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Anesth Analg 2001;93:728-733
© 2001 International Anesthesia Research Society

PAIN MEDICINE

The Release of Spinal Prostaglandin E2 and the Effect of Nitric Oxide Synthetase Inhibition During Strychnine-Induced Allodynia

Brian Milne, MD, FRCP, Sean R. Hall, MSc, Michael E. Sullivan, MSc, and Chris Loomis, PhD*

Department of Anesthesiology, Pharmacology, and Toxicology, Queen’s University, Kingston, Ontario; and the *School of PharmacyMemorial University of Newfoundland, St. John’s, Newfoundland, Canada

Address correspondence and reprint requests to Dr. Brian Milne, Department of Anesthesiology, Kingston General Hospital, 76 Stuart St., Kingston, Ontario, K7L 2V7.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The removal of spinal glycinergic inhibition by intrathecal strychnine produces an allodynia-like state in rodents. Our objective was to measure spinal prostaglandin E2 (PGE2) release during strychnine-allodynia and examine the effects of N{omega}-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthetase. Under halothane, rats were fitted with intrathecal and spinal microdialysis catheters, and microelectrodes implanted into the locus coeruleus for measurement of catechol oxidation current (CAOC) using voltammetry. Animals were then administered urethane and treated as follows: 1) baseline control 10 min, intrathecal strychnine (40 µg) 10 min, 10 min of hair deflection, and 2) 10-min control followed by intrathecal strychnine (40 µg) with hair deflection for 60 min. Spinal dialysate samples were collected for PGE2 levels determined by using immunoassay. In separate experiments, the effect of intrathecal strychnine (40 µg) followed by hair deflection was studied in rats pretreated with intrathecal l-NOARG (50 nmol). After intrathecal strychnine, hair deflection significantly increased spinal PGE2 release (619% ± 143%), locus coeruleus CAOC (181% ± 6%), and mean arterial pressure (123% ± 2%) P < 0.05. Pretreatment with intrathecal l-NOARG significantly inhibited strychnine-allodynia. In this model, hair deflection evokes spinal PGE2 release, locus coeruleus activation, and an increase in mean arterial pressure. L-NOARG pretreatment attenuated the locus coeruleus CAOC, a biochemical index of strychnine-allodynia, suggesting a mediator role of nitric oxide. A mediator role of nitric oxide is also implicated, helping to explain the pathophysiology of this allodynic pain.

Implications: In a rodent model of allodynia, where pain is triggered by nonpainful stimuli, hair deflection evokes release of spinal prostaglandin E2, locus coeruleus activation, and a blood pressure increase. A mediator role of nitric oxide is also implicated, helping to explain the pathophysiology of this allodynic pain.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Neuropathic pain may be triggered by nonpainful stimuli, a sensory abnormality termed allodynia. The pathophysiology of this condition is incompletely understood; however, loss of spinal cord inhibitory mechanisms modulating low-threshold afferent input have been implicated. Removal of spinal glycinergic inhibition by acute injection of intrathecal strychnine induces a reversible allodynic-like state in rodents (1,2). Thus, normally innocuous hair deflection in the presence of intrathecal strychnine evokes cardiovascular responses and an increase in locus coeruleus activity (3,4), similar to that produced by a nociceptive event.

Recent evidence has implicated the role of spinal prostanoids in spinal N-methyl-D-aspartate-induced hyperalgesia (5–7). At the spinal level, sustained C fiber activity induces a rapid increase in prostaglandin (PG) synthesis, suggesting that spinal prostanoids may facilitate abnormal neurotransmission in allodynia. It is assumed that nitric oxide (NO) produced by excitatory amino acids may increase PG production by cyclooxygenase activation (7). We showed that intrathecally administered ketorolac and S(+)-ibuprofen suppress the locus coeruleus and cardiovascular peak responses evoked during strychnine-allodynia (8).

Our objective was to measure spinal prostaglandin E2 (PGE2) release during strychnine-allodynia and to examine the effects of N{omega}-nitro-L-arginine (L-NOARG), an inhibitor of NO synthetase (NOS), during strychnine-allodynia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were performed after approval of the Animal Care Committee of Queen’s University. Male Sprague-Dawley rats (250–300 g; Charles River, St. Constant, Quebec) were housed in group cages on a 12/h light/dark cycle at ambient temperature 22°C.

