This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Koppert, W. Articles by Sittl, R. Search for Related Content PubMed PubMed Citation Articles by Koppert, W. Articles by Sittl, R.

---

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The Effects of Intradermal Fentanyl and Ketamine on Capsaicin-Induced Secondary Hyperalgesia and Flare Reaction

Wolfgang Koppert, MD^*, Susanne Zeck, MD^*, James A. Blunk, MD^*, Martin Schmelz, MD, Rudolf Likar, MD, and Reinhard Sittl, MD^*

Departments of *Anesthesiology and Physiology I, University of Erlangen-Nuremberg, Erlangen, Germany; and Department of Anesthesiology, LKH Klagenfurt, Austria

Address correspondence and reprint requests to Dr. W. Koppert, Department of Anesthesiology, University of Erlangen-Nuremberg, Germany, Krankenhausstr. 12, D-91054 Erlangen, Germany. Address e-mail to koppert{at}physiologie1.uni-erlangen.de

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
In this study, we evaluated the effects of intradermal fentanyl and ketamine on capsaicin-induced hyperalgesia and axon-reflex flare. In addition, we obtained dose-response curves for possible local anesthetic effects. Saline (200 µL) and either fentanyl (1 µg or 10 µg in 200 µL) or ketamine (100 µg or 1000 µg in 200 µL) were injected simultaneously into the central volar forearm of 12 healthy volunteers. Nine minutes later, capsaicin (10 µg in 20 µL) was injected intracutaneously exactly between the two injection sites. Areas of touch-evoked allodynia and pinprick hyperalgesia, as well as intensity of pinprick hyperalgesia at the injection sites and axon-reflex flare, were evaluated. Fentanyl did not affect the area or intensity of secondary hyperalgesia. Only the larger concentration of fentanyl locally diminished axon-reflex flare without affecting mechanical detection thresholds. Inhibitory effects of ketamine on intensity of secondary hyperalgesia and axon reflex flare were observed only in the larger concentration. However, this concentration also clearly elevated mechanical detection thresholds. No inhibitory effects of ketamine in the smaller concentrations were observed. We conclude that fentanyl inhibits neuropeptide release on peripheral application without modulating secondary hyperalgesia. Ketamine failed to inhibit both secondary hyperalgesia and axon reflex flare as long as nonlocal anesthetic concentrations were applied.

Implications: We investigated the peripheral effects of fentanyl and ketamine on capsaicin-induced hyperalgesia and axon-reflex flare. In large concentrations, the opioid diminished axon-reflex flare without effects on secondary hyperalgesia. We found no evidence for the involvement of endogenous glutamate in secondary hyperalgesia or axon reflex flare.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Our knowledge of the antinociceptive effects of analgesics has significantly progressed in recent years, mainly because of a better understanding of plasticity in peripheral nociception and spinal processing. Nociceptive nerve endings clearly can be sensitized after tissue injury by physical changes around the damaged tissues (edema, low pH, etc.) and by inflammatory mediators like bradykinin, serotonin, and prostaglandins (1). Under these conditions, nociceptors show enhanced responses to noxious stimuli applied to the injury site (primary hyperalgesia). Additionally, recruitment of previously "silent" nociceptors that become active after tissue damage can add a component of spatial summation of nociceptive input to spinal processing (2). Both mechanisms, temporal and spatial summation of input from afferent nociceptive nerves, cause spinal cord neurons to alter their responsiveness. This has been demonstrated most conclusively in wide dynamic range neurons, in which sustained nociceptive input causes a decrease of mechanical thresholds for activation of these neurons as well as enlarged peripheral receptive areas (3). These changes are signs of central sensitization and are the mechanisms thought to underlie the phenomenon of secondary hyperalgesia. Interactions of glutamate with the -amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid- and the N-methyl-D-aspartate- (NMDA) receptors play an important role in developing central sensitization. Upon spinal and systemic administration of opioids, NMDA-receptor antagonists can prevent central sensitization (4–6). However, some experimental research suggests that these types of drugs can have direct antinociceptive effects on peripheral nerve endings and may play an important role in the modulation of both primary and secondary hyperalgesia (7,8). We evaluated the peripheral effects of the opioid fentanyl and of the NMDA-receptor antagonist ketamine on capsaicin-induced hyperalgesia. An intradermal injection of a small dose of capsaicin represents a commonly used experimental human pain model, which reliably produces dermal neurogenic inflammation with intense burning pain, secondary brush-evoked allodynia, and secondary hyperalgesia to punctate stimuli (9,10). Besides determination of sensory capacities, the activation of C nociceptors was evaluated. For this purpose, the axon-reflex flare was examined by measuring the superficial blood flow around the injection sites with laser-Doppler imaging. Short accounts of the present work have been published in abstract form.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Twelve healthy subjects (3 women and 9 men; mean age, 30.8 yr; range, 23–49 yr) participated in this randomized, double-blinded study. Each subject gave written, informed consent to take part in the study; the experimental protocol was approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Nuremberg.

