Local effect of tramadol on formalin evoked flinching behavior in rats

Sousa, Angela Maria; Franco, Paula Andrea Baptista; Ashmawi, Hazem Adel; Posso, Irimar de Paula

doi:10.1590/S0034-70942008000400006

Abstracts

BACKGROUND AND OBJECTIVES: Tramadol hydrochloride is known as a centrally acting analgesic drug, used for the treatment of moderate to severe pain. A local analgesic effect has been demonstrated, but its mechanism of action remains unclear. METHODS: In this study, we examined the effect of local, systemic and nerve block tramadol on the nociceptive flinching behavior elicited by injection of 50 µL of 1% formalin into the dorsal region of hind paw of rats. Nociceptive flinching behavior was observed for 60 minutes. RESULTS: Local tramadol in higher concentrations (2.5 and 5mg) almost eliminated flinching behavior during the entire test. Systemic and neural block tramadol did not affect flinching behavior in phase I and partially decreased it in phase II. CONCLUSIONS: Tramadol presented a local analgesic effect in formalin nociceptive flinching behavior that is different from its central analgesic effect. This analgesic effect, in this model, seems not to be linked to a local anesthetic like effect.

ANALGESICS; ANIMALS; PAIN; PAIN; PHARMACOLOGY, Pharmacodynamic

JUSTIFICATIVA E OBJETIVOS: O cloridrato de tramadol é um fármaco analgésico de ação central, utilizado no tratamento de dores moderadas e intensas. Foi demonstrado efeito analgésico local do tramadol, mas seu mecanismo de ação não foi estabelecido. MÉTODO: Estudou-se o efeito da administração local, sistêmica e por bloqueio de nervo periférico do tramadol sobre o comportamento de elevação da pata gerado pela injeção de 50 µL de formalina a 1% na região dorsal da pata de ratos. O número de elevações da pata foi observado pelo período de 60 minutos. RESULTADOS: A administração local de tramadol em concentrações maiores (2,5 e 5 mg) levou ao bloqueio praticamente completo do comportamento de elevação da pata durante todo o teste. A administração sistêmica e por bloqueio de nervo periférico não afetou o comportamento de elevação da pata na fase I e diminuiu parcialmente na fase II. CONCLUSÕES: O tramadol apresentou efeito analgésico local no modelo de comportamento de elevações da pata com formalina, que é diferente de sua ação central. Esse efeito, nesse modelo, não parece ser ligado a efeito anestésico local.

ANALGÉSICOS; ANIMAIS; DOR, Experimental; FARMACOLOGIA, Farmacodinâmica

JUSTIFICATIVA Y OBJETIVOS: El clorhidrato de tramadol es un fármaco analgésico de acción central, utilizado en el tratamiento de dolores moderados e intensos. Quedó demostrado un efecto analgésico local del tramadol, pero su mecanismo de acción no fue establecido. MÉTODO: Se estudió el efecto de la administración local, sistémica y por bloqueo de nervio periférico del tramadol sobre el comportamiento de elevación de la pata generado por la inyección de 50 µL de formalina a 1% en la región dorsal de la pata de los ratones. El número de elevaciones de la pata fue observado durante 60 minutos. RESULTADOS: La administración local de tramadol en concentraciones mayores (2,5 y 5 mg) conllevó al bloqueo prácticamente completo del comportamiento de elevación de la pata durante todo el test. La administración sistémica y por bloqueo de nervio periférico, no afectó el comportamiento de elevación de la pata en la fase I y se redujo parcialmente en la fase II. CONCLUSIONES: El tramadol presentó un efecto analgésico local en el modelo de comportamiento de elevaciones de la pata con formalina, que es diferente de su acción central. Ese efecto, en ese modelo, no parece estar vinculado al efecto anestésico local.

