[ effect of intrathecal administration of cocaine and serotonergic antagonist [cyproheptadine] on nociception in rat]

Cocaine by effect on central nervous system inhibits reuptake of monoamines [serotonin, norepinephrine and dopamine] to presynaptic terminal and increases their concentration. Monoamines such as serotonin cause analgesia at the spinal level. This study investigates the effects of systemic and spinal administration of cocaine on pain sensation and the relation between these effects and serotonin. Male Wistar rats [200-250g] were set in groups: saline [i.p], saline/DMSO [i.p], cocaine 25mg/kg [i.p], saline [i.t], saline/DMSO [i.t], cocaine 100micro g/10 micro l [i.t], cyproheptadine 33 micro g/10 micro l [i.t.] and cyproheptadine 33 micro g/10 micro l/cocaine 100 micro g/10 micro l [i.t]. Tail flick latency was measured before and after administration. Intraplantar formalin was used for induction of chemical pain. The data was analyzed by T-Test and ANOVA. Pain in both phases of formalin test was reduced in both cocaine 25mg/kg [i.p] [P<0.01] and cocaine 100 micro g/10 micro l [i.t.] [P<0.01]. However, in cyproheptadine 33 micro g/10 micro l [i.t], was increased in the first phase [P<0.01]. In cyproheptadine 33 micro g/10 micro l/cocaine 100 micro g/10 micro l [i.t.], the part of pain reduction induced by cocaine was reversed, in both phases [P<0.01]. In tail flick test the results of cyproheptadine 33 micro g/10 micro l [i.t.] showed reduced tail flick latency [P<0.001]. Inhibition of serotonin reuptake at the spinal level plays role in analgesic effects of cocaine probably, because release of serotonin from the spinal serotonergic terminals causes inhibition of pain neurons and reduction of pain. In addition, inhibition of spinal serotonin receptors by cyproheptadine reduced part of analgesic effects of cocaine probably

Germinating seeds of the mung bean, Vigna radiata (Fabaceae), as a model for the preliminary evaluation of cytotoxic effects of drugs

Cytotoxic properties of plant extracts and drugs being developed for cancer treatment are usually evaluated by a variety of in vivo and in vitro tests carried out in animal or plant based models. In the present study we have evaluated the possibility of using the germinating mung beans (Vigna radiata), for rapid and inexpensive screening of drugs exhibiting cytotoxic properties. Mung beans were allowed to germinate either in tap water or in different drug solutions, and parameters like percent germination, increase in radicle length, change in seedling weight and mitotic index of apical root meristems were determined at two time intervals coinciding with the time at which the radicle length in control group was 1.0 to 1.5 cm (time 0, T0) and 48 h later (T48). Methanol extract of Calotropis procera latex as well as drugs like podophyllotoxin, cyclophosphamide, cyproheptadine and aspirin produced a dose-dependent inhibitory effect on seed germination, seed weight gain, radicle growth and mitotic index in the radicle meristems. The inhibitory effect of some of the drugs tested was associated with reduction in water imbibition. Some of the drugs at higher concentrations allowed seed germination to take place but produced radicle decay and seedling weight loss. Our study shows that germinating V radiata beans could be used as a convenient model for the preliminary screening of drugs exhibiting cytotoxic properties.

Isolation of a haemorrhagic protein toxin (SA-HT) from the Indian venomous butterfish (Scatophagus argus, Linn) sting extract.

A haemorrhagic protein toxin (SA-HT) was isolated and purified from the spine extract of the Indian venomous butterfish, S. argus Linn, by two step ion exchange chromatography. The toxin was homogeneous in native and SDS-PAGE gel. SDS-molecular weight of the toxin was found to be 18.1 +/- 0.09 kDa. SA-HT produced severe haemorrhage on stomach wall but devoid of cutaneous haemorrhage. UV, EDTA, trypsin, protease, cyproheptadine, indomethacin, acetylsalicylic acid and BW755C treatment significantly antagonized the haemorrhagic activity of SA-HT. The toxin produced dose and time dependent oedema on mice hind paw, which was significantly encountered by cyproheptadine, indomethacin and BW755C. SA-HT increased capillary permeability on guinea pig dorsal flank. On isolated guineapig ileum, rat fundus and uterus, SA-HT produced slow contraction which was completely antagonised by prostaglandin blocker SC19220. On isolated rat duodenum, SA-HT produced slow relaxation. SA-HT significantly increased plasma plasmin, serum MDA level and decreased serum SOD level indicating the possible involvement of cyclooxygenase and lipooxygenase pathway.