In two series of experiments, either 200 µL saline 0.9% and 200 µL fentanyl solution (1 µg or 10 µg, respectively) or 200 µL saline 0.9% and 200 µL ketamine solution (100 µg or 1000 µg, respectively) were simultaneously injected intradermally into the central volar forearm 4 cm apart (Fig. 1). Nine minutes later, 20 µL of a capsaicin solution (10 µg in 7% ethanol and H₂O) was injected intradermally exactly between the two previous injection sites by using a 100-µL syringe topped with a sterile filter (Fig. 1B). The volunteers rated the pain magnitude at 15-s intervals for 2 min after capsaicin injection. Pain ratings were given on a horizontal visual analog scale; the end points of the scale were defined as "no pain" (0) and "maximum imaginable pain" (10).

View larger version (52K): [in this window] [in a new window]   Figure 1. A, Schematic illustration of the experimental protocol. After capsaicin injection, areas of hyperalgesia and allodynia were determined along six linear paths to the injection sites. Flare reactions were analyzed by repeated laser-Doppler images of the flare profile (a) and the mean blood flow inside an area of 1 cm2 around the injection sites of saline and either fentanyl or ketamine (b). B, Time course of the experiment including intradermal drug injection, sensory testing (allodynia, pinprick hyperalgesia), and determination of flare reaction (laser-Doppler imager [LDI]).

Superficial blood flow around the injection site was repeatedly assessed using a laser-Doppler imager (Moor Instruments Ltd., Devon, UK). An area of 9 x 4.5 cm around the injection sites was scanned with a resolution of 16380 pixels, from which each pixel represented a separate Doppler-flux measurement. Flare profile and mean flux around the injection sites of the drugs were determined and processed with dedicated software (Fig. 1A). Images were taken twice under control conditions, three times after the injection of the drugs, and four times after capsaicin injection (Fig. 1B).

In another series of experiments, direct analgesic effects of peripheral fentanyl and ketamine were investigated comparing saline 0.9% (negative control) and lidocaine 1% (positive control) with fentanyl (1, 5, and 10 µg) and ketamine (100, 500, and 1000 µg). According to the preceding experiment, 200 µL was injected intradermally in the medial aspect of the central volar forearm of the subjects. Calibrated von Frey filaments were used to determine the detection thresholds. The subjects were instructed to close their eyes and report when they felt a touch sensation. Filaments exerting increasing bending forces were applied five times each for 1 s until the subject had correctly sensed at least 3 of 5 trials.