SCIENTIFIC ARTICLE

Local effect of tramadol on formalin evoked flinching behavior in rats^*

Efecto analgésico local del tramadol en modelo de dolor provocado por formalina en ratones

Angela Maria Sousa, TSA^I; Paula Andrea Baptista Franco^II; Hazem Adel Ashmawi, TSA^III; Irimar de Paula Posso, TSA^IV

^IMestre em Farmacologia pela Faculdade de Medicina de Ribeirão Preto da USP; Médica Assistente da Equipe de Controle de Dor da Divisão de Anestesia do Instituto Central do Hospital das Clínicas da FM/USP e do Laboratório de Investigação Médica - LIM 08, FM/USP

^IIAnestesiologista; Médica Assistente do Serviço de Anestesia do Instituto do Coração do Hospital das Clínicas da FM/USP

^IIIDoutor em Medicina; Professor Adjunto do Departamento de Medicina do Centro de Ciências Biológicas e da Saúde da Universidade Federal de São Carlos; Professor Colaborador do Departamento de Cirurgia FM/USP e Laboratório de Investigação Médica - LIM-08 da FM/USP

^IVLivre-Docente pela FM/USP; Professor-Associado do Departamento de Cirurgia da FM/USP; Supervisor da Equipe de Controle de Dor da Divisão de Anestesia do Instituto Central do Hospital das Clínicas da FM/USP

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Tramadol hydrochloride is known as a centrally acting analgesic drug, used for the treatment of moderate to severe pain. A local analgesic effect has been demonstrated, but its mechanism of action remains unclear.

METHODS: In this study, we examined the effect of local, systemic and nerve block tramadol on the nociceptive flinching behavior elicited by injection of 50 mL of 1% formalin into the dorsal region of hind paw of rats. Nociceptive flinching behavior was observed for 60 minutes.

RESULTS: Local tramadol in higher concentrations (2.5 and 5mg) almost eliminated flinching behavior during the entire test. Systemic and neural block tramadol did not affect flinching behavior in phase I and partially decreased it in phase II.

CONCLUSIONS: Tramadol presented a local analgesic effect in formalin nociceptive flinching behavior that is different from its central analgesic effect. This analgesic effect, in this model, seems not to be linked to a local anesthetic like effect.

Key Words: ANALGESICS: tramadol; ANIMALS: rats; PAIN: Experimental: formalin; PHARMACOLOGY, Pharmacodynamic: action mecanisms.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El clorhidrato de tramadol es un fármaco analgésico de acción central, utilizado en el tratamiento de dolores moderados e intensos. Quedó demostrado un efecto analgésico local del tramadol, pero su mecanismo de acción no fue establecido.

MÉTODO: Se estudió el efecto de la administración local, sistémica y por bloqueo de nervio periférico del tramadol sobre el comportamiento de elevación de la pata generado por la inyección de 50 µL de formalina a 1% en la región dorsal de la pata de los ratones. El número de elevaciones de la pata fue observado durante 60 minutos.

RESULTADOS: La administración local de tramadol en concentraciones mayores (2,5 y 5 mg) conllevó al bloqueo prácticamente completo del comportamiento de elevación de la pata durante todo el test. La administración sistémica y por bloqueo de nervio periférico, no afectó el comportamiento de elevación de la pata en la fase I y se redujo parcialmente en la fase II.

CONCLUSIONES: El tramadol presentó un efecto analgésico local en el modelo de comportamiento de elevaciones de la pata con formalina, que es diferente de su acción central. Ese efecto, en ese modelo, no parece estar vinculado al efecto anestésico local.

INTRODUCTION

Tramadol hydrochloride (1RS, 2RS)-2-[(dimethylamino)-methyl]-1(3-methoxyphenyl)-cyclohexanol hydrochloride is a centrally acting analgesic drug used mainly for treatment of moderate to severe, as well as acute and chronic pain ^1,2. A synthetic analog of codeine, tramadol is a 1:1 racemic mixture of two enantiomers [(+)- and (-)-tramadol] with different pharmacological properties, mainly in receptor affinities, which have synergic and complementary actions that result in the analgesic effect of tramadol ^1-4. Two mechanisms of action are known for tramadol. Tramadol and its active metabolite M1 exhibit a low and selective affinity for µ opioid receptors ^1,2,5. Tramadol presents indirect action on monoaminergic receptors through noradrenaline and serotonin reuptake inhibition, blocking nociceptive inputs at the medular level ^1,4,6-10. Pre-treatment with a₂adrenergic receptor antagonists, yohimbine and idazoxan, and µ opioid receptor antagonist, naloxone, reduced analgesic effects of tramadol ^1,11,12. Its direct action on µ opioid receptors and indirect action in inhibition of monoaminergic reuptake are synergic for analgesic effect ⁴.