High altitude exposure on body weight in male rats: effect of cyproheptadine

The role of 5-hydroxytryptamine (5-HT) as mediator of body weight changes during high altitude exposure was investigated in male rats using cyproheptadine, a 5-HT antagonist. At sea level male rats dayly injected with either 10mg/kg of cyproheptadine chlorhydrate or saline solution showed no differences in body weight after five days of treatment. Other rats were acutely exposed to an altitude of 4,338 m. and they were daily injected with either cyproheptadine vehicle. Tat weight was recorded daily of exposure, a similar reduction in body weight was observed in both groups. After three days of exposure at high altitude, cyproheptadine-treated group decreases body weight to a lesser extent then the control group. Between the third and fourth days of permanence at high altitude a gain of weight only occurred in the cyproheptanide treated group. Since cyproheptadine and saline treated groups at sea level showed the same pattern of weight curves whereas hypoxic male animals cyproheptadine-treated group had a better weight than those obtained in saline treated group, it is suggested that 5-HT may be mediating body weight reduction during high altitude exposure of male rats

Effect of cyproheptadine on glucose tolerance, serum insulin and structure of pancreatic islets in rats.

The effect of cyproheptadine (CPH) on glucose tolerance, serum immunoreactive insulin (IRI) and structure of pancreatic islets in albino rats has been studied. Hyperglycemia with glucose intolerance was observed after 10 days of administration of CPH (40 mg/kg, ip). There was insignificant change of fasting IRI after the treatment. Histological studies indicated degranulation and vacuolation of beta cells with enlargement of capillaries. Improvement in blood glucose, glucose tolerance and structure of islets with proliferation of small pancreatic ducts and cell cords were observed 10 days after the withdrawal of CPH.

Investigation of influence of diazepam, valproate, cyproheptadine and cortisol on the rewarding ventral tegmental self-stimulation behaviour.

Experiments were carried on in the Wistar rats having self-stimulation (SS) electrodes implanted chronically in substantia nigra-ventral tegmental area (SN-VTA) to examine whether modulations of GABAergic, serotonergic, histaminergic, dopaminergic, and glucocorticoid neuronal receptor functions will affect or not the brain reward system and the SS behaviour. The modulators are the wellknown drugs: diazepam which is a facilitator of some of the GABA receptors, and used clinically for its tranquilizing, anxiolytic, sedative-hypnotic and anti-convulsant properties; sodium valproate which is known to enhance the GABA synapse function, and used clinically for its anti-convulsant property; haloperidol which is a dopaminergic receptor (D2) blocker, and clinically used for its anti-psychotic property; cyproheptadine which is both anti-histaminic and anti-serotonergic (blocks 5-HT2 receptor), used clinically for its antihistaminic and other beneficial properties; and hydrocortisone which is the stress-resisting glucocorticoid having direct effects on both brain and body cells, used clinically for the wide-ranging glucocorticoid therapeutic effects. The results revealed that systemic administration of these drugs, except haloperidol, caused no significant influence on the SS behaviour, thereby indicating that these nondopaminergic drugs have no effect on brain-reward system and also these categories of synaptic actions are not likely to be involved in the primary organization of the mechanisms of the brain-reward system.

Uterine and placental 5-HT profile in different gestational period of albino rats.

Possible role of 5-HT in pregnancy was investigated in albino rats by biological estimation of uterine and placental 5-HT contents in different periods of gestation in normal and drug treated rats. Uterine 5-HT level increased steadily from day-1 of gestation to reach the peak on day-7; thereafter, the level continued to decline throughout the period till day-20 when 5-HT level was lowest. From day-20, a mild secondary rise started and remained persistent even after parturition. The results show that a critical level of 5-HT in early gestational period is necessary for conception. Manipulation of endogenous 5-HT do not influence duration of gestation.

