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The effect of narcotic analgesics on the homovanillic acid content of rat nucleus caudatus
EUROPEAN JOURNAL OF PHARMACOLOGY 22 (1973) 206-208.
NORTH-HOLLAND PUBLISHJNC
PANY
Short communication THE EFFECT OF NARCOTIC ANALGESICS ON THE HOMOVANttLtC ACtD CONTENT OF RAT NUCLEUS CAUDATUS Liisa AHTEE and Ilpo K;6XRI#lNEN Department of JYtarmacdogy, University of He&i&, Siltavuorenpenger 10, SF-001 70 Helsinki I 7, Finbnd
Accepted I3 Fe
Received 26 January 1973
1973
L. AHTEE and I. KXXRIXINEN, 77te effect of nurcotic andgesics oe the homownSUk?odd content of’ candatus, EuropeanJ. Pharmacol. 22 (1973) 206-208.
The cataleptogeniceffects of 10 narcotic analgesicsand related drugs were compared to tholt acid (HVA) in the nucleus caudatus of the tat. CeneralIy the HVA in cataleptogenicproperties of the drugs ran parallel. The results indicate that the structuralrequirumsntsfor the for the cataleptogenicand HVA-increasingpropertiesof the narcoticanalgesicsbear mrnerelationto thw
content of homovanilk
pain-Akving properties of these drugs. Catalepsy
Narcotic analgesics
1. Introduction The narcotic analgesics, morphine and methadone cause cataleptic rigidity and increase the homovanillic acid (HVA) content in the nucleus caudatus of several animal species (Ahtee et al., 1972; Fukui and Takagi, 1972; Kuschinsky and Homykiewicz, 1972; Laverty
and Sharman, 1965; Sasame et al., 1972). Moreover, the analgesic oripavine derivative, M99, also increases the HVA content in the mouse brain (Sharman, 1967). In the present work the effects of several narcotic analgesic and related drugs on the HVA content in the nucleus caudatus of the rats and on the muscum Jar tone and behaviour of the rats have been studied,
2. Materials and methods Male Wistar rats weighing 220-280 g were used. During the experiments the rats were kept in cages housing 2-4 animals each and they were allowed to eat and drink ad libitum. The experiments were car= tied out at a temperature of 23-25’C. Catalepsy w\s measured by placing the front paw of the rat on a
HVA in nucleus caudatus
5 cm high wooden bl in this position were brain was rapidly remo from two brains were The mew sveight of caudata from one brai
most probably due to the dissection t et al., 1972). HVA was estimated by th (1968). Recovery for added HVA (mean f S&M. from 9 estimations). been corrected for losses. The drugs used were (-)=codsine Oy, Helsinki), (+cyclazoclne Inc., New York, N.Y.), dext chloride (Oy Astn Ab, Helsinki), (z+rne drochloride (teiras Oy, Turku), M99 etheno-7(2-hydrox~2=pentyl)-tetrahydrao hydrochloride) (Teckitt Bt Sons Ltd.; kin us by Dr. D.F. Sharman), (-)-morphha ride (Pharmacopoea Nordi chloride (Sterl@Winthrop Inc., New York, N.Y.),
cmHYA Content
L
207
of thebaine and cychmcine, all the drugs studied increased the HVA content in the nucleus caudatus. Both ~rtalcpsy and HVA increase were to some detent ~t~epto~~c drug was M99 folodine, methadone and morphine. The *treated rats were maxhnally cataleptic during hole 754nin observation period after the catahad started at 2 min after the drug administration. Piminodine4nduced catalepsy started with S-10 m&t, was maximal at 30 min, and began to disappear at 75 min when the rats were killed. Met~done-~duced catalepsy started witbin 10-20 min and had not reached its peak at 75 min. Morphine-treated rats were markedly less rigid than the pimidone-, methadone or NH-treated rats. Codeine caused qualitativety similar catalepsy to morphine. Both of these drugs induced catalepsy in about 10 min and the catalepsy lasted over 75 min. The dextropropoxyphene-treated rats were not as rigid as the methadone-treated rats and they were highly excitable. Pentazocine caused catalepsy in very few rats and the pethidine-treated rats were cataleptic for only lo-20 min. Thebaine and cyclazocine did not cause any catalepsy. Table 1 oa the homwanillic acid (WA) content of rat nucleus caudatus and on the mus-
Excited Marked rigidity Cataleptic for only lo-20
min
Markedrigidity Harked rigidity Excited:116died
0.62 f 0.02 _..~
(3)
-_-
Gnawing, piloerection; l/8 died Bizarre behaviour***
p t,p < O.O2;2,p < 0.01. of rats cauteptic; ++, EOburns
t mra~ round to oae directiononly.
of rats cataleptic; +++, 100% cata!eptic.