It has been observed in clinical studies that tramadol has a local analgesic effect when injected intradermally ⁹, reducing propofol pain injection ¹³, prolonging brachial plexus blockade when added to mepivacaine ^11,14 and reducing consumption of lidocaine in intravenous regional anesthesia ¹². Tramadol analgesic effects in experimental pain models were shown in thermal hyperalgesia model ¹⁵, intraplantar carrageenan inflammation ¹⁶, not being related to a direct inhibitory action on prostaglandin endoperoxidase synthases ¹⁷, and in spinal somatosensory evoked potential measurements ¹⁸.

The formalin test is widely used to evaluate analgesic drugs, being considered a reliable model of tonic inflammatory pain ^19-21. Subcutaneous injection of formalin into a rat hind paw evokes an array of stereotyped behaviors. Among these behaviors, flinching (elevating and withdrawing the injected paw) is a reliable parameter of pain behavior ²². Nociceptive response to formalin occurs in a biphasic pattern: there is an initial acute period (phase I, duration of 5 ± 10 min), and then after a short period of remission, phase II begins, consisting of a longer period (20 ± 40 min) of sustained activity ^23-25. The initial response is usually attributed to a direct activation of nociceptors ^26,27, whereas phase II is associated with the release of local endogenous mediators, leading to local inflammation responsible for sensitisation of primary and spinal sensory neurons and subsequent activation of nociceptors ^23,28.

This study aimed to verify whether there is a local analgesic effect for tramadol in a formalin pain model and to investigate a possible mechanism of action.

METHODS

All experiments were performed on Wistar male rats (280 - 360 g), which had free access to food and water and were supplied by own breeding facilities of the University of São Paulo Faculty of Medicine. The experiments were approved by the Bioethics Committee of the Hospital das Clínicas of the University of São Paulo Faculty of Medicine in accordance with the Committee for Research and Ethical Issues of IASP (29). All behavioral experiments were conducted between 9:00 a.m. and 3:00 p.m. and under the same temperature.

Formalin-evoked nociceptive flinching behavior test

Pain was induced with formalin 1% (50 µL) in the dorsal region of a right hind paw. Before receiving the injection, the rats were placed in an open plexiglass observation chamber for 20 minutes to acclimate them to the surroundings, then removed for the drug administration and returned to the observation chamber. A mirror was placed behind the chamber to enable unhindered observation of the formalin-injected paw. The rats were observed for nociceptive behavior immediately after formalin injection, every 5 minutes until 60 minutes after injection. Nociceptive flinching behavior was quantified as the number of flinches of the injected paw during the observation period. Such behavior varied from a simple lifting of the paw (not associated with locomotion) to a vigorous shaking of the limb, or a rippling of the back muscles associated with movement. The flinches were discrete and easily quantifiable ^{23,24,30,31-33}.

In the first part of the study, twenty five animals were used, divided into five groups, containing five animals each: FORM (formalin 1%, 50 µL in hind paw), TRA1.25 (50 µL containing 1.25 mg of tramadol in hind paw and 10 minutes later, 50ìL of 1% formalin solution in hind paw), TRA2.5 (50 µL containing 2.5 mg of tramadol in hind paw and 10 minutes later, 50 µL of 1% formalin solution in hind paw) TRA5 (50 µL containing 5mg of tramadol in hind paw and 10 minutes later, 50 µL of 1% formalin solution in hind paw). A group with tramadol via intraperitoneal route, TRA-IP (100 µL containing 5mg of tramadol intraperitoneally, and 10 minutes later 50 µL of 1% formalin solution in hind paw), was used to show possible systemic analgesic effect. In the second part of the study a group of five animals was used for neural blockade of the dorsal region of hind paw with tramadol, TRA-BLOC (50 µL containing 10mg of tramadol at the anterior region of ankle, to block nervus fibularis profundus and superficialis and 10 minutes later, 50 µL of 1% formalin).

