The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs.

It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. Magnesium sulfate and calcium channel blockers were given i.p., 30 min before the administration of butorphanol tartrate and paracetamol. Analgesia was measured using "hot-plate" ( 52.5( composite function)C), "tail-flick" (radiant heat source), "writhing" (acetic acid, 1%, i.p.) and "tail-clip" tests. The pain threshold was evaluated before and after the administration (i.p.) of the different agents. The effect of the combined administration of different agents on behavior, blood pressure and heart rate, was also determined. Nifedipine (5 mg kg(-1), i.p.) and verapamil (10 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol tartrate (0.25-2 mg kg(-1), i.p.) in all tests (synergism) and enhanced analgesic effect of paracetamol (50-125 mg kg(-1), i.p.), only in acetic acid writhing and tail-clip tests. Magensium sulfate (2.5 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol, but not that of paracetamol. Co-administration of nifedipine and verapamil with either of butorphanol (0.25-2 mg kg(-1)) or paracetamol (50-125 mg kg(-1), i.p.) produced no significant effects on motor coordination, motor performance, locomotor activity, long-term memory or on the blood pressure and heart rate of experimental animals. Co-administration of magnesium sulfate, however, significantly induced sedation, inhibition of locomotor activity, motor performance and coordination, as well as impairing of long-term memory, as compared with butorphanol and paracetamol, administered alone. We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of butorphanol against thermal, mechanical and chemical pain but enhanced that of paracetamol only against mechanical and chemical pain. Magensium sulfate enhanced the analgesic effect of butorphanol, but not that of paracetamol. These findings, merit further studies in animals and humans to evaluate the potential therapeutic benefits of such interactions.

N6-cyclohexyladenosine and 3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid enhance the effect of antiepileptic drugs against induced seizures in mice.

PURPOSE: The influence of N(6)-Cyclohexyladenosine (CHA), an adenosine A(1) agonist and 3-(2-Carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (CPPene), a selective N-methyl-D-aspartate (NMDA) antagonist upon the anticonvulsant activity of diazepam (DA), sodium valproate (VP), diphenylhydantoin (DPH), phenobarbital (PB) and carbamazepine (CAZ) was investigated in mice. All agents were administered intraperitoneally. METHODS: Convulsive seizures were induced by the use of electro shocks and pentylenetetrazole (PTZ). RESULTS: CHA (2 mg/kg, i.p.) and CPPene (2.5 mg/kg, i.p.) were found to enhance the anticonvulsant activity of the tested antiepileptic drugs against both electro convulsions and PTZ-induced convulsions. Both CHA and CPPene significantly decreased the ED50 values of these drugs against both electro convulsions and PTZ-induced convulsions, and increased the convulsive threshold. CHA (2 mg/kg, i.p.) and CPPene (2.5 mg/kg, i.p.) did not affect the plasma level of any of the tested antiepileptic drugs, indicating no pharmacokinetic interactions at the systemic administration. CHA (2 mg/kg, i.p.) or CPPene (2.5 mg/kg, i.p.), alone or in combination with the tested antiepileptic drugs produced no significant changes in their effects on the heart rate, blood pressure, body temperature, gross behavior or on the locomotor activity of experimental animals. Combinations of the antiepileptic drugs with CHA (2 mg/kg, i.p.) or CPPene (2.5 mg/kg, i.p.) were also devoid of significant effects on the motor performance and long-term memory in mice demonstrated by the Chimney test and passive avoidance task. CHA (5 mg/kg, i.p.) alone or in combination with the tested antiepileptic drugs produced inhibition of locomotor activity and motor coordination, sedation and hypothermia as well as impairing of long-term memory. CONCLUSION: Adenosine A1 agonists and NMDA antagonists enhance the efficacy of common antiepileptic drugs, indicating the involvement of adenosine and NMDA receptors in the convulsive pathway. The potential therapeutic benefits of such interactions may be taken into consideration and merit further investigations in animals and humans.

A selective phosphodiesterase IV inhibitor, rolipram blocks both withdrawal behavioral manifestations, and c-Fos protein expression in morphine dependent mice.

We investigated the effect of rolipram, a selective phosphodiesterase IV inhibitor, on morphine dependence in mice. The withdrawal manifestations were significantly reduced in mice that were treated with rolipram in combination with morphine repeatedly, compared to the mice treated with morphine and saline. Immunohistochemical study of c-Fos protein revealed a significant increase in the protein expression, 1 h after naloxone induced withdrawal manifestations. A combination of rolipram and morphine treatment for 5 days prevented the increase of c-Fos protein expression. Acute rolipram treatment prior to the naloxone challenge had no effect. Repeated treatment with rolipram itself had no effect either on behavior, or on c-Fos protein expression. These results suggest that chronic rolipram treatment in combination with morphine in mice will abolish the development of morphine dependence and the expression of c-Fos protein induced by naloxone challenge.

An in vitro and in vivo study of some biological and biochemical effects of Sistrurus Malarius Barbouri venom.

Some possible biological and biochemical effects of Sistrurus Malarius Barbouri (SMB) crude venom were investigated. The acute median lethal doses of the venom under investigation were found to be 14.4 and 9.72 microg/g body weight (b.w.), respectively, in rats on i.p. administration. The possible neurotoxicity of acute, subchronic and chronic doses was investigated in-vivo and in-vitro. The venom at a dose level of 2 microg/g b.w. significantly impaired motor coordination, learning and retention, spontaneous activity and produced behavioural changes, muscle weakness and loss of righting reflex in mice. The same dose also produced a significant decrease in body temperature and inhibited acetylcholine-induced contraction of the isolated smooth (rabbit intestine) and skeletal (frog rectus abdominis) muscles and impaired transmission at the nerve muscle synapse of the rat phrenic nerve diaphragm preparation. The effects of the acute sublethal and chronic doses on carbohydrate metabolism revealed a hyperglycemic effect associated with a diminution of liver and muscle glycogen, while its effects on blood electrolytes (sodium and potassium) showed a significant elevation in the blood sodium level and a significant reduction in that of potassium. Serum enzymes were also affected. Levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were moderately increased. The crude venom had an aggregatory effect on platelets and had also a phospholipase A2 activity while, on the other hand, it showed no L-amino acid oxidase activity. Testing of the effect of the venom on the plasma recalcification time showed that the venom had an anticoagulant effect in case of high dose (200 microg), while a coagulant effect was produced at a low dose of the venom (2.5 microg). SMB venom at a dose level of 1.94 microg/g b.w. (LD10) was found to exhibit no significant inhibitory effect on tumor growth when injected into mice.