L. Ahtee, I. KMtZnen, Narcotic analgesicson HVA content
208
4, DMcsrssion Those results show that not only morphine, meth*
done and M99 but also several other narcotic analgesics cause catalepsy and increase the HVA content in the nucleus caudatus of the rats. Generally the c&aleptogenic and HVA increasing properties of the drugs ran parallel. Cyciazocine and thebaine which did not cause catalepsy did not change the HVA content of nucleus caudatus. With the exception of the narcotic agonist-antagonist, cyclazocine, which is about 30 times more potent an analgesic in man than is morphine (Lasagna et al., 1964), the catalepsy and HVA increase caused by the drugs studied was to some degree related to ti7e analgesic potency of these drugs. The most potent cataleptogenic drug in these experiment, M99, is 1280 times more potent an analgesic in mice than is morphine (Cox and Weinstock, 1966). Piminodine and methadone are slightly more potent analgesics in man than morphine (Jaffe, 1970) and they also caused slightly more catalepsy and HVA increase than morphine. Pethidine, codeine and dextropropoxyphene which are less active analgesics than morphine, only caused catalepsy and an increase in HVA in higher doses than morphine. Thebaine which does not cause analgesia was inactive in both respects. The other narcotic agonist-antagonist studied, pentazotine, has more agonistic (morphine-like) properties than cyclazocine and it also produced some catalepsy and HVA increase. The present results as well as the earlier findings that naloxone and nalorphine antagonize the cataleptic effect and HVA increase caused by morphine and methadone (Ahtee et al., 1972; Kuschinsky and Hornykiewicz, 1972) indicate that the structural requirements for the cataleptogenic and HVA increasing properties of narcotic analgesics bear some relation to those required for the pain-relieving properties of these drugs.
Aekmnvledgements We wish to thank Dr. Marthe Vogt, F.R.S. for helpful
suggestions. This researchwas supported in part by grants from the YrjB Jahnsson Foundation and the National Ra search Council for MedicalSciences, Finland.Oy L&as Ab, Turku,kindly providedus the ratsused.
References Ahtee, L., I. KUirBinenand M.K. Paasonen, 1972, Effect of
nalorphine and antiparkinsonhndrugson the methadoneinduced rigidity;relationto the homovanillicacid content of nucleus caudatus, Ann. Med. Exptl. Biol. Fenn. Gn press). Cox, B.M. and M. Weinstock, 1966, The effect of analgesic
drugs on the release of acetylcholine from electrically stimulatedguinea-pigileum, Brit.J. Pharmacol.27,81. Fukui, K. and H. Takagi, 1972, Effect of morphineon the cerebralcontents of metabolites of dopaminein normal and tolerant mice: its possiblerelation to analgesicaction, Brit. J. Pharmacol. 44,45. Jaffe, J.H., Narcotic analgesics, 1970,
in: The Pharmacologi-
cal Basis of Therapeutics,4th edn., eds. L.S. Goodman and A. Gilman (The MacMillanCompany, New York) p. 237. Kuschinsky. K. and 0. Hornykiewicz,1972, Morphinecatalepsy in the rat: relation to striatal dopamine metabolism, European J. Pharmacol. 19,119. Lasagna, L., T.J. De Kornfeld and J.W. Pearson, 1964, The analgesicefficacy and respiratoryeffects in manof a ben-
zomorphan ‘narcotic antagonist’, J. Pharmacol.Expt. Therap. 144, 12. Laverty,R. and D.F. Sharman, 1965, Modification by drugs of the metabolism of 3,4-dihydroxyphenylethylamine, noradrenaline and 5hydroxytryptamine in the brain,Brit. J. Pharmacol.24,759. Portig, P.J., D.F. Sharmanand M. Vogt, 1968, Release by tubocurarineof dopamineand homovanillicacid from the superfused caudate nucleus, J. Physiol. (London) 194, 565. Sasame, H.A., J. PerezCruet, G. Di Chiara, A. Tagliamonte, P. Tagliamonte and F.L. Gessa, 1972. Evidence that methadone blocks dopamine receptors in the brain, J. Neurochem. 19,1953. Sharman,D.F., 1967, A discussion of the modesof action of drugs which increase the concentration of 4hydroxy-3methoxyphenylacetic acid (homovanillicacid) in the striatum of the mouse, Brit. J. Pharmacol. 30,620.