The mean number of flinches was compared by ANOVA. When a significant difference was observed in phase I, Dunnet multiple comparisons procedure was used to identify the noteworthy groups. Tukey multiple comparisons procedure was used in phase II. A value of p < 0.05 was considered as statistically significant.

RESULTS

Effects on nociceptive flinching behavior.

The number of flinches were grouped in two phases, the first 10 minutes (1-10 minutes) and the following 50 minutes (11-60 minutes), recorded in two phases, first (0-10 minutes) and second (11-60 minutes). Nociceptive flinching behavior scores of all groups throughout the test are shown in figure 1. FORM displayed the typical biphasic behavior of formalin. TRA-BLOC and TRA-IP also presented biphasic behavior, not present in TRA1.25, TRA2.5 and TRA5 (Figure 1). In phase I, tramadol, when used locally, blocked almost completely flinching response with the three doses used, significant differences occurred among group means of TRA1.25, TRA2.5 and TRA5 and means of the control group (FORM) and systemic tramadol (TRA-IP), as shown in figure 2. In phase II, the number of flinches in local injected tramadol groups decreased with the increase of amount of drug, with significant difference between TRA1.25 group mean compared to TRA2.5 and TRA5 means. The blockade of flinching response was almost complete in higher doses (Fig. 3). TRA-BLOC in phase I was not different from FORM and TRA-IP, but it presented significant differences when compared to local injected groups (Figure 2). In phase II TRA-BLOC resulted in similar mean to TRA-IP, but different from FORM and local injected groups (Figure 3).

DISCUSSION

In the present investigation, flinches were used to quantify formalin evoked pain behaviors since they correlate well with formalin evoked cardiovascular responses and provide a reliable correlation of pain in the conscious and freely moving rat ²². Among various stereotyped behaviors observed in the formalin test, the frequency of flinches is simple to assess as well as directly proportional to formalin concentration ^23-25,30-32.

A local analgesic effect of tramadol has been shown in this pain model with formalin in rats. Analgesia was found in both phases of the nociceptive flinching behavior test. Some authors have attributed the analgesic effect as part of local anesthetic effect ^18,34, similar to clonidine ¹² or anti-inflammatory effects ¹⁶. In this study the possibility of this analgesic effect being due to a local anesthetic effect was tested. This was done through the use of a neural blockade of the area where the nociceptive stimuli was applied (nervus fibularis profundus and superficialis). A higher dose of tramadol was used in this group to avoid an insufficient block of the nerves. When tramadol was used to block neural transmission, nociceptive flinching behavior did not change in phase I and showed a small decrease in phase II. These results support the possibility that the analgesic action of tramadol observed is not linked to a local anesthetic effect in the flinching behavior elicited by formalin in rats hind paw.

In previous study, TSAI et al (2001) have found that direct application of tramadol in the sciatic nerve of rats led to a dose-dependent reduction in both amplitude and conduction speed of somatosensory evoked potentials when compared to pre-treatment measures. This inhibition was attributed to a local anesthetic effect of tramadol. The doses of tramadol used were the same in our and their study. The discrepancy between the results may be explained by the local anesthetic effect of tramadol (electrophysiological data) observed in their study, being of no clinical relevance as observed in ours. The small decrease observed in phase II seems to be consequence of a systemic effect of tramadol since it did not occur in phase I. The same phenomenon was observed when tramadol was used through the intraperitoneal route. However, systemic tramadol analgesia only occurred in phase II, and was less than that observed in local injected tramadol groups. It is expected that systemic effect occurs after tramadol reaches peak in CNS. These results may represent analgesia provided by tramadol central action through classical mechanisms, a decrease in serotonin and noradrenaline reuptake, similar to the findings observed in the same model using tramadol enantiomers via intraperitoneal route and serotonin and noradrenalin antagonists ³⁵. Tramadol effect on serotonin receptors present on sensory afferent nerve endings is questionable. Serotonin receptors present, like 5-HT_1A, 5-HT₃ and 5-HT₄, have pronociceptive action on sensory afferent nerve endings on formalin pain model while 5-HT_2A seems not to affect pain behavior ^30,32. To explain local tramadol analgesia through action on serotonin receptors, it would be necessary to conceive that tramadol acts in different modes at central level and primary afferent neuron ending, decreasing reuptake of serotonin and noradrenalin in the former and acting as serotonin antagonist in the latter. A possible anti-inflammatory effect for tramadol in the formalin pain model to explain the analgesia observed may be present. Although phase I is believed to be linked to direct stimulation of nociceptors ^26,27, some authors believe that phase I is also a consequence of local inflammation³². Phase II is known to be inflammatory ²⁰ and tramadol presented anti-inflammatory action after yeast injection in paw, reducing paw edema, though this reduction was also small ¹⁶. However, it is not probable that only the anti-inflammatory effect of tramadol may explain local analgesia obtained in evoked flinching behavior, since the analgesia observed was complete, and anti-inflammatory effect seems to be partial.

