|
|
ORIGINAL ARTICLE |
|
|
|
| Year : 2003 | Volume
: 57
| Issue : 4 | Page : 164-170 |
| |
Effect of undernutrition on morphine analgesia, haloperidol catalepsy and pentobarbitone sodium hypnosis in developing new born rats.
KP Singh, AK Sanyal
Pharmacology, Clinical Research Unit (H), Centre of Experimental Medicine and Surgery, Banaras Hindu University, Varanasi 221005,
| Date of Acceptance | 04-Jan-2003 |
Correspondence Address:
K P Singh
Pharmacology, Clinical Research Unit (H), Centre of Experimental Medicine and Surgery, Banaras Hindu University, Varanasi 221005
PMID: 14510349
In the present study, half of the pups of a litter were undernourished by 12 h daily maternal deprivation from day 5 to day 18 postnatal and were subsequently nutritionally rehabilitated. Responses of CNS-acting drugs (morphine analgesia, pentobarbitone sodium hypnosis, haloperidol catalepsy) were studied at the age of day 9, 12 and 18 in maternally deprived and of day 25 in nutritionally rehabilitated new born rats as compared to that of their nourished littermates. The results showed that the response of these CNS-acting drugs was maximum at the age of day 9 postnatal and progressively decreased thereafter as the age of the animal advanced. The responses of these drugs in maternally deprived animals varied on different days of undernourishment as compared to that of their nourished littermates. The responses were significantly less in first half and were significantly more in second half period of undernourishment. The changes observed in the responses of these CNS-acting drugs were directly related to the changes observed in brain serotonin level in maternally deprived and nutritionally rehabilitated new born rats. The present findings suggest that the nature and degree of undernutrition imposed in suckling rats might only produce temporary effects on the response of CNS-actin drugs and on brain serotonin levels which is reversible if undernourished new born rats were nutritionally rehabilitated on an appropriate time of brain development.
Keywords: Analgesia, Analgesics, Opioid, pharmacology,Animals, Animals, Newborn, Behavior, Animal, drug effects,Catalepsy, chemically induced,Central Nervous System Agents, pharmacology,Drug Tolerance, Female, Haloperidol, pharmacology,Morphine, pharmacology,Nutrition Disorders, Phenobarbital, pharmacology,Rats, Rats, Inbred F344,
How to cite this article:
Singh K P, Sanyal A K. Effect of undernutrition on morphine analgesia, haloperidol catalepsy and pentobarbitone sodium hypnosis in developing new born rats. Indian J Med Sci 2003;57:164-70 |
How to cite this URL:
Singh K P, Sanyal A K. Effect of undernutrition on morphine analgesia, haloperidol catalepsy and pentobarbitone sodium hypnosis in developing new born rats. Indian J Med Sci [serial online] 2003 [cited 2013 May 25];57:164-70. Available from: http://www.indianjmedsci.org/text.asp?2003/57/4/164/11920 |
Protein deficiency, including starvation, is known to modify the pharmacological and toxicological activities of many drugs. In earlier studies, augmented activity of barbiturates and decreased activity of organophosphorus compounds were being correlated with the decreased microsomal enzymatic activity, in particular mixed function oxidase (MFO) in Liver[1]z and decreased binding capacity of plasma protein to the drugs[3] during undernutrition. Few workers have also reported that morphine analgesia,[4] haloperidol catalepsy[5],[6] and hexobarbitone sodium induced hypnosis[7] are mediated through serotonergic neuronal activity. Earlier, Singh and Sanyal[6] have reported that undernutrition had greatly influenced the serotonergic neuronal activity of developing brain in the new born rats. The present study was, therefore, undertaken to confirm whether the differences observed in the morphine analgesia, haloperiodol catalepsy and pentobarbitone sodium induced hypnosis in undernourished developing new born rats were related to the altered serotonergic activity of brain or some other mechanism(s) also contributed.
| ¤ Materials and methods | |  |
Albino adult female rats (Fisher strain) were bred in the animal house of the department in order to get new born suckling rats of a desired age. All the experiments were conducted at a room temperature of 25±2°C. Undernutrition in developing new born rats was produced according to the method of Mishra and Shankar[9], as described earlier.[10] Undernourished rats were rehabilitated on normal feeding after day 18 postnatal, similar to their nourished littermates.
