a catechol oxidation current (CA · OC) using differential normal pulse voltammetry (DNPV). Placement of the electrode in the RVLM was identified by gradually lowering the electrode at 0.2-mm increments until the CA · OC peak signal recorded in the RVLM began to diminish in height. The electrode was then raised to the position at which the peak signal was recorded. An auxiliary electrode and an Ag/AgCl reference electrode were placed on the skull surface by means of a semi-liquid contact. The response of C1 adrenergic neurons of the RVLM was recorded by measuring the CA · OC at 3-min intervals using DNPV (variables: linear sweep potential from -0.25 to 0.15V, scan rate 4 mV/0.4 s, pulse amplitude 30–40 mV, pulse duration 40–60 ms, and prepulse duration 80–100 ms) as described elsewhere (12). The CA · OC was identified as a voltammetric peak occurring at 55 mV both in vitro and in vivo.

During baseline voltammetric recordings, a light plane of anesthesia was maintained with urethane (1–1.2 g/kg IV; Sigma Chemical Co.) infused over a 10-min period after an increment reduction of the halothane concentration to zero. Once the RVLM CA · OC signal had stabilized after 1 h of baseline recordings, isotonic sodium chloride solution or strychnine (40 µg) was injected intrathecally in a 5-µL volume and flushed with 10 µL of saline. After injection, animals underwent repeated hair deflection with a cotton tip applicator bilaterally to the legs, flanks, and lower back. Brushing was done with no more force than that required to move through the hair, and only the pelage was disturbed. Sensitive dermatomes, determined by hair deflection-induced increases in blood pressure, heart rate (HR), and motor withdrawal response, were brushed in an oscillating motion (1–2 Hz for 3 min) at 3-min intervals for 1 h. The maximal evoked increase in the RVLM CA · OC, mean arterial pressure (MAP), and HR for each stimulus period was determined. To examine the spontaneous effects of spinal strychnine on RVLM CA · OC, MAP, and HR, a separate group of animals received intrathecal strychnine (40 µg) without repeated hair deflection.

At the end of each experiment, the monoamine oxidase inhibitor pargyline (75 mg/kg; Sigma Chemical Co.) was administered intraperitoneally. Subsequent decay of the voltammetric peak confirmed that the signal was caused by catechol oxidation occurring at 55 mV (13).

All voltammetric data (CA · OC peak height) are expressed as a percentage of the mean baseline value calculated by averaging the four consecutive catechol oxidation peak heights measured before intrathecal strychnine or saline administration. MAP was calculated from the following equation: diastolic + 1/3 (systolic - diastolic), and the evoked change was also expressed as a percentage of baseline response. The maximal evoked increase in MAP recorded in each 3-min period was used. Variability associated with single measurements concerning CA · OC and MAP were expressed as the mean ± SEM. Statistical analysis within each group was performed using a one-way repeated-measures analysis of variance. Significant (P < 0.05) differences were identified using the post hoc Newman-Keul's test.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Representative voltammograms of differential normal pulse oxidation recorded using electrochemically treated carbon fiber electrodes from known solutions in vitro and in vivo are shown in Figure 1. In a phosphate-buffered saline solution, DNPV resulted in no oxidation peaks (Fig. 1A). Voltammetric recordings in a phosphate-buffered saline solution containing known concentrations of ascorbic acid (200 µM) and DOPAC (20 µM) resulted in two distinct peaks at -89 mV (Peak 1) and 55 mV (Peak 2), corresponding to the oxidation of ascorbic acid and DOPAC, respectively (Fig. 1B). Implantation of the carbon fiber electrode at a depth of approximately 2.5 mm below the dorsal medullary surface resulted in the appearance of an oxidation current peak at 55 mV that was not well defined (Fig. 1C, peak 2). At the level of 3.0 mm below the medullary surface, the oxidation current peak occurring at 55 mV and corresponding to DOPAC in vitro became well resolved and was distinguishable from the signal corresponding to the oxidation of ascorbic acid at -89 mV (Fig. 1D). To confirm that the source of this oxidation peak was DOPAC, the monoamine oxidase inhibitor pargyline (75 mg/kg) was administered intraperitoneally at the end of each experiment. Pargyline treatment resulted in a complete decay of the oxidation peak detected at 55 mV within 20 min after injection. The ascorbic acid peak, which occurred at a potential of -89 mV (Fig. 1E), remained unchanged.