After induction of anesthesia (4% halothane/oxygen and maintenance with 1.5% halothane) and tracheostomy, rats were maintained on artificial ventilation (Harvard Apparatus rodent respirator, frequency 40 strokes/min, tidal volume 12 mL/kg) (Harvard Apparatus, Hollister, MA). Temperature was maintained at 37°C by using a warming blanket attached to a temperature controller (Yellow Springs Instruments, Yellow Springs, OH). The carotid artery and jugular vein were cannulated for measurement of arterial blood pressure (Statham pressure transducer connected to a Grass 7 physiograph) and drug administration, respectively. Carotid and jugular cannulation were used to keep hair deflection away from the surgical field. Normal saline (5/mL · kg-1 · h-1) was infused IV throughout the experiment by using a Harvard syringe infusion pump and muscle relaxation was induced with metocurine (200 µg/kg). Anesthetized rats were placed prone in a stereotaxic frame with the incisor bar 10 mm below the interaural line. An intrathecal catheter (PE-10 tubing) was inserted through a slit in the atlanto-occipital membrane 8.5 cm and guided through the spinal subarachnoid space with the tip terminating near the L1 spinal segment (approximately 8.5 cm caudally). Spinal extracellular microdialysis catheters were prepared by using PE-50, PE-10, and dialysis tubing, and positioned through the atlanto-occipital membrane terminating at the L1 segment. Carbon fiber microelectrodes were then implanted into the locus coeruleus as described below.

Differential normal pulse voltammetry is an electrochemical technique providing a dynamic measure of central catecholaminergic activity and is suited for studies in the locus coeruleus because of the dense concentration of noradrenergic neurons in this structure (9). Carbon fiber microelectrodes (8-µm diameter and 500-µm length) insulated by a glass micropipette were manufactured in our laboratory (10) and, to distinguish between catechol and ascorbic acid oxidation, were electrochemically pretreated (11). Before implantation, the microelectrodes were tested in vitro by using a standard phosphate buffered saline solution (pH 7.4) containing ascorbic acid (200 µM; Sigma, St. Louis, MO) and 3,4-dihydroxyphenylacetic acid (DOPAC, 20 µM, Sigma). The catechol oxidation current (CAOC) was identified as a peak occurring at +55 mV both in vitroand in vivo. Differential normal pulse voltammetry was conducted with a Biopulse pulse voltammetry system (Tacussel, Villeurbanne, France). Implantation of the carbon fiber microelectrodes was made through a skull burr hole after dural exposure and puncturing of the pia with a 30-gauge needle into the locus coeruleus (0.7 mm posterior from the interaural line, 1.3 mm lateral from bregma, and 5.5–6.5 mm below the cerebellar surface) (4,12). Placement of the microelectrode in the locus coeruleus was confirmed by detection of a maximal catechol oxidation peak. An auxiliary and an Ag/Cl reference electrode were placed in contact with the skull surface using saline-soaked Gelfoam®. The response of noradrenergic neurons was recorded by measuring the CAOC at 3-min intervals using differential normal pulse voltammetry (variables: linear sweep potential -0.25 to 0.15 V, scan rate 4 mV and 0.4 s, pulse amplitude 30–40 mV, pulse duration 40–60 ms, and prepulse 80–100 ms) (3,4,8).

After catheter insertion and electrode implantation, halothane was discontinued and anesthesia was maintained with IV urethane (1–1.2 g/kg, Sigma Chemical Co.). The locus coeruleus CAOC was then allowed to stabilize for 1 h before experimentation. Intrathecal drugs were injected in a volume of 5 µL and flushed with 10 µL of normal saline.