Student’s t-tests were performed to examine differences between single pain ratings and hyperalgesic as well as allodynic areas after the different treatments. Repetitive pain ratings after capsaicin injection and data obtained from the laser-Doppler imager measurements were statistically evaluated using analysis of variance in a two-way within-subjects (repeated measures) model. Scheffé post hoc tests were performed when suitable. Changes in detection thresholds were evaluated using Wilcoxon’s signed rank test. Significance levels throughout this study were P < 0.05; all data were expressed as mean ± SD, except for figures (mean ± SEM, median ± 25th/75th percentile). The STATISTICA software package (Statsoft, Tulsa, NC) was used for statistical analyses.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Intradermal injection of fentanyl 1 µg, fentanyl 10 µg, and ketamine 100 µg caused similar pain ratings when compared with saline (1.5 ± 1.1 vs 1.0 ± 1.2, 1.7 ± 1.4 vs 1.4 ± 1.9, and 1.1 ± 1.2 vs 0.9 ± 1.2, respectively; differences not significant using Student’s t-tests). However, intradermal injection of ketamine 1000 µg evoked more intense burning pain when compared with saline (3.4 ± 1.9 vs 1.4 ± 1.1; P < 0.05 using Student’s t-tests). The superficial blood flow, determined as mean laser-Doppler flux around the injection sites, was increased after all treatments (Fig. 2). Injections of fentanyl and saline induced similar changes in blood flow (Fig. 3A); ketamine-induced vasodilation was dose-dependently enhanced (Fig. 3B).

View larger version (42K): [in this window] [in a new window]   Figure 2. Flare profiles determined with the laser-Doppler imager under baseline conditions (t = 2 min), after injection of saline (at 2 cm) and either fentanyl (at 6 cm, A) or ketamine (at 6 cm, B) (t = 8 min), and after capsaicin injection (at 4 cm) (t = 31 min). Blood flow was further evaluated inside the areas marked by the gray bars (see Figure 3). Values are mean ± SEM.

View larger version (20K): [in this window] [in a new window]   Figure 3. Normalized mean blood flow during the time of the experiment inside an area of 1 cm2 around the injection sites of either fentanyl (A) or ketamine (B) versus saline. Values are mean ± SEM. *P < 0.05 by analysis of variance and Scheffé post hoc test for comparisons between the groups. #P < 0.05 by Student’s t-tests for intraindividual changes within every group.

After capsaicin injection, pain ratings induced by mechanical stimulation (pinprick hyperalgesia) around the injection sites of fentanyl and ketamine 100 µg did not differ significantly from the ratings of the saline injection site (Table 1). In contrast, pain ratings induced by stimulation around the injection site of ketamine 1000 µg were significantly reduced during the observation period (Table 1). However, no significant differences were found in the size (radius) of the hyperalgesic and allodynic areas between fentanyl and saline or between ketamine and saline (Table 2).

Local anesthetic effects on mechanical stimulation were found after ketamine injection (Fig. 4). Ketamine led to a dose-dependent increase of von Frey detection thresholds, whereas fentanyl, even in the largest concentration, did not cause impairment of touch sensation. After the injection of ketamine (1000 µg), von Frey detection thresholds increased approximately four-fold (3.8, 3.6–8.9; median, 25th–75th percentile) (Fig. 4).

View larger version (34K): [in this window] [in a new window]   Figure 4. Ratio of detection thresholds before and after intradermal injection of saline 0.9% (negative control), lidocaine 1% (positive control), fentanyl (1 µg, 5 µg and 10 µg), and ketamine (100 µg, 500 µg and 1000 µg). Values represent median, 25th and 75th percentiles; * P < 0.05, ** P < 0.01 by Wilcoxon’s signed rank test. v.Frey = von Frey.

	Discussion

Top Abstract Introduction Methods Results Discussion References

In microneurographic experiments in humans, burning pain after capsaicin injection was observed in parallel with continuing discharges in polymodal C fibers (11). Both pain and C fiber discharges disappeared after cooling the skin (11). Therefore, continuous nociceptor discharges near the injection site are most probably the source of burning pain after capsaicin injection. In our study, drugs were injected intradermally 2 cm from the capsaicin injection site and, thus, had no effect on the magnitude or time course of pain.