Morphine analgesia: Morphine analgesia at the age of 9,12],18 days in undernourished and at 25 day in nutritionally rehabilitated developing new born rats was studies as compared to that to their respective nourished littermates by hot plate technique as described earlier[10] with some modifications.
Haloperiodol Catalepsy: The depth of haloperiodol catalepsy (4 mg/kg) expressed in terms of percent immobility was studied in 9, 12, and 18 days old undernourished and in 25 day old nuritionally rehabilitated developing new born rats as compared to that of their respective nourished littermates by the method of Pertwee.[11] The diameter of the upper retrot ring (3.5 cm for 9 and 12 days old rats of both groups and 18 day old rats of undernourished group, and 5 cm for 18 day old nourished group and 25 day old rats of both groups) and the height of the lower retrot ring (3.5 cm) was adjusted according to the size of the test animals.
Pentobarbitone sodium induced hypnosis: Sleeping time calculated in terms of duration of the loss of writing reflex by pentobarbitone sodium (20 mg/ kg, i.p) was determined in 9,12 and 18 days old undernourished and in 25 day old nutritionally rehabilitated developing new born rats as compared to that of their nourished littrmates.
Statistical analysis: The mean value and the standard error of the mean of each group was calculated. The level of the significance of difference in between two groups (viz. undernourished or rehabilitated versus nourished littermates) was analysed by student -'t' test.
| ¤ Results | | |
Morphine analgesia in nourished, undernourished and nutritionally rehabilitated developing new born rats: [Table - 1] shows that the sensitivity of developing new born rats to morphine progressively decreases with increasing age. In the contrary, undernourished developing new born rats behaved differently on the different days of undernourishment as compared to that of their respective nourished littermates. In the early phase of undernutrition i.e. just 3 days of undernutrition, the duration of morphine analgesia was less but it was more in the late phase of undernutrition i.e. after 6 days of undernourishment as compared with that of their respective nourished littermates [Table - 1]. Undernourished rats rehabilitated on normal feeding on day 18 postnatal, showed comparable duration of morphine analgesia with that of their nourished littermates when subjected for test after one week of rehabilitation [Table - 1].
Haloperidol catalepsy in nourished, undernourished and nutritionally rehabilitated developing new born rats: [Table - 1] shows that cataleptic response to haloperiodol decreased progressively up to day 18 postnatal while the response of the drug in 25 days old rats was similar to that of 12 days old developing new born rats. Like morphine analgesia, the cataleptic response to haloperidol (4 mg/kg, i.p.) in undernourished developing new born rats decreased significantly in 9 days old rats but increased thereafter in 12 and 18 days old rats as compared to that of their respective nourished littermates. On the contrary, undernourished rats rehabilitated on normal feeding for one week also showed higher values for cataleptic response to haloperidol than that of their respective nourished littermates [Table - 1].
Pentobarbitone sodium induced hypnosis in nourished, undernourished and nutritionally rehabilitated developing new born rats: Like morphine, the sensitivity of developing new born rats to pentobarbitone sodium decreases progressively with increasing age. Duration of sleep induced by pentobarbitone sodium (20 mg/kg) in 9 day old rat 177.1±6.0 min as compared to that of 58.o±3.3 min in 25 day old developing new born rats [Table - 1]. Likewise undernourished developing new born rats also behaved to pentobarbitone sodium very similar to that of morphine response i.e. the duration of hypnosis induced by pentobarbitone sodium in 9 day rats decreased significantly but increased thereafter in 12 and 18 days old rats as compared to that of their nourished littermates. Undernourished rats rehabilitated on normal feeding for a week showed comparable duration of sleep to that of nourished littermates [Table - 1].
| ¤ Discussion | | |
Earlier reports indicate that the altered response of a drug in undernourished animals was related to the decrease activity of mircrosomal enzymes, particularly the mixed function oxidase (MFO) in liver .[2] As a result, administered drug was not adequately biotransformed peripherally and thus more drug was available to brain for the observed augmented response.[12] It was felt that the above hypothesis could explain fully the reduced toxicity of carbon tetrachloride,[13] heptachlor[14] and octamethylpyrophosphoromnide[15] since they are not biotransformed to their toxic metabolites. This postulate, however, could not fully explain the altered response of a drug whose action is primarily mediated through serotonergic neuronal activity such as morphine analgesia[16],[17] haloperidol catalepsy[5],[6] and hexoobarbitone hypnosis.[7]
There are many reports which revealed that undernutrition also altered the serotonergic neuronal activity of the brain.[8],[18],[19],[20] It has also been reported earlier that liver microsomal enzymatic activity was very low during suckling period and it developed fully by 4-6 week after birth.[21] The present study was therefore undertaken on the premise that altered brain serotonergic neuronal activity in brain but not the liver microsomal enzymatic activity of undernourished suckling rats might be the cause of altered drug response of CNS-acting drugs.