Effect of beta-adrenoceptor antagonists and some related drugs on maximal electroshock seizures in mice.

(+/-) Propranolol (1-50 mg/kg), (+) propranolol (50 mg/kg) and pindolol (10-50 mg/kg) exhibited significant protective effects against MES (maximum electroshock seizures), whereas, timolol (1 mg/kg), the propranolol analog, UM-272 (1 and 10 mg/kg), and the beta-agonist, terbutaline (1 and 10 mg/kg) were ineffective. Cholinergic agents, physostigmine (0.01-1.0 mg/kg), and atropine (1 and 10 mg/kg), the serotonin antagonist, cyproheptadine (0.05 mg/kg), and the prostaglandin synthesis inhibitor, indomethacin (10 mg/kg), were also without effect on the MES extensor phase. Further, pretreatment of mice with terbutaline, atropine, cyproheptadine or indomethacin did not influence the anti-MES effect of propranolol to any significant extent. The results indicate that the observed anticonvulsant effects of beta-adrenoceptor antagonists are unrelated to noradrenergic or other central neurotransmitter systems and that a non-specific mechanism, probably a membrane stabilizing effect is involved.

Role of 5-HT on increased permeability of blood-brain barrier under heat stress.

Exposure of young rats (9-10 wks) to chronic summer heat (36 degrees C) or acute heat (38 degrees C 4hr) increased the BBB permeability to Evans blue albumin complex (MW 68,000) and 131I-sodium (MW 154) in different brain regions which correlated well with the increased level of 5-HT in plasma and brain. This increased permeability of BBB and the increased 5-HT level were prevented by pretreatment with p-CPA, indomethacin and diazepam. Cyproheptadine and vinblastine pretreatment however, prevented only the increased permeability of BBB, the plasma and brain 5-HT level continued to remain high. These results indicate a probable role of 5-HT as one of the factors leading to the increased permeability of BBB in young rats following heat stress.

Anti-spasmogenic effect of cyproheptadine on guinea-pig ileum.

Antagonistic activity of cyproheptadine against common spasmogens, like acetylcholine, histamine, serotonin, bradykinin and angiotensin, was studied on isolated guinea-pig ileum. Cyproheptadine produced a reversible antagonism of non-competitive type and was most effective against serotonin. It was less potent against histamine, bradykinin and angiotensin and least potent against acetylcholine.

Effect of cyproheptadine on bar-pressing for food reward in rats.

Lever pressing rate under a continuous reinforcement schedule for food reward in rats was reduced significantly by cyproheptadine in the dose of 5 and 10 mg/kg body weight. Under fixed ratio schedule of reinforcement, the responding was also suppressed significantly by 5 and 10 mg/kg body weight doses of cyproheptadine. However, high dose (20 mg/kg) of cyproheptadine administered subsequent to the low doses, failed to inhibit the bar pressing rate under either continuous or fixed ratio schedules.

Evidence for histamine and 5-hydroxytryptamine like effects of MK-212 on guinea pig ileum, taenia coli and rat fundus strip.

MK-212 (1 x 10(-7)M -- 1 x 10(-5)M) produced dose-dependent contractions of guinea pig ileum, taenia coil and rat fundus strip. The responses to MK-212 in all three preparations were blocked competitively by cyproheptadine (1 x 10(-8)M) a 5-HT receptor antagonist. Mepyramine (1 x 10(-8)M)-H1 receptor antagonist also inhibited competitively the responses of guinea pig ileum and taenia coli to MK-212. However, it failed to block significantly the responses of rat fundus strip to MK-212. Metiamide (1 x 10(-6)M), propranolol (1 x 10(-6)M) or atropine (1 x 10(-6)M) did not produce any significant effects on MK-212 induced contractile responses of guinea pig ileum, taenia coli and rat fundus strip. Our findings suggest that MK-212 produces both 5-HT as well as histamine like effects on the guinea-pig ileum, taenia coli and rat fundus strip.