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Anesth Analg 2006;102:1775-1780
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000219588.25375.36

PAIN MEDICINE

The Role of the Craniospinal Nerves in Mediating the Antinociceptive Effect of Transcranial Electrostimulation in the Rat

Vladimir Nekhendzy, MD, M. Frances Davies, PhD, Hendrikus J. M. Lemmens, MD, PhD, and Mervyn Maze, MB, ChB, FRCP, FRCA

Department of Anesthesiology, Stanford University School of Medicine, Stanford, California; Department of Anaesthetics and Intensive Care, Imperial College, London and Chelsea and Westminster NHS Hospital Trust, London, UK

Address correspondence and reprint requests to Vladimir Nekhendzy, MD, Clinical Associate Professor of Anesthesia, Stanford University Medical Center, Department of Anesthesia, 300 Pasteur Drive Stanford, CA 94305–5640. Address e-mail to nek{at}stanford.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES antinociceptive effect, suggesting involvement of the sensory nerves of the rat's scalp in mediating that effect. In this study, we have further investigated the role of the craniospinal nerves by attempting to block the TES antinociceptive effect with local anesthetic injected under the TES electrodes. We also applied different transcutaneous electrical nerve stimulation modalities through the TES electrodes and compared the elicited antinociceptive effect to that of TES. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick latency test in awake, unrestrained male rats. Data were analyzed by one-way analysis of variance followed by the Bonferroni t-test. The TES antinociceptive effect was significantly reduced after local anesthetic injection, and administration of 100 Hz transcutaneous electrical nerve stimulation was, over time, capable of eliciting the same degree of antinociceptive effect as TES. We conclude that sensory craniospinal nerves play a critical role in mediating the TES antinociceptive action and offer a hypothesis on the underlying mechanism(s) responsible for this action.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Transcranial electrostimulation (TES), a method of eliciting analgesia by administering electrical currents through the skin of the subject's head, has been reported to produce clinically significant effects (1,2). However, lack of randomized, double-blind, placebo-controlled TES clinical studies (3) and unidentified neurobiological substrate(s) to explain observed analgesia keep mainstream medical opinion skeptical, and TES remains more a curiosity than an established part of anesthetic management outside of certain centers in France and Russia.

Adequate validation of TES is also hampered by inconclusive animal data regarding the actual presence and degree of the TES antinociceptive effect (4) and the overall applicability of the animal data to humans because of the different stimulating conditions used; bone-affixed TES electrodes are most commonly used in animal studies in lieu of skin electrodes (4,5). To resolve this controversy, we have recently (6) introduced and validated a novel rat model of cutaneously administered TES, where the positioning of the TES electrodes mimics the stimulating conditions used in clinical practice. Using standard behavioral tests for nociception in rats, we were able, for the first time, to demonstrate that administration of TES with combined direct current (DC) and alternating current (AC) produces significant, sustained, reproducible, and an almost immediate frequency-dependent antinociceptive effect in freely moving rats. Some of the characteristics of the observed effect suggested that stimulation of the sensory nerves of the rat's scalp, by the electrical current, may play a leading role in mediating the TES-induced antinociception.

The importance of these findings is not only in establishing the presence of the TES antinociceptive effect per se but also in highlighting the fact that the use of cutaneous electrodes in an animal model may help duplicate the actual mechanism(s) responsible for the TES antinociceptive action in humans. In this study, we have further explored the role of the sensory craniospinal nerves in initiating the TES antinociceptive action by attempting to block the TES antinociceptive effect with local anesthetic bupivacaine (BP) injected under the electrode sites. The involvement of the cutaneous nerves of the rat's cranium in a TES antinociceptive effect was further investigated by application of different transcutaneous electrical nerve stimulation (TENS) modalities through the TES electrodes and by comparing the elicited antinociceptive effect to that of TES.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The subjects were two groups (BP group, n = 9; TENS group, n = 16) of male Sprague-Dawley rats (Bantin and Kingman, Fremont, CA) weighing 408–557 g (BP group) and 455–637 g (TENS group) at the beginning of the experiments. Rats were housed individually at a constant ambient room temperature and a 12-h light-dark cycle and had unrestricted access to food and water. All experiments were performed during the light part of a day-night cycle. The study was conducted according to the experimental protocol approved by the Palo Alto VA Health Care System Animal Care Committee.