We observed the well known features of capsaicin-induced secondary hyperalgesia to mechanical stimulation after intradermal injection of capsaicin, including touch-evoked allodynia and pinprick hyperalgesia. There is evidence that allodynia and pinprick hyperalgesia are generated by sensitization of spinal neurons by noxious input of primary nociceptive fibers (12,13). Opioids, as well as NMDA-receptor antagonists, significantly reduced pain and signs of secondary hyperalgesia when administered systemically or spinally, which would also favor a central mechanism (4,5). Fentanyl exerts its effects on spinal cord neurons preferentially via µ-, but also - and -receptors, by blocking voltage-gated calcium channels or by opening potassium channels, resulting in neuronal hyperpolarization. In contrast, ketamine interacts with multiple binding sites, including NMDA and non-NMDA glutamate receptors and cholinergic and opioid receptors, with the latter two having only a minor role in its analgesic effect (14).

However, peripheral mechanisms for the induction of pinprick hyperalgesia have also been postulated. Using infrared thermography, Ochoa et al. (15) found precise matching of punctate mechanical hyperalgesia and heat hyperalgesia with the flare response after intradermal injection of capsaicin. This vascular-sensory matching was described by Lewis (16) and was assumed to be of peripheral origin, because it seems unlikely that central sensitization occurs exactly in those dorsal horn neurons that match a local vascular process in the skin. Polymodal C fibers do not change their properties in the area of secondary hyperalgesia. Thus, Ochoa et al. (15) argued that sensitization of silent C nociceptors in areas of secondary hyperalgesia after capsaicin injection in human skin could be a peripheral mechanism for secondary hyperalgesia. However, this report is in conflict with the unaltered sensitivity of silent nociceptors after capsaicin injection found by an another group (17).

In our study, no effects of peripherally administrated opioids and NMDA-receptor antagonists on the area of secondary hyperalgesia were observed. Opioids produce antinociceptive effects on terminal nerve endings, mainly under inflammatory conditions (18); convincing results were achieved only in reducing primary hyperalgesia to heat and to mechanical stimulation (7,19,20). Kinnman et al. (7) reported that morphine, administered subcutaneously before capsaicin injection, attenuates capsaicin-evoked primary and secondary hyperalgesia to mechanical stimulation. Although no effect on capsaicin-induced continuous pain was observed in their study, the reduction of primary hyperalgesia is most likely mediated by altered responsiveness of polymodal C fibers by morphine. We assumed that the decreased temporal summation of nociceptive input from the primary site contributes to the antihyperalgesic effects of opioids in the secondary zone.

Similar mechanisms were observed for the NMDA-receptor antagonist ketamine. Warncke et al. (8) found local antihyperalgesic effects of ketamine after burn-induced hyperalgesia. Pain thresholds to mechanical and heat stimulation at the site of primary hyperalgesia were elevated and the area of secondary hyperalgesia was diminished after ketamine pretreatment. Again, a combination of antihyperalgesic effects on primary and secondary hyperalgesia was observed.

Thus, the modulation of secondary hyperalgesia by peripherally-applied opioids and NMDA-receptor antagonists seen in previous studies is most likely a spinal effect after a diminished nociceptive input from the area of primary hyperalgesia, because no effect on the area in which secondary hyperalgesia was seen when the primary hyperalgesic zone was unaffected.

The axon-reflex flare (neurogenic flare) mechanism is resolved locally in the skin and spreads through the arborizations of activated polymodal C nociceptor. The activation of terminal nerve endings causes the release of substance P and calcitonin gene-related peptide with subsequent vasodilatation of small arterioles in the receptive fields of activated nociceptors surrounding the injury site. Laser-Doppler imaging provides a rapid, noninvasive, detailed analysis of intensity and spatial pattern of vasodilation in the skin, and in contrast to the analysis of the visible flare, is a more sensitive method for investigating changes of superficial blood flow.

In our study, fentanyl 10 µg and ketamine 1000 µg inhibited the capsaicin-induced axon-reflex flare only around the injection sites. We propose distinct mechanisms for either fentanyl or ketamine based on observations that ketamine 1000 µg did increase mechanical thresholds while fentanyl 10 µg did not.

