Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain.

The involvement of adenosinergic pathway in the anti-nociceptive effect of duloxetine, a balanced 5-HT/NE reuptake inhibitor, was evaluated in streptozotocin induced diabetic male albino mice of Laca strain. After four weeks of single injection of streptozotocin (200 mg/kg, ip), mice were tested in the tail immersion and hot-plate assays. Cerebral adenosine levels were measured by high-performance liquid chromatography (HPLC/PDA detector). Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose, decreased body weights and reduced cerebral adenosine levels. Administration of duloxetine (5, 10 and 20 mg/kg, ip) to diabetic mice produced dose-dependent anti-nociceptive effect in both tail-immersion and hot-plate assays. Adenosine levels were also significantly and dose-dependently increased by different doses of duloxetine. The results demonstrated the involvement of adenosinergic pathway in duloxetine mediated anti-hyperalgesia in diabetic neuropathic pain.

In vivo microdialysis studies of striatal level of neurotransmitters after haloperidol and chlorpromazine administration.

Therapeutic success of atypical antipsychotics has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated acute (Parkinson's like syndrome) and chronic (tardive dyskinesia) extrapyramidal side effects. This study was planned to investigate changes in striatal levels of norepinephrine, dopamine and serotonin after acute and chronic administration of classical neuroleptics (haloperidol and chlorpromazine). These changes were correlated with behavioural alterations in rats. In vivo microdialysis with HPLC/ECD system revealed that there was a marked decrease in striatal neurotransmitter contents (NE, DA and 5-HT), which was also correlated with severe cataleptic response in rats after acute administration of haloperidol (2 mg/kg) and chlorpromazine (20 mg/kg). Chronic administration of haloperidol (1 mg/kg for 21 days) and chlorpromazine (5 mg/kg for 21 days) resulted in time dependent increase in orofacial hyperkinetic movements. The microdialysis studies also showed a significant decrease in the striatal levels of all the neurotransmitters. The results provide evidence for the involvement of striatal adrenergic and serotonergic systems, besides dopaminergic system in neuroleptic-induced acute and chronic extrapyramidal symptoms.

Comparative behavioural profile of newer antianxiety drugs on different mazes.

Anxiety is associated with diverse range of psychiatric conditions. In the present study, antianxiety effect of fluoxetine, citalopram (SSRI's), gabapentin (antiepileptic drugs), venlafaxine (SNRI), clozapine and resperidone (atypical antipsychotics) and a herbal preparation ashwagandha on elevated zero maze and elevated plus maze paradigms was examined. Anti-anxiety potentials of these drugs were compared with diazepam. The drugs tested i.e. fluoxetine (10 mg/kg), citalopram (10 mg/kg), clozapine (0.25, 0.5, 1 mg/kg), resperidone.(0.5, 1 mg/kg), venlafaxine (4, 8, 16 mg/kg), citalopram (10 mg/kg), fluoxetine (10 mg/kg), gabapentin (10, 20 mg/kg) and ashwagandha (100, 200 mg/kg) significantly increased the number of open arm entries and time spent in open arm. These drugs also decreased the latency to enter in open arm as compared to control in both the paradigms. Present study confirms the antianxiety activity of different newer classes of drugs and found some of them comparable to diazepam in both the elevated zero maze and elevated plus maze paradigm.

Involvement of adenosinergic receptors in anxiety related behaviours.

In the present study, the effect of adenosine (A1 and A2 receptor agonist), caffeine (A2A receptor antagonist), theophylline (A2A receptor antagonist) and their combination was studied in anxiety related behaviours using elevated zero maze and elevated plus maze paradigms and compared their various behavioural profiles. Adenosine (10, 25, 50,100 mg/kg) significantly showed anxiolytic effect at all the doses, whereas caffeine (8, 15, 30, 60 mg/kg) and theophylline (30, 60 mg/kg) showed psychostimulatory action at lower doses and anxiogenic effect at higher doses. Pretreatment with caffeine (8, 15, 30 mg/kg) and theophylline (30 mg/kg) reversed the anxiolytic effect of adenosine. The study suggested the involvement of adenosinergic receptor system in anxiety related behaviours.

Comparative neurochemical changes associated with chronic administration of typical and atypical neuroleptics: implications in tardive dyskinesia.

An important goal of current neuroleptic research is to develop antipsychotic compounds with the low incidence of extrapyramidal side effects. The therapeutic success and less side-effect of atypical anti-psychotics such as clozapine and risperidone has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated extrapyramidal side effects. The present study compares the effect of chronic administration of typical and atypical antipsychotics on neurochemical profile in rat forebrain. The study was planned to study changes in extracellular levels of norepinephrine, dopamine and serotonin in forebrain region of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements (VCM's), tongue protrusions and facial jerking) in rats, hall mark of chronic extrapyramidal side-effect of neuroleptic therapy tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in significant increase in orofacial hyperkinetic movements where as clozapine and risperidone showed less significant increase in orofacial hyperkinetic movements as compared to control. There were also significant decrease in the extracellular levels of neurotransmitters dopamine, norepinephrine and serotonin in fore-brain as measured by HPLC/ED after chronic administration of haloperidol and chlorpromazine. Chronic administration of atypical neuroleptics clozapine and risperidone resulted in the decrease in extracellular concentration of dopamine and norepinephrine but the effect was less significant as compared to typical drugs. However, treatment with atypical neuroleptics resulted in 3 fold increase in serotonin levels as compared to forebrain of control rats. Typical and atypical neuroleptics showed varying effects on neurotransmitters, especially serotonin which may account for the difference in their profile of side effects (Tardive dyskinesia).

Potentiation of antinociceptive effect of NSAIDs by a specific lipooxygenase inhibitor, acetyl 11-keto-beta boswellic acid.

The present study was aimed to assess the combined effects of cyclooxygenase and 5-lipoxygenase (COX/5-LOX) inhibitors in different animal models of nociception. Naproxen, nimesulide and rofecoxib are well-established antinociceptive agents acting via COX inhibition. AKBA (acetyl-keto-beta-boswellic acid) is a 5-LOX inhibitor. AKBA (50-200 mg/kg) produced a dose dependent and significant antinociceptive effect in different animal models of nociception. Based on the earlier reports from our laboratory, sub effective doses of all the three COX Inhibitors were selected and they were administered (naproxen, 5 mg/kg; nimesulide, 1 mg/kg; and rofecoxib, 1 mg/kg) with AKBA (100 mg/kg). This produced a more significant antinociceptive effect as compared to per se effect observed in all the three models of nociception. However, the effect of combination of nimesulide with AKBA was more pronounced as compared to naproxen and rofecoxib and their combination with AKBA. The present finding provided an evidence for the potentiation of antinociceptive effect of NSAIDs with AKBA. Such a combination may help to reduce the therapeutic doses of conventional NSAIDs and also reduce side effects (gastric, cardiac and renal) that are popularly associated with the NSAIDs.