For a detailed description of the TES current characteristics and apparatus, TES electrode placement protocol, TES procedure, and nociceptive testing we refer the reader to our previous publication (6). In brief, with the rats anesthetized, the TES electrodes (In Vivo Metric, Inc., Healdsburg, CA) were affixed, in a reproducible manner, to the skin of the rat's head in the frontal and mastoid areas, mimicking application of the TES electrodes in clinical practice. Once the rats' recovery from anesthesia was documented, electrical stimulation (TES or TENS) was administered through the applied TES electrodes to freely moving rats. The antinociceptive effect of TES or TENS was assessed by measuring nociceptive thresholds in the tail-flick latency (TFL) test (Tail Flick Analgesia Meter; Columbus Instruments, Columbus, OH), which has been shown to correlate well with the analgesic potency of drugs in humans (7). The antinociceptive effect of TES or TENS was calculated similarly, as a percentage of the maximum possible effect (7):



Formula 1

In the BP group the experiments were conducted as follows. Once the antinociceptive effect of 60 Hz TES with combined DC:AC current (TES60Hz) for each rat was established (TES60Hz was identified in our previous study as one of the preferred antinociceptive frequencies) (6), rats were randomized to receive further TES treatments after each of the following 3 test conditions: a) 0.2 mL of 0.125% racemic BP hydrochloride (Abbott Laboratories, North Chicago, IL) injected SC under each of the TES electrodes; b) 0.2 mL of preservative-free normal saline (NS) (Abbott Laboratories) injected SC under each of the TES electrodes; c) 0.2 mL of 0.125% racemic BP injected SC in each of the selected 3 sites on the rat's back. This combination of BP concentration and volume proved to be effective for blunting the TES60Hz antinociceptive effect in pilot experiments, without producing adverse signs of the systemic BP effect as judged by rats' normal, unsedated behavior and uninhibited exploratory activity (8). The person performing injections and electrode placement was blinded as to the randomized test solutions. All injections of BP and NS were done in a reproducible manner immediately before the TES electrode placement. The start time for all TES60Hz treatments was held constant, at 1 h after the TES electrode application was completed, and the intensity of TES current was similar in all experiments. TFL testing was conducted at 15 min of TES stimulation, and the assessor of the antinociceptive response was blinded as to the randomized test solutions.

The experiments in the TENS group were randomized but not blinded: rats received either TES60Hz, or high- and low-frequency TENS treatments (TENS60Hz, TENS100Hz, TENS4Hz), all of which are used in clinical practice (9). Asymmetrical biphasic square wave TENS pulses (GF-3 TENS neurostimulator; Graham-Field, Inc., Hauppauge, NY) were delivered at a continuous mode, with the pulse duration and amplitude held constant. Similar to our previous study (6), a "physiological calibration procedure" described by Woolf et al. (10) was performed for each rat during the TES or TENS treatment to standardize stimulation intensity: current was adjusted to the maximal value that would not elicit aversion responses or escape behavior (e.g., jumping, struggling, vocalizations) and maintained at that level for the full duration of stimulation. Maintaining constant intensity of the behavioral response preserved the optimal current-frequency relationship (11) for all the stimulation modalities tested. TFL testing was conducted at 15 and 45 min of TES or TENS stimulation.

In both groups, each rat was subjected to a TES/TENS procedure only once on each particular day, and at least 2 days were allowed for the rat's recovery before the next treatment. As a control, rats of both BP and TENS groups also randomly received no-current TES, when the TES electrodes were applied in a usual manner, but no TES/TENS was administered during nociceptive testing. Data are presented as mean ± sd. Differences between groups were analyzed by one-way analysis of variance followed by the Bonferroni t-test. A value of P < 0.05 was regarded as statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Figure 1 demonstrates the effect of BP injection compared with different controls. The antinociceptive effect of TES60Hz was significantly reduced by the injection of BP, but not NS, under the electrode sites. This reduction cannot be explained by a systemic antinociceptive effect of injected BP, as the TES60Hz-induced antinociception was not affected by administration of the same dose of BP on the rat's back.