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  		Figure 1. Representative voltammetric traces of differential normal pulse oxidation current monitored in vitro and in vivo from the rostral ventrolateral medulla (RVLM). Voltammograms were recorded using differential normal pulse voltammetry in combination with electrochemically treated carbon fiber electrodes. A, Phosphate-buffered saline (pH 7.4) in which no oxidation peaks are present. B, Phosphate-buffered saline containing 200 µM ascorbic acid (Peak 1, -89 mV) and 20 µM 3,4-dihydroxyphenylacetic acid (DOPAC; Peak 2, 55 mV). C, In the brain 2.5 mm below the cerebellar surface, detection of the beginning of an oxidation peak corresponding to DOPAC (Peak 2) was observed. D, In the brain 3.0 mm below the cerebellar surface, the presence of a well resolved peak at 55 mV corresponds to the oxidation of DOPAC (Peak 2). E, In the brain 20 min after the intraperitoneal injection of the monoamine oxidase inhibitor pargyline (75 mg/kg), the decay of the peak corresponds to the oxidation of DOPAC. F, The RVLM before hair deflection after the administration of intrathecal strychnine (40 µg) (baseline). G, The RVLM 3 min after the onset of hair deflection after the administration of intrathecal strychnine.

 
In the absence of hair deflection, intrathecal strychnine (40 µg) had no effect on RVLM activity over a 60-min recording period (Fig. 2). However, repeated brushing of the lumbosacral dermatomes after the administration of intrathecal strychnine evoked an immediate and significant increase in RVLM neuronal activity, as reflected by an increase in the CA · OC signal (Fig. 1F and 1G). A significant increase was observed within 18 min after intrathecal strychnine administration, the maximal effect (peak height 146.4% ± 5.6% of baseline; P < 0.05) occurred 39 min after the onset of stimulation and remained significantly increased for the remainder of the stimulation period (Fig. 2). Innocuous hair deflection did not significantly affect CA · OC in intrathecal saline-treated rats (Fig. 2).



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  		Figure 2. The effect of hair deflection (HD) on catechol oxidation current (CA · OC) peak height measured over a 60-min period from a microelectrode implanted in the rostral ventrolateral medulla after the intrathecal administration of strychnine (40 µg) (•) or saline ({triangledown}). Each HD stimulus (3 min) is indicated by the horizontal bar. The spontaneous effect of intrathecal strychnine (40 µg) ({circ}) without HD is also illustrated. Each point represents the mean ± SEM. n = 4–5 in each group. *P < 0.05 compared with pre-strychnine levels.

 
Intrathecal strychnine (40 µg) without subsequent hair deflection had no effect on resting blood pressure (Fig. 3). However, a significant increase in MAP was observed during repeated brushing of sensitive lumbosacral dermatomes after the administration of intrathecal strychnine. MAP was significantly increased within 1 min after strychnine administration and the onset of hair deflection. The maximal effect (peak height 159% ± 18.4% of baseline; P < 0.05) (Fig. 3) occurred 25 min after the onset of stimulation. MAP did not recover between stimulus trains and remained increased throughout the time course. There was a smaller, nonsignificant increase in HR, for which a maximal response occurred 15 min after stimulation (data not shown). In contrast, in saline-treated animals, repeated hair deflection to the same caudal dermatomes failed to evoke changes in MAP (Fig. 3) or HR (data not shown).



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  		Figure 3. The effect of hair deflection (HD) on peak mean arterial pressure (MAP) after the intrathecal administration of strychnine (40 µg) (•) or saline ({triangledown}). Each HD stimulus (3 min) is indicated by the horizontal bar. The spontaneous effect of intrathecal strychnine (40 µg) ({circ}) without HD is also illustrated. Each point represents the mean ± SEM. n = 4–5 in each group. *P < 0.05 compared with pre-strychnine levels.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of the present study support the hypothesis that normally innocuous hair deflection is a nociceptive event in the presence of intrathecal strychnine. Hair deflection, applied to caudal dermatomes sensitized by spinal strychnine, evoked a significant increase in CA · OC in the RVLM and a significant increase in MAP. To the extent that changes in CA · OC reflect changes in adrenergic neuronal activity as measured by in vivo DNPV, the present findings demonstrate a correlation between changes in RVLM activity and blood pressure and provide further data supporting the role of the RVLM in integrating cardiovascular responses after nociceptive stimulation.

By using DNPV, changes in adrenergic neuronal activity, reflected by changes in CA · OC, have been monitored on-line in a biochemical-specific manner in the RVLM. Measuring changes in RVLM activity using this method allows selective study of the adrenergic neuronal population in the RVLM. Tissue damage and compression of the brainstem is minimal; this is important because the integrity of this brain area is essential for control of blood pressure and autonomic function. Before in vivo use, a standard electrochemical pretreatment is applied to the active surface of all manufactured carbon fiber electrodes, which are then tested in vitro. The function of the in vitro test is to ensure that pretreatment enables the electrode to produce a valid voltammogram exhibiting well resolved peaks at -89 mV and 55 mV, corresponding to the redox potentials of ascorbic acid and DOPAC, respectively, in a standard solution representative of conditions in the brain. It is important that both peaks increase during successive scans until equilibrium is achieved to relate the current and concentration of the electroactive species (ascorbic acid and DOPAC) detected to determine the temporal response of the electrode. The CA · OC results from the oxidation of the extracellular deaminated metabolite of DOPAC synthesized by catecholaminergic neurons. The in vivo monitoring of changes in CA · OC is a useful index of functional activity of catecholaminergic neurons and has previously been monitored in the RVLM and other brain areas using DNPV (8,10,11). The CA · OC signal observed in the present study satisfied all the criteria established in earlier studies (12–14). It was identified as an oxidation current peak appearing at the potential of 55 mV, corresponding to that of DOPAC in vitro, in a restricted area of the ventrolateral medulla (2.5–3.5 mm below the dorsal medullary surface). Systemic administration of the monoamine oxidase inhibitor pargyline produced a complete decay of the signal. This distinguished it from the ascorbate signal, which appeared at a potential of -89 mV and was not affected by pargyline treatment.