The sensitivity of developing new born rats to CNS acting drugs decreased progressively as the age advanced. The maximum response of these drugs was observed on day 9 after birth (i.e. the day on which the drugs were first administered). On day 18 postnatal, either the response of the drug was reduced (pentobarbitone sodium, haloperidol) or the dose of the drug was increased to produce its desired effect (morphine). The gradual decrease in the sensitivity of developing new born rats to these CNS acting drugs could be related to the corresponding decrease in their respective concentration in developing brain due to simultaneous decrease in permeability of blood brain barrier and the neuronal cells. High permeability of blood brain barrier[22] low levels of plasma proteins and its binding capacity to drug molecules[23] and low levels of drug metabolizing enzymes[21],[24] reported in suckling rats are few reasons responsible for higher levels of free drugs available to neuronal cells which might be the main cause for higher sensitivity of new born developing rats as compared to that of adult rats.
The pattern of morphine analgesia, haloperidol catalepsy and pentobarbitone sodium induced hypnosis in developing new born rats was consonant to the observed change in brain serotonin concentrations in undernourished brain of new born rats i.e. an increase in brain serotonin biosynthesis in undernourished brain was associated with an increase in the response of these CNS acting drugs as compared to that of their respective nourished littermates and vice - versa. Further, the responses of these CNS acting drugs and the brain serotonin level in undernourished rehabilitated rats on day 25 postnatal were 'more or less' comparable with that of their nourished littermates, suggesting that the nature and degree of undernutrition imposed on suckling rats in the present study might only produce temporary effects on serotonergic neuronal activity and on the response of CNS acting drugs which could be reversible by adequate nutritional rehabilitation on an appropriate time of brain development [Table - 1]. Earlier, Chakrabarty et al[25] in our laboratory have shown that pchlorophenylalanine (p-CPA), a blocker of serotonin biosynthesis, significantly reduced pentobarbitone sodium induced hypnosis in both undernourished and nourished groups of 18 days old suckling rats. Thus the present results support the view that the central action of these drugs in undernourished suckling rats is serotonergic neurotransmitter mediated.
| ¤ References | | |
| 1. | Mgbodile MVK, CampbelI TC. Effect of protein deprivation of male wealing rats on the kinetics of hepatic microsomal enzyme activity. J Nutr 1972;102:53-60.  |
| 2. | CampbelI TC, Hayes JR. The effect of quantity and quality of dietary protein on drug metabolism. Feb Proc 1976;35:2470-2424. |
| 3. | Spector AA, Fletcher JE. Nutrition and Drug Interactions In: Hathcock JN, Coon J. eds., Academic Press N. Y 1978;p.477. |
| 4. | Bhattacharya SK, Jaiswal BK, Reddy PKSP, Das PK. Studies on the role of brain monoamines in the antinociceptive action of morphine in albino rats. Indian J Pharmacol 1975;7:58-68. |
| 5. | Carter CJ, Pycock CJ. A study of the sites of interaction between dopamine and 5hydroxytryptamine for the production of fluphenazine induced catalepsy. Naun-Schm Arch Pharmacol 1978;304:135-139. |
| 6. | Balsara JJ, Jadhav JH, Chandorkar AG. Effect of drugs influencing central serotonergic mechanisms on haloperiodol induced catalepsy. Psychopharmacol 1979;62:67-69. |