Figure 134
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  		Figure 1. Effect of injection of 0.125% bupivacaine under the electrodes on the antinociceptive effect of the 60 Hz transcranial electrostimulation (TES) in the tail-flick latency (TFL) test. TES60Hz, baseline 60-Hz TES; TESBP, 60-Hz TES administered after injection of bupivacaine under the TES electrodes; TESNS, 60-Hz TES administered after injection of normal saline under the TES electrodes; TESback, 60-Hz TES administered after subcutaneous injection of bupivacaine in the back; NC, no-current TES. Data are presented as mean ± sd of the maximum possible effect (%MPE). *P < 0.05 compared with baseline (control) TES60Hz.

 

A comparison of the antinociceptive effects of TES60Hz and TENS stimulating modalities is presented in Figure 2. The data show that the TES60Hz antinociceptive effect evolved quickly and was sustained throughout the entire duration of stimulation. The antinociceptive response to TENS100Hz reached statistical significance only at 45 min of stimulation. Other TENS frequencies failed to produce any significant degree of antinociception.


Figure 234
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  		Figure 2. Comparison of the antinociceptive effect of the 60 Hz transcranial electrostimulation (TES60Hz) and different transcutaneous electrical nerve stimulation (TENS) modalities in the tail-flick latency (TFL) test. A, 15 min of stimulation; B, 45 min of stimulation. TES60Hz, 60-Hz TES; TENS100Hz, 100-Hz TENS administered through the TES electrodes; TENS4Hz, 4-Hz TENS administered through the TES electrodes; TENS60Hz, 60-Hz TENS administered through the TES electrodes; NC, no-current TES. Data are presented as mean ± sd of the maximum possible effect (%MPE). *P < 0.05 compared with NC (control) TES.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of our study indicate that activation of the sensory nerves of the skull by the electrical current is likely the mechanism primarily responsible for the TES antinociceptive action in the rat. A profound reduction of the antinociceptive response after BP injection (Fig. 1) cannot be explained simply by displacement of the TES electrodes by the injected solution, thus preventing electrical current from targeting certain "critical areas" (12) within the brain, as the same injected volume of NS failed to significantly reduce the magnitude of the antinociceptive response. Moreover, pilot experiments have demonstrated that the absorption rate for both BP and NS, as measured by the diameter of a skin wheal at the electrode sites, was similar over the 3-hour period (data not shown). An observed trend towards reduction of the TES antinociceptive effect in the NS group (albeit not statistically significant) (Fig. 1) can be explained by a decrease in the density of sensory axonal innervation and/or decrease in the dorsal root ganglia neurons' cutaneous receptive fields caused by spread of the injected solution.

The results of our study are in accordance with the earlier reports suggesting a possible critical role of cutaneous craniospinal nerves, especially greater occipital nerves, in mediating the TES antinociceptive effect in primates (12,13). As shown in Figure 3, the TES electrodes in the rat overlie the mastoid areas innervated by the cutaneous branches of the greater occipital nerves, lesser occipital nerves, and greater auricular nerves, and the frontal area of the head innervated by the frontal nerve, a cutaneous branch of the ophthalmic (V1) division of the trigeminal nerve (14,15). The primary afferent fibers of these sensory nerves and their corresponding dorsal root ganglia project directly to the upper cervical spinal cord (15–17), trigeminal subnucleus caudalis (18,19), and nucleus of the tractus solitarius (16,17,19), where they extensively overlap with the location of the wide-dynamic range (WDR) and nociceptive-specific second-order neurons that target a variety of centers intimately involved in processing and modulation of the nociceptive input (20). Based on their cutaneous receptive field properties, the WDR neurons respond proportionally to a variety of innocuous and noxious mechanical, thermal and chemical stimuli, while the nociceptive-specific neurons respond only to noxious stimuli. Although a detailed description of the pathways originating in these neurons is beyond the scope of this discussion, the monosynaptic character of these projecting pathways and generally excitatory nature of the connections between primary sensory afferents and second-order neurons (21) suggest that TES may induce activation of a variety of the supraspinal antinociceptive systems.


Figure 334
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  		Figure 3. Distribution of the cutaneous nerves under the transcranial electrostimulation (TES) electrodes in a rat. The TES electrodes overlie the mastoid areas innervated by the cutaneous branches of the nerves originating in the C2-C4 dorsal root ganglia: greater occipital nerves (GON), lesser occipital nerves (LON), greater auricular nerves (GAN), and the frontal area of the head innervated by the frontal nerve originating in the trigeminal (V) ganglion.