After the stabilization period, animals (n = 4) were treated as follows. Baseline control 10 min (no hair deflection), intrathecal strychnine (40 µg, Sigma) 10 min (no hair deflection), and 10 min of repeated hair deflection (2 min on/1 min off). Hair deflection involved repeated brushing with a cotton-tipped applicator applied bilaterally to the legs, flanks, lower back, and tail in an oscillating motion (rate 1–2/s). Brushing was done with no more force than that required to move through the hair, and only the pelage was disturbed. This was followed by another 10-min control period (no hair deflection) followed by intrathecal strychnine (40 µg) with repeated hair deflection (2 min on/1 min off) for 60 min. The effects of intrathecal strychnine are dose dependent and reversible lasting 15–30 min (13). Locus coeruleus CAOC and mean arterial pressure (MAP) were recorded every 3 min, and spinal dialysate samples (10 µL/min flow rate) were collected every 10 min. The concentration of PGE2 was determined by using a Titerzyme® prostaglandin E2 enzyme immunoassay kit (Perspective Biosystems, Inc., Framingham, MA).

To investigate the effects of NO in strychnine-allodynia, animals were pretreated with intrathecal L-NOARG (50 nmol, Sigma) (n = 7), or intrathecal saline (n = 7) 20 min before intrathecal strychnine (40 µg). The hair deflection stimulus was repeated at 5-min intervals. A separate group of animals was given intrathecal saline plus L-NOARG (50 nmol) followed by hair deflection (n = 4).

Voltammetry data (CAOC peak height) were expressed as a percent of mean baseline value, which was calculated by averaging four CAOC peak heights measured during the baseline period before intrathecal saline or strychnine administration. The evoked change in MAP (diastolic plus 1/3 [systolic minus diastolic]) was expressed as percent of baseline. The maximal increase in MAP in each recording time period was used. Data are shown as the mean ± SEM. Statistical analysis within each group was performed using a one-way repeated measure analysis of variance. Significant (P < 0.05) differences were identified by using the post hoc Newman-Keuls test.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
After intrathecal strychnine, repeated hair deflection significantly increased PGE2 release (maximum 619% ± 143%, P < 0.05) (Fig. 1). PGE2 levels returned to baseline between the first and second strychnine injections and were not significantly increased in the initial period poststrychnine and before hair deflection. This response was accompanied by both an increase in locus coeruleus CAOC (maximum 181% ± 6%, P < 0.05) and MAP (123% ± 2%, P < 0.05) (Fig. 2). In the absence of intrathecal L-NOARG, hair deflection evoked similar increases in the locus coeruleus CAOC (maximum 141% ± 20%) and MAP (maximum 115% ± 14%) after intrathecal strychnine. After pretreatment with L-NOARG, hair deflection had no significant effect on CAOC or MAP in strychnine-treated rats. In control animals pretreated with L-NOARG, intrathecal saline followed by hair deflection had no effect on locus coeruleus CAOC or MAP as compared with baseline (Figs. 3 and 4).



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  		Figure 1. The effect of hair deflection (HD, horizontal bar at the bottom of the figure) on prostaglandin E2 (PGE2) release after intrathecal 40 µg strychnine (STR) injection. Each point represents the mean ± SEM, n = 4, *P < 0.05 compared with prestrychnine levels (one-way repeated measures analysis of variance followed by post hoc Newman-Keuls test).

 


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  		Figure 2. The effect of hair deflection (HD, horizontal bar at the bottom of the figure) on catechol oxidation current (CAOC) peak height (A) and mean arterial pressure (MAP) (B) after intrathecal 40-µg strychnine (STR) injection. Each point represents the mean ± SEM, n = 4, *P < 0.05 compared with prestrychnine levels (one-way repeated measures analysis of variance followed by post hoc Newman-Keuls test).

 


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  		Figure 3. The effect of hair deflection (HD) (5 min on/off beginning at time zero) on the catechol oxidation current (CAOC) peak height after intrathecal (IT) administration of strychnine (STR) 40 µg ({blacksquare}, n = 7), strychnine 40 µg + N{omega}-nitro-L-arginine (L-NOARG) 50 nmol ({square}, n = 7), or L-NOARG 50 nmol + saline ({diamond}, n = 4). Each point represents the mean ± SEM, *P < 0.05 compared with prestrychnine levels.

