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* From the Departments of Anesthesiology, The University of Tokyo, Faculty of Medicine, Tokyo; and
the Yamanashi University, Medical School, Yamanashi, Japan.
Address correspondence to: Dr. Tomoki Nishiyama, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama 332-0015, Japan. Phone: 81-3-5800-8668; Fax: 81-3-5800-9655; E-mail: nishit-tky{at}umin.ac.jp
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Abstract |
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-aminobutyric acid receptors, which have some role in pain transmission in the spinal cord. In this study, we examined the effects of intrathecal propofol on acute thermally- or inflammation-induced pain in rats. Methods: Lumbar intrathecal catheters were implanted in Male Sprague-Dawley rats. The tail withdrawal response to thermal stimulation (tail flick test) or paw flinching and shaking response by sc formalin injection into the hind paw (formalin test) were tested. Propofol 1000, 300 or 100 µg or saline (control) was administered as 10 µL intrathecally. Motor disturbance and behavioural side effects were also monitored in the rats during the tail flick test. Eight rats were used for each dose in each test.
Results: No analgesic effects were observed in the tail flick test. In the formalin test, 50% of effective doses were 449 µg (95% confidence interval, 80–3180 µg) in phase 1 and 275 µg (146–519 µg) in phase 2. Motor disturbance was observed in one rat with 100 µg and agitation and allodynia were seen in one rat with 300 µg. However, both were reversible in 120 min.
Conclusions: Intrathecal administration of propofol had analgesic effects on inflammation-induced acute and facilitated pain but not on thermally-induced acute pain. Transient motor and sensory disturbance could not rule out the possibility of neurotoxicity.
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Introduction |
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-aminobutyric acid (GABA)A receptors,1 voltage dependent sodium channels,2 or cannabinoid receptors3 in the central nervous system. Propofol acts as a modulator of both GABAA and glycine receptors.1 These receptors exist also in the spinal cord and they play a crucial role in nociception.4,5 Propofol facilitation of GABAA and glycine receptors at the spinal level might contribute to analgesia.6 Propofol enhances GABAA receptor mediated presynaptic inhibition at primary afferent terminals in the human spinal cord.7 With iv subhypnotic doses (0.25 mg·kg–1), propofol decreased the acute pain evoked by argon laser stimulation in humans.8 In an animal experiment, intraperitoneally administered propofol retarded tail withdrawal latencies and decreased writhing numbers of mice in a dose-dependent manner in dosages of 5 and 10 mg·kg–1.9 These effects may be mediated through an action on the spinal cord. However, there are no studies directly showing spinally mediated analgesic effects of propofol. The purpose of this study was to investigate whether spinally administered propofol has analgesic effects in two different pain models in rats. |
Methods |
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Drug
Propofol (100 mg·mL–1 100% original solution without any vehicle, Astra Zeneca, Cheshire, UK) was dissolved in normal saline to make a solution of 100, 300, or 1000 µg (original) in 10 µL. Normal saline 10 µL was used as a control. After injection of the drug, the catheter was flushed with normal saline 10 µL to clear the dead space of the catheter (8 ± 0.5 µL).
Tail-flick test
The tail-flick test was performed with the tail-flick analgesia meter (MK-330A, Muromachi Kikai Co. Ltd., Tokyo, Japan). Rats were placed in a clear plastic cage with their tails extending through a slot located at the rear of the cage. Thermal stimulation consisted of a beam of high intensity light focused on the tail 2 to 3 cm proximal to the end. The intensity of the beam was adjusted to keep the tail-flick latency of normal rats between three to four seconds. The time between the start of the stimulation and tail withdrawal was measured as the tail-flick latency. The cutoff time in the absence of a response was set to 14 sec to prevent tissue injury. The test was done at five, ten, 15, 30, 60, 90 and 120 min after drug injection. The data are shown as the percent of maximum possible effect (% MPE) as follows, % MPE = (post-drug latency – pre-drug latency) x 100 /(cut-off time – pre-drug latency). The area under the curve (AUC) of % MPE x time (min) was calculated.
Formalin test
The formalin test was performed ten minutes after intrathecal drug injection. Fifty microlitres of 5% formalin were injected subcutaneously into the dorsal surface of the right hind paw with a 30-G needle. Immediately after injection, the rat was placed in an open clear plastic chamber. A flinching or shaking paw response was observed at one and five minutes after formalin injection, and every five minutes thereafter for 60 min. The number of flinches and shaking was counted for each period of one minute. Usually two phases are observed: phase 1, from zero to six minutes after the injection; and phase 2, beginning about ten minutes after the injection with an interval of no flinches or shaking between phases. The AUC (number of flinches and shaking x time) of both phase 1 and 2 were obtained and the 50% effective dose (ED50) was calculated from the AUC by the computer programs devised in the anesthesiology laboratory of the University of California, San Diego (Takano, personal communication).