NORTH-HOLLAND PUBLISHJNC
PANY
Short communication THE EFFECT OF NARCOTIC ANALGESICS ON THE HOMOVANttLtC ACtD CONTENT OF RAT NUCLEUS CAUDATUS Liisa AHTEE and Ilpo K;6XRI#lNEN Department of JYtarmacdogy, University of He&i&, Siltavuorenpenger 10, SF-001 70 Helsinki I 7, Finbnd
Accepted I3 Fe
Received 26 January 1973
1973
L. AHTEE and I. KXXRIXINEN, 77te effect of nurcotic andgesics oe the homownSUk?odd content of’ candatus, EuropeanJ. Pharmacol. 22 (1973) 206-208.
The cataleptogeniceffects of 10 narcotic analgesicsand related drugs were compared to tholt acid (HVA) in the nucleus caudatus of the tat. CeneralIy the HVA in cataleptogenicproperties of the drugs ran parallel. The results indicate that the structuralrequirumsntsfor the for the cataleptogenicand HVA-increasingpropertiesof the narcoticanalgesicsbear mrnerelationto thw
content of homovanilk
pain-Akving properties of these drugs. Catalepsy
Narcotic analgesics
1. Introduction The narcotic analgesics, morphine and methadone cause cataleptic rigidity and increase the homovanillic acid (HVA) content in the nucleus caudatus of several animal species (Ahtee et al., 1972; Fukui and Takagi, 1972; Kuschinsky and Homykiewicz, 1972; Laverty
and Sharman, 1965; Sasame et al., 1972). Moreover, the analgesic oripavine derivative, M99, also increases the HVA content in the mouse brain (Sharman, 1967). In the present work the effects of several narcotic analgesic and related drugs on the HVA content in the nucleus caudatus of the rats and on the muscum Jar tone and behaviour of the rats have been studied,
2. Materials and methods Male Wistar rats weighing 220-280 g were used. During the experiments the rats were kept in cages housing 2-4 animals each and they were allowed to eat and drink ad libitum. The experiments were car= tied out at a temperature of 23-25’C. Catalepsy w\s measured by placing the front paw of the rat on a
HVA in nucleus caudatus
5 cm high wooden bl in this position were brain was rapidly remo from two brains were The mew sveight of caudata from one brai
most probably due to the dissection t et al., 1972). HVA was estimated by th (1968). Recovery for added HVA (mean f S&M. from 9 estimations). been corrected for losses. The drugs used were (-)=codsine Oy, Helsinki), (+cyclazoclne Inc., New York, N.Y.), dext chloride (Oy Astn Ab, Helsinki), (z+rne drochloride (teiras Oy, Turku), M99 etheno-7(2-hydrox~2=pentyl)-tetrahydrao hydrochloride) (Teckitt Bt Sons Ltd.; kin us by Dr. D.F. Sharman), (-)-morphha ride (Pharmacopoea Nordi chloride (Sterl@Winthrop Inc., New York, N.Y.),
cmHYA Content
L
207
of thebaine and cychmcine, all the drugs studied increased the HVA content in the nucleus caudatus. Both ~rtalcpsy and HVA increase were to some detent ~t~epto~~c drug was M99 folodine, methadone and morphine. The *treated rats were maxhnally cataleptic during hole 754nin observation period after the catahad started at 2 min after the drug administration. Piminodine4nduced catalepsy started with S-10 m&t, was maximal at 30 min, and began to disappear at 75 min when the rats were killed. Met~done-~duced catalepsy started witbin 10-20 min and had not reached its peak at 75 min. Morphine-treated rats were markedly less rigid than the pimidone-, methadone or NH-treated rats. Codeine caused qualitativety similar catalepsy to morphine. Both of these drugs induced catalepsy in about 10 min and the catalepsy lasted over 75 min. The dextropropoxyphene-treated rats were not as rigid as the methadone-treated rats and they were highly excitable. Pentazocine caused catalepsy in very few rats and the pethidine-treated rats were cataleptic for only lo-20 min. Thebaine and cyclazocine did not cause any catalepsy. Table 1 oa the homwanillic acid (WA) content of rat nucleus caudatus and on the mus-
Excited Marked rigidity Cataleptic for only lo-20
min
Markedrigidity Harked rigidity Excited:116died
0.62 f 0.02 _..~
(3)
-_-
Gnawing, piloerection; l/8 died Bizarre behaviour***
p t,p < O.O2;2,p < 0.01. of rats cauteptic; ++, EOburns
t mra~ round to oae directiononly.
of rats cataleptic; +++, 100% cata!eptic.