 

In particular, central release of endorphins, serotonin and mononamines observed with different TES techniques (1,2,5,22) points to the likely involvement of the periaqueductal gray—rostral ventromedial medulla—locus coeruleus network in modulating descending inhibition of spinal nociceptive input in response to TES. The results of our study allow us to challenge the traditional opinion (1,4,5,23) implicating a direct action of the current on the brain as a primary mechanism responsible for the TES antinociceptive action, suggesting that the recruitment of the periaqueductal gray, rostral ventromedial medulla, locus coeruleus systems during TES may be mediated largely indirectly, through selective cutaneous craniospinal input. This is further supported by the fact that the recruitment of endogenous supraspinal opioidergic, serotonergic, and monoaminergic antinociceptive pathways is also observed with other cutaneously applied electrical conditioning stimuli, such as TENS (9,10,24,25), various types of peripheral electrical stimulation (26), and electroacupuncture (27,28).

Our experiments have demonstrated that transcranially applied TENS100Hz is capable of producing the same degree of extrasegmental nociceptive inhibition as TES, although the effect does not develop until after 15 minutes of stimulation (Fig. 2). This time course parallels the onset of the segmental antinociceptive effect of TENS100Hz applied over the peripheral nerves in both rats (10) and humans (29), further suggesting involvement of the craniospinal nerves in mediating the antinociceptive effect for both transcranially applied TENS and TES. The primary afferent fibers of these mixed sensory nerves show a predominance of the A{delta}- and C-fibers associated with the thermo- and nociceptive function over the low-threshold mechanoreceptive Aß-fibers (15,30), which may explain the difference in the onset of the antinociceptive effect between the TES and TENS.

We suggest that the early appearance and sustained course of the TES antinociceptive effect (Fig. 2) is likely caused by preferential activation of the high-threshold craniospinal afferents (A{delta}-fibers), encoded by a higher discharge rate and/or increased duration of the spike discharges (31) of the second-order upper cervical spinal cord, trigeminal subnucleus caudalis, and nucleus of the tractus solitarius WDR neurons. In contrast, slower onset of the antinociceptive response to TENS100Hz may reflect predominant activation of the Aß-fibers with resultant recruitment of the centrally projecting second-order low-threshold mechanoreceptive neurons (low-threshold mechanoreceptive neurons respond only to innocuous mechanical stimulation) and/or temporal summation of activation on the projecting WDR neurons in response to repetitive innocuous stimuli (31). The reason why the TENS-induced antinociceptive effect was observed at 100 Hz only is open to further speculation, although the antinociceptive effect of peripherally applied TENS100Hz has been proven superior to other TENS frequencies in a number of animal and human studies (10,29,32).

The suggested critical role of the craniospinal primary afferents in TES's antinociceptive action may help explain the failure of TES to modify the nociceptive threshold in the rat TFL test when the electrodes are positioned on the skull bones (4). Moreover, a minimum of 3 hours is required for this TES stimulation paradigm to obtain maximal enhancement of the morphine-induced antinociception (4) or reduction of the minimum alveolar concentration of halothane in drug-naive rats (5), likely reflecting a relatively minor role which the intracranially traversing electrical current plays in generating the TES antinociceptive action. In contrast, with cutaneous electrode placement, a robust TES-induced antinociceptive response in the TFL test can be demonstrated quickly, within 5 minutes of stimulation (6).

The results of our study provide evidence that activation of selected cutaneous craniospinal sensory nerves by the electrical current likely triggers the TES antinociceptive action in the rat. Although the exact degree of TES analgesic potency in humans remains to be determined, detailed physiological and imaging studies are warranted to further define the role of craniospinal sensory afferents in mediating the TES antinociceptive effect and to clarify the exact neurobiological substrate(s) and mechanism(s) responsible for the TES antinociceptive action.

The authors thank Kristof Kaminski and Laurie Kanevsky for excellent technical assistance, and Dr. Pedro Boscan for his personal communication.


   Footnotes
 
Supported, in part, by grant No. NIGMS 30232 from the National Institutes of Health, Bethesda, Maryland to Dr. Maze and a research grant by the Department of Anesthesia of Stanford University, Stanford, California to Dr. Nekhendzy.

Accepted for publication February 17, 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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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 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press