Behavioural study
Side effects were examined and judged as present or absent in rats for the tail-flick test at five, ten, 15, 30, 60, 90 and 120 min after drug injection. Agitation was judged as a spontaneous irritable movement, vocalization, or both. Allodynia-like behaviour was judged as escape, vocalization, or both induced by lightly stroking the flank of the rat with a small probe. The placing or stepping reflex was evoked by drawing the dorsum of either hind paw across the edge of the table. Normal rats try to put the paw ahead into a position to walk. The righting reflex was assessed by placing the rat horizontally with its back on the table. Normally rats resume an upright position immediately. Flaccidity was judged as muscle weakness by putting the forepaw 3 to 5 cm higher than the hind paw. Normal rats will walk up. Pinna reflex and corneal reflex were examined with a paper string. When a string is entered into the ear canal or lightly touches the cornea, rats normally shake their heads to avoid it.
Statistical analysis
Data are expressed as mean ± standard error or 95% confidence interval (CI). Statistical analysis was performed with the one way factorial analysis of variance followed by the Student-Newman-Keuls method as a post hoc test for the AUCs. A P < 0.05 was considered statistically significant. Post hoc power analysis was performed for the sample size with the G PowerTM V 2.1.2 (Trieter University, Trieter, Germany).
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Results |
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). The AUCs were not statistically different between doses (Table). The ED50 could not be obtained.
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). The AUC decreased in a dose-dependent fashion in both phases (Table
). The ED50 was 449 µg (95% CI, 80–3180 µg) in phase 1 and 275 µg (95% CI, 146–519 µg) in phase 2.
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Discussion |
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In a preliminary study, we studied concentrations of 1, 10, and 100 µg per 10 µL intrathecal propofol. As we could not get significant effects, we increased the dose to 1000 µg (original solution) in the present study.
We chose the tail-flick test as our acute pain model since it has also been used in a previous study of ip propofol in mice.9 The formalin test is a well-established model for assessing inflammation-induced nociceptive processes including acute pain and a facilitated state of pain processing.
Propofol has been shown to enhance GABA mediated synaptic inhibition.1 Propofol acts on GABAA receptors, though on a different recognition site from the barbiturates and the benzodiazepines, but unlike barbiturates, potentiates glycinergic transmission1 and may inhibit excitatory glutamatergic transmission.10 Propofol directly activated the GABAA receptor in a dose-dependent manner, potentiated the GABA-induced current and glycine-induced current at small concentrations which were clinically relevant, and inhibited the GABA induced current and glycine induced current at larger concentrations.6 Recently, Patel et al.3 reported that propofol inhibited the anandamide catabolism and then activated the cannabinoid system, which might contribute to a sedative effect.
The antinociceptive actions of propofol were shown to involve the spinal cord.11 In addition, propofol depressed the ventral root potential when the cord was exposed to substance P, a peptide neuro-transmitter thought to be involved in nociception.12 The mechanism of analgesic effect cannot be determined from our study. However, no sedation was observed with analgesic doses of propofol. Therefore, intrathecally administered propofol might exert its analgesic effects in the spinal cord, not in the brain. The phase 1 formalin pain responses are thought to reflect activity that is prominent in Aß, A
and high threshold C nociceptor afferent fibres. Phase 2 behavioural responses likely reflect activity in mechanically insensitive afferent fibres and activity of Aand C fibres.13 Thermally-induced pain is also mediated by Aand C fibres. Therefore, intrathecally administered propofol in the dose range used in the present study might decrease activity of Aß, Aand C fibres against inflammatory-induced activation but not thermally-induced activation.
In the study by Iwasaki et al.,14 ip administration of propofol 100 mg·kg–1 induced analgesia for visceral pain but not for somatic pain in rats. However, Erenmemisoglu et al.9 showed that subhypnotic and non-sedative doses of propofol in a dose-dependent fashion (5 mg·kg–1 and 10 mg·kg–1) retarded tail withdrawal latencies on the tail-flick test and decreased acetic-acid induced writhing in mice, while they did not mention the route of administration. The results of the tail-flick test in our study using 0.3 to 3 mg·kg–1 intrathecal administration are consistent with the report by Iwasaki et al.14 but not with the one by Erenmemisoglu et al.9 The formalin results in our study are consistent with the acetic-acid experiment by Erenmemisoglu et al.9 All other studies8,9,14 administered propofol systemically, i.e., intraperitoneally or intravenously, while we used the intrathecal route. Further study is necessary to know whether the discrepancies between these studies are due to the difference in animals tested and/or the route and the dose administered.
Clinically, iv propofol at 0.25 mg·kg–1 followed by 25 µg·kg–1·min–1 or more produces a significant reduction in pain intensity.15 Allodynia associated with central, but not neuropathic, pain has been completely controlled by propofol at subhypnotic doses, without major side effects.16 Propofol 0.25 mg·kg–1 and 0.5 mg·kg–1 decreases the amount of pain induced by tibial pressure algesimetry.17 However, in another study,18 propofol 0.5 mg·kg–1 and 83.3 µg·kg–1·min–1 did not alter thermal pain detection thresholds. It has also been reported that propofol, in subhypnotic doses, has no analgesic effect on painful electrical and heat stimulations, but has a hyperalgesic effect on mechanical pressure pain.19 All these clinical studies were performed with the iv administration of propofol, not with the intrathecal route. We did not investigate mechanical pain in our rat experiment, but the absence of thermally-induced pain in these clinical studies are consistent with our results.