In the present study, we have shown that repeated nonnoxious hair deflection, which had no measurable effect on the RVLM CA · OC of saline-treated rats, resulted in an increase in RVLM adrenergic neuronal activity after intrathecal strychnine administration. The increase in RVLM adrenergic neuronal activity after repeated activation of low-threshold mechanoreceptors is mediated, in part, by mechanisms at the level of the spinal cord. This observation is indicated by the restricted caudal sites, corresponding to dermatomes innervated by spinal segments affected by intrathecal strychnine, at which hair deflection evoked this response (15) and is further supported by the lack of spontaneous effects after the administration of intrathecal strychnine. Importantly, these were the same lumbosacral sites from which concurrent autonomic responses were elicited by hair deflection, which confirms the development of strychnine allodynia (6,7,15,16). There seems to be a consistent relationship between RVLM neuronal firing rate and blood pressure. Several studies have demonstrated that chemical or electrical stimulation of the RVLM results in an increase in sympathetic outflow and increased blood pressure (17). By contrast, bilateral chemical or electrolytic lesions of this area result in significant hypotension (17). Thus, the RVLM may play a role in integrating the cardiovascular behaviors elicited during strychnine-induced allodynia.

The RVLM has been implicated in the regulation of sympathoexcitatory tone, and because allodynia is dependent on intact sympathetic function (18), it could be expected that this brain region is involved in the integration of cardiovascular responses during this neural pain state. Evidence demonstrates that C1 adrenergic neurons of the RVLM are involved in pain processing, as revealed by the increased expression of c-Fos protein in this region after somatic inflammation in the rat (19). Additionally, Stornetta et al. (20) demonstrated that noxious stimulation of afferent nerves results in a somatic pressor response mediated by neurons of the RVLM. Electrical or chemical lesions of phenylethanolamine N-methyltransferase–labeled C1 adrenergic neurons abolished this pressor response. Most importantly, lesions of other autonomic areas, including the parabrachial nucleus, the nucleus tractus solitarius, or the A5 region, failed to affect the pressor reflex. Sun and Spyer (21) have shown that high-threshold electrical or noxious stimulation associated with an increase in arterial pressure evokes excitation of C1 adrenergic neurons. These same RVLM-spinal projecting vasomotor neurons failed to respond to nonnoxious stimulation. Results from these studies highlight the importance of the RVLM in the hemodynamic response to pain, and they support our finding of a temporal relationship between an increase in RVLM activity and arterial pressure during allodynic stimulation.

The activation of the RVLM seen in this study is comparable to the activation of the LC observed in a similar model of spinal allodynia (16). The LC has efferent projections to widespread regions and relays information to higher brain centers during pain processing (22). It receives extensive medullary innervation from adrenergic neurons in the RVLM (23). Thus, in addition to integrating cardiovascular responses, the RVLM may modulate coeruleur activity during strychnine-induced allodynia.

In this study, we demonstrated that central sympathetic hyperactivity, as reflected by an increase in RVLM CA · OC, occurs in a spinal model of allodynia. Touch-evoked allodynia is an important symptom of neural injury-induced pain. Nociception results not only from the activation of high-threshold C fibers, but also from the stimulation of low-threshold mechanoreceptors (24). The mechanisms of this pain state are not completely understood, but they may involve changes at the spinal cord level and in the autonomic nervous system. Using a model similar to that used in this study, Sherman and Loomis (15) demonstrated that the cardiovascular and motor responses characterizing allodynia result from the removal of spinal glycinergic modulation by intrathecal strychnine. In addition, the effectiveness of sympathectomy in treating allodynia associated with nerve injury in the clinical and experimental milieu (25) suggests involvement of autonomic mechanisms. Although the sympathetic hyperactivity observed in this study is a manifestation of strychnine-induced allodynia, we cannot preclude its potential role in augmenting and sustaining this abnormal pain state.

The in vivo electrochemical technique of DNPV can be reliably used to study neurochemical changes in catecholaminergic neurons in the RVLM. In the present study, we demonstrated that innocuous hair deflection evokes a nociceptive-like activation of CA · OC in C1 adrenergic neurons in the rat RVLM after the administration of intrathecal strychnine. This response was temporally correlated with increased blood pressure. These results suggest that hyperactivity in adrenergic neurons in the RVLM mediate, at least in part, the cardiovascular responses after nociceptive stimulation.


   Acknowledgments
 
This work was supported by the Medical Research Council of Canada.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 7, 1999.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press