ACKNOWLEDGEMENTS

Tramadol hydrochloride was kindly provided by Cristália Prod. Quim. Farm., Brazil.

REFERENCES

01. Dayer P, Desmeules J, Collart L - Pharmacologie du tramadol. Drugs, 1997;53 (Suppl 2):18-24.
02. Lewis KS, Han NH - Tramadol: a new centrally acting analgesic. Am J Health Syst Pharm, 1997;54:643-652.
03. Raffa RB, Friderichs E - The basic science aspect of tramadol hydrochloride. Pain Rev, 1996;3:249-271.
04. Scott LJ, Perry CM - Tramadol: a review of its use in perioperative pain. Drugs, 2000;60:139-176.
05. Gillen C, Haurand M, Kobelt DJ et al. - Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedeberg´s Arch Pharmacol, 2000; 362:116-121.
06. Driessen B, Reimann W, Giertz H - Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol, 1993;108:806-811.
07. Lee CR, Mctavish D, Sorkin EM - Tramadol. A preliminary review of its pharmacodynamic and phamacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs, 1993;46:313-340.
08. Lehmann KA - Le tramadol dans les doulers aigues. Drugs, 1997; 53(Suppl 2):25-33.
09. Pang WW, Mok MS, Chang DP et al. - Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med, 1998;23:580-583.
10. Sindrup SH, Andersen G, Madsen C et al. - Tramadol relieves pain and allodynia in polyneuropathy: a radomized, double-blind, controlled trial. Pain, 1999;83:85-90.
11. Kapral S, Gollmann G, Waltl B et al. - Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg, 1999; 88:853-856.
12. Acalovschi I, Cristea T, Margarit S et al. - Tramadol added to lidocaine for intravenous regional anesthesia. Anesth Analg, 2001;92:209-214.
13. Pang WW, Mok MS; Chang DP et al. - The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med, 1999;24:246-249.
14. Buttner J, Ott B, Klose R - Effects of adding clonidine to mevacaine: axillary brachial plexus blockade. Anaesthesist, 1992; 41:548-554.
15. Bianchi M, Panerai AE - Anti-hyperalgesic effects of tramadol in rat. Brain Res, 1998;797:163-166.
16. Bianchi M, Rossoni G, Sacerdote P et al. - Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol, 1999; 13:220-225.
17. Buccellati C, Sala A, Ballerio R et al. - Tramadol anti-inflammatory activity is not related to a direct inhibitory action on prostaglandin endoperoxidases synthases. Eur J Pain, 2000;4:413-415.
18. Tsai YC, Chang PJ, Jou IM - Direct tramadol application on sciatic nerve inhibits spinal somatosensory evoked potentials in rats. Anesth Analg, 2001;92:1547-1551.
19. Dubuisson D, Dennis SG - The formalin test: A quantitative study of analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, 1977;4:161-174.
20. Tjÿlsen A, Berge OG, Hunskaar S et al. - The formalin test: an evaluation of the method. Pain, 1992;51:5-18.
21. Abbott FV, Franklin KBJ, Westbrook RF - The formalin test: scoring properties of first and second phases of pain response in rats. Pain, 1995;60:91-102.
22. Taylor BK, Peterson MA, Basbaum AI - Persistent cardiovascular and behavioural nociceptive responses to subcutaneous formalin require peripheral nerve input. J Neurosci, 1995;15: 7575-7584.
23. Shibata M, Ohkubo T, Takahashi H et al. - Modified formalin test: characteristic bifasic pain response. Pain, 1989;38: 347-352.
24. Wheeler-Aceto H, Cowan A - Standardization of the rat paw formalin test for the evaluation of analgesics. Psychopharmacology (Berl), 1991;104:35-44.
25. Teng CJ, Abbott FV - The formalin test: a dose-response analysis at three developmental stages. Pain, 1998;76:337-347.
26. Hunskaar S, Hole K - The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain, 1987;30: 103-114.
27. Puig S, Sorkin LS - Formalin-evoked activity in identified primary afferent fibers systemic lidocaine suppresses phase-2 activity. Pain, 1996; 64:345-355.
28. Coderre TJ, Vacarino AL, Melzack R - Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res, 1990;535:155-158.
29. Zimmermann M - Ethical guidelines for investigation of experimental pain in conscious animals. Pain, 1983;16:109-110.
30. Doak GJ, Sawynok J - Formalin induced nociceptive behavior and oedema: involvement of multiple peripheral 5-hydroxitryptamine receptor subtypes. Neuroscience, 1997;80:939-949.
31. Granados-Soto V, Rufino MO, Lopes LDG et al. - Evidence for the involvement of the nitric oxide - cGMP pathway in the antinociception of morphine in the formalin test. Eur J Pharmacol, 1997;340:177-180.
32. Parada CA, Tambeli CH, Cunha FQ et al. - The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin induced nociception. Neuroscience, 2001;102:937-944.
33. Ashmawi HA, Chambergo FS, Araujo Palmeira CA et al. - The effects of pyrilamine and cimetidine on mRNA C-fos expression and nociceptive flinching behavior in rats. Anesth Analg, 2003; 97:541-546.
34. Mert P, Gunes Y, Ozcengiz, Gunay I et al. - Comparative effects of lidocaine and tramadol on injured peripheral nerves. Eur J Pharmacol, 2006;543:54-62.
35. Oliva P, Aurilio C, Massimo F et al. - The antinociceptive of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol, 2002;445:179-185.