One rat receiving intrathecal propofol 300 µg showed agitation and allodynia. This might have resulted from the action of propofol on the brain. Motor disturbance, resulting from the action of propofol on the spinal cord or cannabinoid receptor in the brain,3 was observed in one rat who received 100 µg propofol. We interpreted this as an anesthetic effect, not neurotoxicity, because of its reversibility. Three hundred micrograms is close to and 100 µg is less than the ED50 in the formalin test. Therefore, even though these side effects were observed in only one rat each, were not dose-dependent and reversible, further study is necessary to exclude neurotoxicity before administering propofol intrathecally as an analgesic.
In conclusion, the intrathecal administration of propofol had analgesic effects on inflammation-induced acute and facilitated pain but not on thermally-induced acute pain in rats. Transient motor disturbance, agitation and allodynia were observed with the doses smaller than or close to the ED50 in inflammation-induced pain. Motor disturbance could not rule out neurotoxicity, which should be further investigated.
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Acknowledgments |
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Footnotes |
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2 Ratnakumari L, Hemmings HC Jr. Effects of propofol on sodium channel-dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes. Anesthesiology 1997; 86: 428–39.[Medline]
3 Patel S, Wohlfeil ER, Rademacher DJ, et al. The general anesthetic propofol increases brain N-arachi-donylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase. Br J Pharmacol 2003; 139: 1005–13.[Medline]
4 Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999; 57: 1–164.[Medline]
5 Xu TL. -aminobutyric acid-induced responses in acutely dissociated neurons from the rat sacral dorsal commissural nucleus. J Auton Nerv Syst 1999; 75: 156–63.[Medline]
6 Dong XP, Xu TL. The actions of propofol on -aminobutyric acid-A and glycine receptors in acutely dissociated spinal dorsal horn neurons of the rat. Anesth Analg 2002; 95: 907–14.
7 Shimizu M, Yamakura T, Tobita T, et al. Propofol enhances GABAA receptor-mediated presynaptic inhibition in human spinal cord. Neuroreport 2002; 13: 357–60.[Medline]
8 Anker-Moller E, Spangsberg N, Arendt-Nielsen L, Schultz P, Kristensen MS, Bjerring P. Subhypnotic doses of thiopentone and propofol cause analgesia to experimentally induced acute pain. Br J Anaesth 1991; 66: 185–8.
9 Erenmemisoglu A, Madenoglu H, Tekol Y. Antinociceptive effect of propofol on somatic and visceral pain in subhypnotic doses. Curr Ther Res 1993; 53: 677–81.
10 Concas A, Santoro G, Serra M, Sanna E, Biggio G. Neurochemical action of the general anaesthetic propofol on the chloride ion channel coupled with GABAA receptors. Brain Res 1991; 542: 225–32.[Medline]
11 Nadeson R, Goodchild CS. Antinociceptive properties of propofol: involvement of spinal cord -aminobutyric acidA receptors. J Pharmacol Exp Ther 1997; 283: 1181–6.
12 Jewett BA, Gibbs LM, Tarasiuk A, Kendig JJ. Propofol and barbiturate depression of spinal nociceptive neuro-transmission. Anesthesiology 1992; 77: 1148–54.[Medline]
13 Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 1996; 64: 345–55.[Medline]
14 Iwasaki H, Collins JG, Namiki A, et al. Comparison of the effect of propofol and that of pentobarbital on behavioral responses to somatic and visceral stimuli in rats (Japanese). Masui 1991; 40: 1308–13.[Medline]
15 Zancy JP, Coalson DW, Young CJ, et al. Propofol at conscious sedation doses produces mild analgesia to cold pressor-induced pain in healthy volunteers. J Clin Anesth 1996; 8: 469–74.[Medline]
16 Canavero S, Bonicalzi V, Pagni CA, et al. Propofol analgesia in central pain: preliminary clinical observations. J Neurol 1995; 242: 561–7.[Medline]
17 Briggs LP, Dundee JW, Bahar M, Clarke RS. Comparison of the effect of diisopropyl phenol (ICI 35 868) and thiopentone on response to somatic pain. Br J Anaesth 1982; 54: 307–11.
18 Wilder-Smith OH, Kolletzki M, Wilder-Smith CH. Sedation with intravenous infusions of propofol or thiopentone. Effects on pain perception. Anaesthesia 1995; 50: 218–22.[Medline]
19 Petersen-Felix S, Arendt-Nielsen L, Bak P, Fischer M, Zbinden AM. Psychophysical and electrophysiological responses to experimental pain may be influenced by sedation: comparison of the effects of a hypnotic (propofol) and an analgesic (alfentanil). Br J Anaesth 1996; 77: 165–71.
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