The inhibition of the axon-reflex flare by fentanyl 10 µg without effecting mechanical thresholds is a result of a peripheral inhibition of neuropeptide release by opioids (21). Polymodal C nociceptors are the most likely the target for the peripheral site of action of opioids (20,22). Some authors have hypothesized that, by preventing neurogenic inflammation, opioids could reduce capsaicin-induced activation of C nociceptors with subsequent central sensitization (7). However, although an inhibition of neuropeptide release by fentanyl was determined in our study, no antihyperalgesic effect was visible. Additionally, our findings do not support the concept of a tight relation between vascular and sensory changes observed after capsaicin injection, which has been discussed as evidence for a peripheral mechanism of secondary mechanical hyperalgesia (15).

In contrast, ketamine in a concentration of 1.8 mM (100 µg in 200 µL) did not significantly reduce capsaicin-induced axon-reflex vasodilation or secondary hyperalgesia. It should be emphasized that the concentration of 1.8 mM is already supramaximal for the blockade of NMDA-receptors by ketamine (half maximal inhibiting concentrations [IC₅₀] in cultured neurons: 1–9 µM) (23,24).

When the ketamine concentration was even increased to 18 mM (1000 µg in 200 µL), a decrease in capsaicin-induced axon-reflex vasodilation and secondary hyperalgesia was observed at the injection site. In parallel, this concentration of ketamine massively increased mechanical detection threshold, indicating a local anesthetic effect. Laboratory investigations have revealed different target sites for ketamine on peripheral nerves. Besides its effect on NMDA- and opioid-receptors, ketamine also shows local anesthetic properties by blocking Na⁺ and K⁺ currents in peripheral nerve preparations (25–27). The concentrations necessary, however, were much larger than those reached during systemic administration and could only be achieved by local application. The IC₅₀ for the peak Na⁺ currents varied from 325 µM to 2 mM, depending on differences in species and experimental conditions (26–28). In contrast, IC₅₀ values for blockade of NMDA-receptors have been reported to be in the range of 1–9 µM for ketamine. The concentrations we used varied from 1.8 to 18 mM. Therefore, we assume that the analgesic effect of peripheral ketamine observed at a concentration of 18 mM is most probably a result of local anesthetic properties rather than blocking NMDA-receptors.

In conclusion, we have demonstrated that peripherally administered fentanyl and ketamine do not affect the area of capsaicin-induced secondary hyperalgesia. In previous studies, antihyperalgesic effects of both drugs in primary and secondary hyperalgesia have been demonstrated when injected into the primary hyperalgesic area. We assume that modulation of secondary hyperalgesia by opioids and NMDA-receptor antagonists seen in these studies is most likely caused by a diminished nociceptive input from the area of primary hyperalgesia, leading to a reduction of spinal secondary hyperalgesia. Our findings do not support a role of opioids or endogenous glutamate in peripheral sensitization of nociceptors in the secondary zone. In contrast, the results are consistent with a spinal origin of secondary hyperalgesia to touch and punctate stimuli.

	Acknowledgments

 
Supported by the Deutsche Forschungsgemeinschaft (SFB 353).

The authors thank Dieter Märkert for his technical assistance.