Endereço para correspondência:

Dr. Hazem Adel Ashmawi

LIM-08, Anestesiologia Experimental

Faculdade de Medicina da Universidade de São Paulo

Av. Dr. Arnaldo, 455, 2º andar

01246-903 São Paulo, SP

E-mail:

hazem@hcnet.usp.br,

hazem@ufscar.br

*

Recebido do Laboratório de Investigação Médica LIM-08 da Faculdade de Medicina da Universidade de São Paulo (FM/USP), São Paulo, SP

Publication Dates

Publication in this collection
14 Oct 2011
Date of issue
Aug 2008

History

Accepted
14 Apr 2008
Received
13 Nov 2007

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

[1] 01. Dayer P, Desmeules J, Collart L - Pharmacologie du tramadol. Drugs, 1997;53 (Suppl 2):18-24.

[2] 02. Lewis KS, Han NH - Tramadol: a new centrally acting analgesic. Am J Health Syst Pharm, 1997;54:643-652.

[3] 03. Raffa RB, Friderichs E - The basic science aspect of tramadol hydrochloride. Pain Rev, 1996;3:249-271.

[4] 04. Scott LJ, Perry CM - Tramadol: a review of its use in perioperative pain. Drugs, 2000;60:139-176.

[5] 05. Gillen C, Haurand M, Kobelt DJ et al. - Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedeberg´s Arch Pharmacol, 2000; 362:116-121.

[6] 06. Driessen B, Reimann W, Giertz H - Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol, 1993;108:806-811.

