Indian J Physiol Pharmacol1996; 40(3): 271-273

SHORT COMMUNICATION

INVOLVEMENT OF DOPAMINERGIC MECHANISMS IN RACEMATEPENTAZOCINE INDUCED STEREOTYPED BEHAVIOUR IN RATS

B. B. BHOSALE, J. J. BALSARA* AND J. H. JADHAV**

Department of Pharmacology,Krishna Institute of Medical Sciences,Karad - 415 110

and 'H'Department ot' Pharmacology,Government Medical College,Mira) - 416 410

(Received on December 7,1994 )

Abstract : Racemate pentazocine was found to induce stereotypedbehaviour (Sm in rats. Pretreatment with haloperidol and alpha­methyl-p-tyrosine significantly antagonised dl-pentazocine inducedSB. This indicates that dl-pentazocine induces SB by releasing dopamine(DA) from the nigrostriatal and meso limbic dopaminergic neuroneswith resultant activation of the post~ynaptic striatal and mesolimbicD2 DA receptors by the released DA. However, pretreatment withnaloxone failed to significantly modify dl-pentazocine induced SBindicating thereby that opioid mechanisms are not involved in the DAreleasing action of dl-pentazocine. Our findings are explained on thebasis of recent reports that the d-isomer of pentazocine releases DA bystimulating sigma receptors located on the nigrostriatal and mesolimbicdopaminergic neurones.

Key words : dl-pentazocine haloperidol rat naloxonealpha-methyl-p-tyrosine stereotyped behaviour

INTRODUCTION

Pentazocine, an opioid analgesic, is a mixedagonist-antagonist having powerful agonisticaction at kappa and a weaker antagonisticaction at mu opioid receptors (1). While studyingthe behavioural effects of racemate pentazocinewe observed that the drug induced stereotypedsniffing, gnawing, biting and licking behaviourin the rat. Such type of stereotyped behaviour(SB) occurs as a result of hyperfunctioning ofthe nigrostriatal and mesolimbic dopaminergicsystems (2). The directly acting dopamine (DA)agonist apomorphine induces SB by directlystimulating the postsynaptic striatal andmesolimbic D2 DA receptors while the indirectlyacting OA agonists, like amphetamines, induceBB by releasing DA with resultant activation ofthe postsynaptic striatal and mesolimbic D2 DA

*Corresponding Author

receptors by the released DA (2). Classicalneuroleptics, ego haloperidol, which blockpostsynaptic striatal and mesolimbic D2 DAreceptors, effectively antagonise bothapomorphine and amphetamine stereotypies,while the catecholamine depletor, alpha-methyl­p-tyrosine, is only effective in antagonisingamphetamine stereotypy (2). In the presentstudy, we have investigated on dl-pentazocine­induced SB in the rat the effect of pretreatmentwith haloperidol, alpha-methyl-p-tyrosine andnaloxone, an opioid receptor antllgonist (1).

METHODS

Male albino rats (120-180 g) with free accessto a standard diet and tap water were used.Each animal was used only once. Allobservations were made between 10 and 16 h

272 Bhosale et al Indian J Physiol Pharmacol 1996; 40(3)

DISCUSSION

*p < 0.001 (Mann-Whitney U test!.Numerals following the drugs mdicat.e theIr doses (mg/kg).

TABLE I: Effect of haloperidol (HAL), alpha-methyl-p­tyrosine (AMT) and naloxone (NAL) pretreatmenton dl-pentazocine (PEN) induced stereotypedbehaviour in rats. (n = 10 in each group)

dependent SB (Table 1). The SB usuallymanifested 10 to 15 min after drugadministration and depending on the dose used,lasted for about 2 h.

Pretreatment with 0.25 mg/kg haloperidolcompletely abolished the SB induced by10 mg/kg dl-pentazocine and significantlyantagonised the SB induced by 20 and40 mg/kg dl-pentazocine (Table n. The SBinduced by 40 mglkg dl-pentazocine wasabolished by pretreatment with a higherdose (0.5 mglkg) of haloperidol (Table I).Pretreatment with 100 mglkg alpha-methyl-p­tyrosine abolished the SB induced by 10 mg/kgdl-pentazocine and significantly antagonised theSB induced by 20 and 40 mg/kg dl-pentazocine(Table n. The SB induced by 40 mg/kg dl­pentazocine was abolished by pretreatment with200 mg/kg alpha-methyl-p-tyrosine (Table 1).

Naloxone 0.25, 2.5, 5 and 10 mg/kg) didnot induce SB in rats. Further, pretreatmentwith naloxone (1.25 to 10 mglkg) did notsignificantly (P > 0.05) influence the SBinduced by 10, 20 and 40 mg/kg dl-pentazocine(Table D.