L. Ahtee, I. KMtZnen, Narcotic analgesicson HVA content
208
4, DMcsrssion Those results show that not only morphine, meth*
done and M99 but also several other narcotic analgesics cause catalepsy and increase the HVA content in the nucleus caudatus of the rats. Generally the c&aleptogenic and HVA increasing properties of the drugs ran parallel. Cyciazocine and thebaine which did not cause catalepsy did not change the HVA content of nucleus caudatus. With the exception of the narcotic agonist-antagonist, cyclazocine, which is about 30 times more potent an analgesic in man than is morphine (Lasagna et al., 1964), the catalepsy and HVA increase caused by the drugs studied was to some degree related to ti7e analgesic potency of these drugs. The most potent cataleptogenic drug in these experiment, M99, is 1280 times more potent an analgesic in mice than is morphine (Cox and Weinstock, 1966). Piminodine and methadone are slightly more potent analgesics in man than morphine (Jaffe, 1970) and they also caused slightly more catalepsy and HVA increase than morphine. Pethidine, codeine and dextropropoxyphene which are less active analgesics than morphine, only caused catalepsy and an increase in HVA in higher doses than morphine. Thebaine which does not cause analgesia was inactive in both respects. The other narcotic agonist-antagonist studied, pentazotine, has more agonistic (morphine-like) properties than cyclazocine and it also produced some catalepsy and HVA increase. The present results as well as the earlier findings that naloxone and nalorphine antagonize the cataleptic effect and HVA increase caused by morphine and methadone (Ahtee et al., 1972; Kuschinsky and Hornykiewicz, 1972) indicate that the structural requirements for the cataleptogenic and HVA increasing properties of narcotic analgesics bear some relation to those required for the pain-relieving properties of these drugs.
Aekmnvledgements We wish to thank Dr. Marthe Vogt, F.R.S. for helpful
suggestions. This researchwas supported in part by grants from the YrjB Jahnsson Foundation and the National Ra search Council for MedicalSciences, Finland.Oy L&as Ab, Turku,kindly providedus the ratsused.
References Ahtee, L., I. KUirBinenand M.K. Paasonen, 1972, Effect of
nalorphine and antiparkinsonhndrugson the methadoneinduced rigidity;relationto the homovanillicacid content of nucleus caudatus, Ann. Med. Exptl. Biol. Fenn. Gn press). Cox, B.M. and M. Weinstock, 1966, The effect of analgesic
drugs on the release of acetylcholine from electrically stimulatedguinea-pigileum, Brit.J. Pharmacol.27,81. Fukui, K. and H. Takagi, 1972, Effect of morphineon the cerebralcontents of metabolites of dopaminein normal and tolerant mice: its possiblerelation to analgesicaction, Brit. J. Pharmacol. 44,45. Jaffe, J.H., Narcotic analgesics, 1970,
in: The Pharmacologi-
cal Basis of Therapeutics,4th edn., eds. L.S. Goodman and A. Gilman (The MacMillanCompany, New York) p. 237. Kuschinsky. K. and 0. Hornykiewicz,1972, Morphinecatalepsy in the rat: relation to striatal dopamine metabolism, European J. Pharmacol. 19,119. Lasagna, L., T.J. De Kornfeld and J.W. Pearson, 1964, The analgesicefficacy and respiratoryeffects in manof a ben-
zomorphan ‘narcotic antagonist’, J. Pharmacol.Expt. Therap. 144, 12. Laverty,R. and D.F. Sharman, 1965, Modification by drugs of the metabolism of 3,4-dihydroxyphenylethylamine, noradrenaline and 5hydroxytryptamine in the brain,Brit. J. Pharmacol.24,759. Portig, P.J., D.F. Sharmanand M. Vogt, 1968, Release by tubocurarineof dopamineand homovanillicacid from the superfused caudate nucleus, J. Physiol. (London) 194, 565. Sasame, H.A., J. PerezCruet, G. Di Chiara, A. Tagliamonte, P. Tagliamonte and F.L. Gessa, 1972. Evidence that methadone blocks dopamine receptors in the brain, J. Neurochem. 19,1953. Sharman,D.F., 1967, A discussion of the modesof action of drugs which increase the concentration of 4hydroxy-3methoxyphenylacetic acid (homovanillicacid) in the striatum of the mouse, Brit. J. Pharmacol. 30,620.