	Footnotes

 
This work has appeared in abstract form in Anesthesiology 1998:89:A1101.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Reeh PW, Sauer S. Chronic aspects in peripheral nociception. In: Jensen TS, Turner JA, and Wiesenfeld-Hallin, Z, eds. Proceedings of the Eighth World Congress on Pain. Seattle:IASP Press, 1997:115–31.
2. Schmidt R, Schmelz M, Forster C, et al. Novel classes of responsive and unresponsive C nociceptors in human skin. Neurosci 1995;15:333–41.[Abstract]
3. Grubb BD. Peripheral and central mechanisms of pain. Br J Anaesth 1998;81:8–11.[Free Full Text]
4. Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994;78:205–9.[Web of Science][Medline]
5. Park KM, Max MB, Robinovitz E, et al. Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain 1995;63:163–72.[Web of Science][Medline]
6. Warncke T, Stubhaug A, Jørum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997;72:99–106.[Web of Science][Medline]
7. Kinnman E, Nygårds EB, Hansson P. Peripherally administrated morphine attenuates capsaicin-induced mechanical hypersensitivity in humans. Anesth Analg 1997;84:595–9.[Abstract]
8. Warncke T, Jørum E, Stubhaug A. Local treatment with the N-methyl-D-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett 1997;227:1–4.[Web of Science][Medline]
9. Carpenter SE, Lynn B. Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin. Br J Pharmacol 1981;73:755–8.[Web of Science][Medline]
10. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989;38:99–107.[Web of Science][Medline]
11. LaMotte RH, Lundberg LER, Torebjörk HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol (Lond) 1992;448:749–64.[Abstract/Free Full Text]
12. Torebjörk HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol (Lond) 1992;448:765–80.[Abstract/Free Full Text]
13. Koltzenburg M, Torebjörk E, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994;117:579–91.[Abstract/Free Full Text]
14. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg 1998;87:1186–93.[Free Full Text]
15. Ochoa JL, Serra J, Campero M. Pathophysiology of human nociceptor function. In: Belmonte C, Cervero F, eds. Neurobiology of nociceptors. Oxford:Oxford University Press, 1996:489–516.
16. Lewis T. Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves. Clin Sci 1936;2:373–423.
17. Schmelz M, Schmidt R, Bickel A, et al. Differential sensitivity of mechanosensitive and -insensitive C-fibers in human skin to tonic pressure and capsaicin [abstract]. Abstr 1997;23:1004.
18. Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993;76:182–91.[Abstract/Free Full Text]
19. Moiniche S, Dahl JB, Kehlet H. Peripheral antinociceptive effects of morphine after burn injury. Acta Anaestesiol Scand 1993;37:710–2.[Web of Science][Medline]
20. Koppert W, Likar R, Geisslinger G, et al. Peripheral antihyperalgesic effect of morphine to heat, but not to mechanical, stimulation in healthy volunteers after ultraviolet-B irradiation. Anesth Analg 1999;88:117–22.[Abstract/Free Full Text]
21. Lembeck F, Donnerer J. Opioid control of the function of primary afferent substance P fibres. Eur J Pharmacol 1985;114:241–6.[Web of Science][Medline]
22. Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58:793–8.[Web of Science][Medline]
23. MacDonald JF, Miljkovic Z, Pennefather P. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J Neurophysiol 1987;58:251–66.[Abstract/Free Full Text]
24. Zeilhofer HU, Swandulla D, Geisslinger G, Brune K. Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. Eur J Pharmacol 1992;213:155–8.[Web of Science][Medline]
25. Shrivastav BB. Mechanism of ketamine block on nerve conduction. J Pharmacol Exp Ther 1977;201:162–70.[Abstract/Free Full Text]
26. Arhem P, Rydqvist B. The mechanism of action of ketamine on the myelinated nerve membrane. Eur J Pharmacol 1986;126:245–51.[Web of Science][Medline]
27. Benoit E, Carratù MR, Dubois JM, Mitolo-Chieppa D. Mechanism of action of ketamine in the current and voltage clamped myelinated nerve fibre of the frog. Br J Pharmacol 1986;87:291–7.[Web of Science][Medline]
28. Bräu ME, Sander F, Vogel W, Hempelmann G. Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments. Anesthesiology 1997;86:394–404.[Web of Science][Medline]

This article has been cited by other articles:

				B. A. Chizh Low dose ketamine: a therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways J Psychopharmacol, May 1, 2007; 21(3): 259 - 271. [Abstract] [PDF]

				T. Sycha, D. Samal, B. Chizh, S. Lehr, B. Gustorff, P. Schnider, and E. Auff A Lack of Antinociceptive or Antiinflammatory Effect of Botulinum Toxin A in an Inflammatory Human Pain Model Anesth. Analg., February 1, 2006; 102(2): 509 - 516. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Koppert, W. Articles by Sittl, R. Search for Related Content PubMed PubMed Citation Articles by Koppert, W. Articles by Sittl, R.