[7] 07. Lee CR, Mctavish D, Sorkin EM - Tramadol. A preliminary review of its pharmacodynamic and phamacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs, 1993;46:313-340.

[8] 08. Lehmann KA - Le tramadol dans les doulers aigues. Drugs, 1997; 53(Suppl 2):25-33.

[9] 09. Pang WW, Mok MS, Chang DP et al. - Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med, 1998;23:580-583.

[10] 10. Sindrup SH, Andersen G, Madsen C et al. - Tramadol relieves pain and allodynia in polyneuropathy: a radomized, double-blind, controlled trial. Pain, 1999;83:85-90.

[11] 11. Kapral S, Gollmann G, Waltl B et al. - Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg, 1999; 88:853-856.

[12] 12. Acalovschi I, Cristea T, Margarit S et al. - Tramadol added to lidocaine for intravenous regional anesthesia. Anesth Analg, 2001;92:209-214.

[13] 13. Pang WW, Mok MS; Chang DP et al. - The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med, 1999;24:246-249.

[14] 14. Buttner J, Ott B, Klose R - Effects of adding clonidine to mevacaine: axillary brachial plexus blockade. Anaesthesist, 1992; 41:548-554.

[15] 15. Bianchi M, Panerai AE - Anti-hyperalgesic effects of tramadol in rat. Brain Res, 1998;797:163-166.

[16] 16. Bianchi M, Rossoni G, Sacerdote P et al. - Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol, 1999; 13:220-225.

[17] 17. Buccellati C, Sala A, Ballerio R et al. - Tramadol anti-inflammatory activity is not related to a direct inhibitory action on prostaglandin endoperoxidases synthases. Eur J Pain, 2000;4:413-415.

[18] 18. Tsai YC, Chang PJ, Jou IM - Direct tramadol application on sciatic nerve inhibits spinal somatosensory evoked potentials in rats. Anesth Analg, 2001;92:1547-1551.

[19] 19. Dubuisson D, Dennis SG - The formalin test: A quantitative study of analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, 1977;4:161-174.

[20] 20. Tjÿlsen A, Berge OG, Hunskaar S et al. - The formalin test: an evaluation of the method. Pain, 1992;51:5-18.

[21] 21. Abbott FV, Franklin KBJ, Westbrook RF - The formalin test: scoring properties of first and second phases of pain response in rats. Pain, 1995;60:91-102.

[22] 22. Taylor BK, Peterson MA, Basbaum AI - Persistent cardiovascular and behavioural nociceptive responses to subcutaneous formalin require peripheral nerve input. J Neurosci, 1995;15: 7575-7584.

[23] 23. Shibata M, Ohkubo T, Takahashi H et al. - Modified formalin test: characteristic bifasic pain response. Pain, 1989;38: 347-352.

[24] 24. Wheeler-Aceto H, Cowan A - Standardization of the rat paw formalin test for the evaluation of analgesics. Psychopharmacology (Berl), 1991;104:35-44.

[25] 25. Teng CJ, Abbott FV - The formalin test: a dose-response analysis at three developmental stages. Pain, 1998;76:337-347.

[26] 26. Hunskaar S, Hole K - The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain, 1987;30: 103-114.

[27] 27. Puig S, Sorkin LS - Formalin-evoked activity in identified primary afferent fibers systemic lidocaine suppresses phase-2 activity. Pain, 1996; 64:345-355.

[28] 28. Coderre TJ, Vacarino AL, Melzack R - Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res, 1990;535:155-158.

[29] 29. Zimmermann M - Ethical guidelines for investigation of experimental pain in conscious animals. Pain, 1983;16:109-110.

[30] 30. Doak GJ, Sawynok J - Formalin induced nociceptive behavior and oedema: involvement of multiple peripheral 5-hydroxitryptamine receptor subtypes. Neuroscience, 1997;80:939-949.

[31] 31. Granados-Soto V, Rufino MO, Lopes LDG et al. - Evidence for the involvement of the nitric oxide - cGMP pathway in the antinociception of morphine in the formalin test. Eur J Pharmacol, 1997;340:177-180.

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Local effect of tramadol on formalin evoked flinching behavior in rats

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