 


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  		Figure 4. The effect of hair deflection (HD) (5 min on/off beginning at time zero) on mean arterial pressure (MAP) after intrathecal (IT) administration of strychnine (STR) 40 µg ({blacksquare}, n = 7), strychnine 40 µg +N{omega}-nitro-L-arginine (L-NOARG) 50 nmol ({square}, n = 7), or L-NOARG 50 nmol + saline ({diamond}, n = 4). Each point represents the mean ± SEM, *P < 0.05 compared with prestrychnine levels.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Spinal cord somatosensory processing in urethane-anesthetized rats is altered during glycinergic inhibition with strychnine so that normally innocuous stimulation evokes nociceptive-like responses (2,3,13–16) including supraspinal activation of the locus coeruleus (4). The locus coeruleus, the major noradrenergic nucleus of the pons, has widespread efferent projections to the cerebral cortex and spinal cord and is activated by various stressors including noxious painful stimuli (17,18). Placing a carbon fiber electrode in this nucleus enables electrochemical catechol detection because catechols are readily oxidized. The current generated by oxidation of DOPAC at the electrode tip, and resultant changes in CAOC are a useful index of func- tional catechol activity with DOPAC formation being directly related to noradrenergic activity in the locus coeruleus (19). In the present study, hair deflection-evoked release of spinal PGE2 was an effect that was accompanied by locus coeruleus activation and increased MAP. Moreover, pretreatment with intrathecal L-NOARG attenuated the strychnine-allodynia, suggesting a mediator role of NO in this abnormal sensory state. These changes were not a secondary response to the increase in blood pressure because there is no consistent relationship between locus coeruleus neuronal firing rate and blood pressure (20). Examination of the data reveals that, after attaining a peak response, both the arterial pressure and CAOC in the locus coeruleus begin their recovery as the effects of strychnine dissipate. The difference in the time course for recovery between these responses is likely attributable to the principles that govern the technique of voltammetry. Voltammetric scans are repeated every three minutes and the appearance of a current is dependent on the central processes of diffusion and neurotransmitter kinetics (21). Therefore, because of the nature of the measuring technique, there is a time lag involving the recovery of locus coeruleus activity when compared with arterial pressure.

Convergent lines of evidence indicate that central PGs facilitate nociceptive (C fiber) spinal cord transmission. Sustained C fiber activity induces a rapid increase in inducible cyclooxygenase and increase in PG synthesis. This effect is mediated by NO and leads to facilitated neurotransmission and hyperalgesia. This process is dependent on N-methyl-D-aspartate-receptor activation and is normally only recruited by nociceptive transmission (22). The ability of PGs to sensitize spinal cord neurons to other forms of input is important, and intrathecal PGE2 and PGF2{alpha} induce behavioral allodynia in conscious rodents (23,24). This allodynia produced by PGE2 is reversed by the glycinoceptor agonist taurine, indicating a close link between PGE2 allodynia and glycine receptor blockade (25). We have previously shown the ability of intrathecal ketorolac and S(+)-ibuprofen, but not R(-)-ibuprofen to suppress the locus coeruleus catechol oxidation and cardiovascular peak responses evoked during strychnine allodynia (8). The present study furthers these findings by showing a marked increase in PGE2 release in this paradigm and a significant attenuation of the biochemical and blood pressure response by L-NOARG, an inhibitor of NOS. This is in keeping with studies showing stimulation of NO release from rat spinal cord by PGE2 (26).

This acute anesthetized reversible model of sensory dysfunction using intrathecal strychnine provides different and complementary information from chronic animal models involving experimental nerve injury. Neural ligation models or partial surgical spinal transection models require a postinjury delay before hyperalgesia or allodynia develop, and the resultant somatosensory dysfunction is the probable outcome of multiple changes in neural plasticity and function. This acute pharmacologic approach involves an individual neurotransmitter (glycine) involved in somatosensory dysfunction of neural injury pain. The intrathecal model allows investigation without injury or exposure of a conscious animal to painful conditions (13).

In summary, hair deflection was shown to evoke a temporal release of spinal PGE2, locus coeruleus activation, and increase in MAP after intrathecal strychnine. Pretreatment with L-NOARG attenuated the locus coeruleus CAOC, a sensitive biochemical index of strychnine allodynia, suggesting a mediator role of NO during this abnormal sensory state.


   Acknowledgments
 
Supported by the Medical Research Council of Canada.


   Footnotes
 
Presented, in part, at the Annual IARS 2000 meeting, Honolulu, Hawaii, March 10–14, 2000.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 11, 2001.




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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 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press