Intensity scoreMean±SEM

± 0.100.00.01.2 ± 0.13

± 0.160.2 ± 0.13*0.4 ± 0.16*2.4 ± 0.16

3.8 ± 0.131.7 ± 0.15*0.01.9 ± 0.10*0.04.0 ± 0.00

Study Treatment dose mg / kg

PEN 10 1.1HALO.25 + PEN 10AMT 100 + PEN 10NAL 10 + PEN 10

II PEN 20 2.4HALO.25 + PEN 20AMT 100 + PEN 20NAL 10 + PEN 20

III PEN40HALO.25 + PEN 40HAL 0.5 + PEN 40AMT 100 + PEN 40

MT 200 + PEN 40NAL 10 + PEN 40

RESULTS

DL-Pentazocine at 5 mg/kg exhibited anincrease III locomotor activity in rats. At 10, 20and 40 mg/kg dl-pentazocine induced dose-

at 27-30°C in a noiseless, diffusely illuminatedroom. For observation of SB, the rats wereplaced in individual cages made of wire netting,measuring 30 x 20 x 20 em, 30 min before drugtreatment to allow adaptation to the newenvironment. Observations were made blindwith respect to the treatments used. Theintensity of SB was assessed over a 30 sobservation period at 10 min intervalsthroughout its duration, using the scoringsystem of Costall and Naylor (3). Thus, periodicsniffing was given a score of 1, continuoussniffing 2, periodic biting, gnawing or licking 3and continuous biting, gnawing or licking 4.The maximum intensity of SB scored by eachrat in the group was used to compute the meanvalue of the group.

The drugs used were pentazocine lactate(Fortwin injection, Ranbaxy), haloperidol(Serenace injection, Searle), dl-alpha-methyl-p­tyrosine methyl ester hydrochloride (Sigma)and naloxone hydrochloride (Endo). Alpha­methyl-p-tyrosine and naloxone were dissolvedin distilled water while pentazocine andhaloperidol injection solutions were diluted torequired strength with distilled water. All drugsolutions were prepared immediately before useand were injected ip in a volume of 2 ml/kgbody weight except alpha-methyl-p-tyrosinewhich was injected in a volume of 10 ml/kgbody weight. Doses refer to the formsmentioned. For each dose 10 animals wereused. Haloperidol and naloxone were injected30 min before pentazocine while &lpha-methyl­p-tyrosine was injected 4 h prior to' pentazocine.Control groups received requisite volume ofdistiUed water ip before receiving pentazocine.

All tests for statistical significance wereperformed by a two-tailed Mann-Whitney Utest for nonparametric data at a critical Pvalue of .05, using the individual maximumscores.

Indian J Physiol Pharmacol 1996; 40(3)

In the present study pretreatment withhaloperid91 and alpha-methyl-p-tyrosinesignificantly antagonised dl-pentazocine inducedSB. This indicates that dl-pentazocine inducesSB by releasing DA from the nigrostriatal andmesolimbic dopaminergic neurones withresultant activation of the postsynaptic striataland mesolimbic D2 DA receptors by the releasedDA. However, since pretreatment with naloxonefailed to significantly influence dl-pentazocinestereotypy it indicates that the DA releasingaction of dl-pentazocine is not mediated throughinteraction of dl-pentazocine with kappa opioidreceptors located on the nigrostriatal andmesolimbic dopaminergic neurones (4) and thatnon-opioid mechanisms might be involved inthe DA releasing action and induction of SB bydl-pentazocine in rats. Our findings concur withthe observations of Holtzman and Jewett (5)who have reported that naloxone failed to blockthe catecholamine releasing action of pentazocineand the resultant stimulation of locomotoractivity in rats.

DL-Pentazocine is a 50/50 mixture oflevo-and dextra-isomers. The I-isomer ofpentazocine is a specific agonist of kappa opioidreceptor (1) while the diisomer is a specificagonist of the sigma receptor (6). Recently sigma

DL.Pentazocine Induced Stereotypy 273

receptors have been shown to be located on thenigrostriatal and mesolimbic dopaminergicneurones and d-pentazocine has been reportedto release DA from these dopaminergic pathwaysby stimulating the sigma receptors (6).Further, Goldstein et al (7) have reported thatunilateral microinjections of d-pentazocine inthe substantia nigra produced contralateralcircling behaviour in rats. Since this circlingbehaviour did not occur in animals with -6 OHDAlesions of ascending DA tracts Goldstein et al(7) concluded that the circling behaviour wasmediated mainly by d-pentazocine stimulatedrelease of DA by an action at sigma receptors.It is possible that in our study the action ofd-isomer of pentazocine on sigma receptors mighthave predominated causing release of DA fromnigrostriatal and mesolimbic dopaminergicneurones with resultant induction of SB.Further, as naloxone is not an antagonist ofsigma receptor (1, 6) it failed to antagonise theDA releasing action of d-pentazocine and theresultant SB in rats.

ACKNOWLEDGEMENTS

The generous gift of naloxone hydrochloridefrom Endo Laboratories Inc. (USA) is gratefullyacknowledged.

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