| 7. | Bhattacharya SK, Debnath PK, Mukhopadhyay SN, Das PK. Role of 5hydroxytryptamine in hexobarbitorn induced hypnosis in albino rats and mice. Indian J Pharmacol 1975;7:35-38. |
| 8. | Singh KP, Sanyal AK. Effect of undernutrition and subsequent rehabilitation on brain 5-HT (serotonin) profile of developing new born rats. Indian J Med Sci 2003 (under consideration) |
| 9. | Mishra OP, Shankar R. Glycine transport in isolated cerebral tissue during malnourished and its response to neurotropic drugs. Indian J Biochem Biophys 1975;12:286-288. |
| 10. | Singh KP, Sanyal AK. Standardisation of evoked response, threshold reaction time and morphine doses for analgesia in new born nourished and undernourished suckling rats to noxious stimulus. Indian J Med Sci 2002;56:481-485. |
| 11. | Pertwee RG. The ring test: a quantitative methods for assessing the cataleptic effect of cannabis in mice. Brit J Pharmacol 1972;46:753-763. |
| 12. | Quinn GP, Axelord J, Brodie BB. Species, Strain and sex differences inmetabolism of hexobarbitonr, amidopyrine, antipyrine and aniline. Biochem Pharmacol 1958;1: 152-159. |
| 13. | Basu TK, Dickerson JWT. Inter-relationship of nutrition and the metabolism of drugs. Chem Biol Interact 1974;8:193-206. |
| 14. | Weatherholtz WW, Campbell TC, Webb RE. Effect of dietary protein levels on the toxicity and metabolism of heptachlor. J Nutr 1969;98:90-94. |
| 15. | Kato R, Oshima T, Tomizawa S. Toxicity and metabolism of drugs in relation to dietary proteins. Jpn J Pharmacol 1968;18:356-366. |
| 16. | Samanin R, Gumulka W, Valzeili L. Reduced effect of morphine inmid brain raphe lesioned rats. Eur J Pharmacol 1970;10:339-343. |
| 17. | Samanin R, Bernasxoni S, Quattrone A. Antinociceptive action of quipazine: Relation to central serotonergic receptor stimulation. Psychopharmaco/ogica (Berl) 1976:46:219-222. |
| 18. | Sereni F, Principi N, Perletti L, Serenl Piceni L. Undernutrition and the developing rat brain. I. Influence on acetylcholinestrase and succinic acid dehydrogenase activities on norepinephrine and 5-hydroxytrypyamine tissue concentrations. Biol Neonat 1966;10:254-265. |
| 19. | Miller M, Leaby JP, Stern WC, Morgane PJ, Resnick 0. Tryptophan availability: relation to elevated brain serotonin in developmentally protein malnourished rats. Exp Neurol 1977;57:142-154. |
| 20. | Ramanamurthy PSV. Maternal and early postnatal malnutrition and transmitter amines in rat brain. J Neurochem 1977;28:253-254. |
| 21. | Dickerson JWT. Nutrition in the Clinical Management of Dibease In: Dickerson JWT, Lee HA. eds., Edward Arnold (Publishers) Ltd., 1978;p.308. |
| 22. | Kupferberg HJ, Way EL. Pharmacologic basis for the increased sensitivity of new born rat to morphine. J. Pharmaocol The rap 1963;141:105-112. |
| 23. | Ehrnebo M, Agurell S, Jailing B, Boreus 10. Age differences in drug binding by plasma proteins; Studies on human foetuses, Neonates and adults. EurJ Clin Pharmaco/ 1971;3:189193. |
| 24. | Fouts JR, Gram JE. Microsomes and Drug Oxidations. In: Gillette JR, Conney AH, Cosmides GJ, Estabrook RW, Fouts JR, Mannering GJ. eds., Academic press, New York, 1969;p.81. |
| 25. | Chakrabarti A, Shankar R, Sanyal AK. Effect of early maternal deprivation on brain 5-HT & pentobarbitone sleeping time in suckling rats. Indian J Med Res 1984;81:286-292. |
Tables
[Table - 1]
| This article has been cited by | | 1 |
Neuropharmacological properties of Launaea resedifolia |
|
| Auzi, A.R.A., Hawisa, N.T., Sherif, F.M., Sarker, S.D. | | Brazilian Journal of Pharmacognsosy. 2007; 17(2): 160-165 | | [Pubmed] | | | 2 |
Endogenous opiates and behavior: 2003 |
|
| Bodnar, R.J., Klein, G.E. | | Peptides. 2004; 25(12): 2205-2256 | | [Pubmed] | |
|
|
|
|
