Ž .Brain Research 797 1998 163–166

Short communication

Anti-hyperalgesic effects of tramadol in the rat

Mauro Bianchi ) , Alberto E. PaneraiDept. Pharmacology, UniÕersity of Milano, Via VanÕitelli, 32, 20129 Milano, Italy

Accepted 7 April 1998

Abstract

A new simple behavioral method was used for the evaluation of the anti-hyperalgesic properties of tramadol in the rat. At the lowestŽ .dose 1.25 mgrkg i.p. , tramadol did not modify thermal nociceptive thresholds, but it was able to prevent and block thermal hindpaw

hyperalgesia induced by the tail injection of formalin. Our results provide evidence that tramadol blocks hyperalgesic behaviors withoutaltering nociception, suggesting that this analgesic drug might represent a valid agent against central sensitization. q 1998 ElsevierScience B.V. All rights reserved.

Keywords: Antinociception; Formalin; Hyperalgesia; Plantar test; Tramadol

Ž . wŽ . xTramadol 1RS, 2 RS -2- dimethylamino -methyl -1-Ž .3-methoxyphenyl -cyclohexanol hydrochloride is a cen-trally acting drug that induces antinociception in animalsw x w x18 and analgesia in humans 13 . The early preclinicalstudies detected an affinity of tramadol for m-opioid recep-tors, albeit with orders of magnitude less than morphine

w xand an order of magnitude less than codeine 12 . How-ever, the binding affinity of tramadol for brain opioidreceptors appears to be too low to account for the antinoci-ceptive efficacy of this drug in animal models or for theanalgesic activity of tramadol in humans. More recently, afurther mode of action of tramadol has been identified, i.e.,

Ž . Ž .the inhibition of norepinephrine NE and serotonin 5-HTw xneuronal reuptake 7–10 . However, the mechanisms in-

volved in the potent analgesic action of tramadol are stillw xnot completely understood 16 .

The experimental models usually used for the study ofanalgesic drugs enable us to simply evaluate their ability toincrease nociceptive thresholds. However, it is well knownthat, in contrast to experimental pain, clinical pain does notrepresent a protective response to noxious stimuli, and it ischaracterised by the appearance of an abnormal hyper-sensitivity, a substantial component of which is generated

w xwithin the spinal cord 19 . Consistently with these obser-vations, hopes have been expressed that drugs will be

w xdeveloped that act specifically on central sensitization 20 .

) Corresponding author. Fax: q 39-2-730470; E-m ail:m.bianchi@airon.it

Therefore, experimental models of centrally-mediated hy-peralgesia might be useful as indicators of the properties ofthe analgesic drugs. We have previously shown that usingthe tail flick test it is possible to demonstrate a centralfacilitation of the responses to a noxious peripheral stimu-

w xlus produced by acute hindpaw inflammation 1,3 . Morerecently, we demonstrated that a noxious stimulus appliedto the tail was able to lower the withdrawal thresholds to

w xthermal noxious stimuli applied to the hindpaw 4 . In thisstudy, we used this latter method in order to investigate theanti-hyperalgesic properties of tramadol. With the aim toevaluate whether the effects of tramadol were preemptiveor fully anti-hyperalgesic, we administered the drug beforeor after the induction of the hyperalgesia.

ŽMale Sprague–Dawley CD rats Charles River, Calco,.Italy , eight in each experimental group, were used. The

animals, 200–250 g body weight, were housed at 228Cwith a 14-h light: 10-h dark cycle, water and food adlibitum.

w xThe method of Hargreaves et al. 11 was used to assessthe hindpaw nociceptive thresholds to thermal stimuli andthe hindpaw hyperalgesia after formalin injection in the

Žtail. We used a Plantar Test apparatus Ugo Basile, Come-.rio, Italy . In brief, the rats were placed in a clear plastic

chamber and left to acclimatise for 5 min before testing.Ž .Light from a 8 V–50 W halogen bulb 64607 OSRAM

was delivered to the plantar surface of the rat’s hindpawthrough the base of the plastic box. The beam was about12 mm in diameter. The time taken for the animal towithdraw its left hindpaw was measured. Treatments wereadministered only to the rats in which basal latency had

0006-8993r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.Ž .PII S0006-8993 98 00388-6

( )M. Bianchi, A.E. PanerairBrain Research 797 1998 163–166164

Fig. 1. Effect of 3 different doses of tramadol on nociceptive thresholds to a thermal stimulus applied on the hindpaw. The evaluation was performed byŽ . Ž . Ž .the Plantar Test PT . Data expressed as mean"S.E.M. of PTL s for the baseline 0 and over time following tramadol administration. ) P-0.05 vs.

saline.

Ž .remained stable "1.5 s for three subsequent measure-ments; the value obtained with the last measurement wasconsidered as the basal latency. Hyperalgesic state was

Žassessed by delta reaction time basal latencyy test la-.tency , positive results thereby indicating hyperalgesia.

Ž .Formalin 10% formaldehyde, 100 ml was injected intra-dermally in the distal part of the tail; 50 ml of this solutionwere injected in the right side of the tail, and 50 ml in the

Žleft side. At the end of the experiments i.e., 120 min after.formalin injection no ulcerations or necrosis of the tail

were present. The rats were anyhow killed immediatelyafter each experimental session. Hindpaw temperature was

Žmeasured with a digital precision thermometer Ellab,.Copenhagen, Denmark at the site where the thermal stim-

ulus was subsequently applied.Ž .Tramadol Contramal, Prodotti Formenti, Italy was

dissolved in 0.9% NaCl and administered i.p. at doses of1.25, 5.0 and 10 mgrkg. In order to fully evaluate theanti-hyperalgesic properties of tramadol, in a group of ratsthe drug was administered 15 min before formalin, and in

Ž .Fig. 2. Effect of tramadol 1.25 mgrkg i.p. on the reduction of hindpaw withdrawal response induced by the injection of formalin in the tail. Tramadolwas administered 15 min before formalin. The evaluation was performed by Plantar Test, 30 min after formalin administration. Data expressed as

Ž .mean"S.E.M. of the algebraic difference between basal and test latencies delta reaction time . ) P-0.05 vs. controls.

( )M. Bianchi, A.E. PanerairBrain Research 797 1998 163–166 165

another group of animals it was injected 30 min afterformalin. The control animals were injected with an equal

Ž .volume of saline 0.9% NaCl .Statistical analysis was performed by analysis of vari-

Ž .ance ANOVA , followed by Tukey’s test for multiplecomparisons. A P value less than 0.05 was assumed asthe significance level. This study adhered to the EthicalGuidelines of the International Association for the study of

w xPain 21 .Fig. 1 shows the effect of tramadol on nociceptive

thresholds to a thermal stimulus applied on the hindpaw. Itis important to note that a dose of 1.25 mgrkg of the drugdid not affect nociceptive thresholds in the Plantar Test,while the administration of the two higher doses of tra-madol induced a significant enhancement of nociceptivethresholds.

In conformity with our previous data, the formalininjection in the tail produced a significant facilitation ofhindpaw withdrawal reflexes that was apparent 20 minfollowing administration and lasted 90 min. In Fig. 2 wehave shown only the results of the observations performed

Ž30 min after formalin administration i.e., 45 min after.tramadol injection , since we have previously observed

that, at this point in time, the hyperalgesic condition wasmore evident. Fig. 2 shows that the central hyperalgesiahad already been completely abolished by pretreatment

Ž .with the lowest dose of tramadol 1.25 mgrkg . Therefore,Žthe effect of the administration of the higher doses 5.0 and

.10 mgrkg on the central hyperalgesia was apparentlyŽidentical to that produced by the lower dose data not

.shown . Moreover, Fig. 3 shows that the administration of

the lower dose of tramadol was also able to block thehyperalgesia when already established.

Neither formalin tail injection nor tramadol administra-Žtion significantly changed hindpaw temperature data not

.shown .We have previously shown that using a classical behav-

ioral test it is possible to demonstrate a central facilitationof the responses to a noxious peripheral stimulus, and that

w xresults in hyperalgesia 4 . In this study, we demonstratethat tramadol is able to prevent and block such a kind ofhyperalgesia. We have previously observed in the sameexperimental conditions that another central analgesic drug

w xsuch as paracetamol 6 was able to prevent, but not blockw xthe hyperalgesia 4 . Therefore, we suggest the opportunity

to discriminate the central analgesic drugs as regards theirability to simply prevent or block hyperalgesia. Moreover,we previously observed that chlomipramine, a drug thatpotentiates both the serotoninergic and noradrenergic tone

w xthrough the blockade of monoamine reuptake 17 , andwhose antinociceptive effect has been demonstrated both

w xin rat and human 2,14 does not exert anti-hyperalgesicw xeffects in the rat 5 . Therefore, we can suggest that the

blockade of monoamine reuptake does not represent theonly mechanism responsible for the anti-hyperalgesic ef-fect of tramadol. Consistently with this hypothesis, it hasbeen suggested that opioid and non-opioid mechanismsinteract in a complementary or synergistic way to produce

w xanalgesia following tramadol administration 15 .In conclusion, we have demonstrated for the first time

that tramadol is able to prevent and reverse hyperalgesicbehavior without altering physiological nociception. In the

Ž .Fig. 3. Effect of tramadol 1.25 mgrkg i.p. on the reduction of hindpaw withdrawal response induced by the injection of formalin in the tail. Tramadolwas administered 30 min after formalin. The evaluation was performed by Plantar Test. Data expressed as mean"S.E.M. of the algebraic difference

Ž . q Ž .between basal and test latencies delta reaction time . ) P-0.05 vs. controls; P-0.01 vs. formalin 10% formaldehyde .

( )M. Bianchi, A.E. PanerairBrain Research 797 1998 163–166166

search for drugs that act specifically on central sensitiza-tion, we think that tramadol deserves attention as ananti-hypersensitivity agent.

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